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Amino Acids

Basic Sciences Biochemistry Cellular Energy
5 questions

The 9 essential amino acids
are histidine, isoleucine, leucine, lysine, methionine,phenylalanine, threonine, t
ryptophan, and valine. These amino acids cannot be synthesized in human cells
and must be obtained from the diet.
less Only L-form (optical isomer) amino acids can be found in proteins.
Mnemonic: Help In Learning These Little Molecules Proves Truly Valuable"
Help = Histidine
In = Isoleucine
Learning = Leucine
These = Threonine
Little = Lysine
Molecules = Methionine
Proves = Phenylalanine
Truly = Tryptophan
Valuable = Valine
The acidic amino acids are aspartic acid and glutamic acid. They are negatively
charged at physiologic pH.
The basic amino acids are arginine, lysine, and histidine. Arginine is the most
basic.Histidine does not have a charge at physiologic pH.
less Found in high concentrations in proteins that need to bind strongly to negative
substrates. For instance, arginine and lysine are over-expressed in histones because
the histones need to bind negatively charged DNA.
Amino acids are divided into glucogenic amino acids and ketogenic amino acids.
Glucogenic amino acids can enter the CAC as either pyruvate, -ketoglutarate,
succinyl-CoA, fumarate, or oxaloacetate and used to produce glucose. The
ketogenic amino acids are degraded to acetyl-CoA or acetoacetate and used to
produce fatty acids or other ketone bodies. These are not mutually exclusive. Some
amino acids are considered both glucogenic and ketogenic.
less The exclusively ketogenic amino acids are leucine and lysine.
The ketogenic and glucogenic amino acids
are threonine, tryptophan, tyrosine,isoleucine, and phenylalanine. Note:
Threonine is converted to glycine and acetyl-CoA via threonine dehydrogenase.
However, some texts do not consider it a ketogenic amino acid.
The exclusively glucogenic amino acids are alanine, arginine, asparagine,
aspartic acid, cysteine, histidine, glutamine, glutamic acid, glycine, serine,
methionine, proline, and valine.
Pyruvate Reactions
Basic Sciences Biochemistry Cellular Energy
3 questions

Pyruvate can undergo 1 of 4 reactions:
1) Dehydrogenation by the Pyruvate Dehydrogenase Complex to yield acetyl-CoA
less Acetyl CoA enters the Citric Acid Cycle
2) Carboxylation by pyruvate carboxylase to yield oxaloacetate
less Used in Citric Acid Cycle or Gluconeogenesis (frst of 2 steps needed to
convert pyruvate back to PEP)
Requires ATP
3) Transamination by alanine aminotransferase (ALT) to yield alanine
less Tissues (e.g. muscle) that use amino acids for fuel generate glutamate
Glutamate can donate its amino group to pyruvate, yielding alanine
Alanine is transported to the liver, which then regenerates pyruvate and
The pyruvate undergoes Gluconeogenesis and is sent out to the body
The glutamate ultimately enters the Urea Cycle urea (nitrogen excretion)
4) Reduction by lactate dehydrogenase to yield lactate
less Consumes NADH
Can enter the Cori cycle
Cori Cycle
Basic Sciences Biochemistry Cellular Energy
4 questions

During strenuous exercise when oxygen supply is insufcient, muscle cells must
resort to anaerobic metabolism, where pyruvate is reduced by NADH to
form lactate and regenerateNAD
, instead of entering the Tricarboxylic Acid (TCA)
Cycle. Lactate dehydrogenase(LDH) is the enzyme responsible for the reaction.
The lactate produced in the muscle cells during anaerobic metabolism enters the
bloodstream and is taken up by the liver. In the liver gluconeogenesis converts
lactate into glucose. Glucose enters the bloodstream and is used by muscle cells,
restarting the cycle.
In the Cori cycle lactate is produced in the muscle cells and converted to glucose in
the liver, so the muscle cells can make more lactate. Glycolysis and anaerobic
metabolism in themuscle cells generate 2 ATP per glucose; gluconeogenesis in
the liver consumes 6 ATPto generate one glucose from two lactate. Overall, 4
net ATP are consumed for each round of the Cori cycle; therefore, there is a
metabolic shift to the liver.
Red blood cells, which lack mitochondria, produce lactate and hence participate in
the Cori cycle.
Pyruvate Dehydrogenase Complex (PDC)
Basic Sciences Biochemistry Cellular Energy
4 questions

The Pyruvate Dehydrogenase Complex (PDC): converts pyruvate into acetyl-CoA
through several reactions, linking glycolysis (cytoplasm) and the citric acid cycle
less PDC is located in the mitochondrial matrix
The transport of pyruvate into mitochondria consumes energy, lowering the
total ATPproduction of aerobic glucose metabolism
The complex has 3 enzymes: E1 (pyruvate dehydrogenase), E2, and E3
Reaction: pyruvate + NAD
+ CoA acetyl-CoA + CO
E1 requires, as a cofactor, thiamine pyrophosphate (TPP), a derivative of vitamin
less The rate limiting step of the reaction
E2 requires, as cofactors, CoA and lipoic acid
less It is this step that produces acetyl-CoA (hence the need for CoA in this step)
E3 requires, as cofactors, FAD (vitamin B2) and NAD
(vitamin B3)
less FAD oxidizes a lipoic acid intermediate back to lipoic acid so it can participate
in more reactions in the process, FAD is reduced to FADH
is then used
to reduce NAD+ to NADH
The PDH complex is regulated directly through phosphorylation
less PDH kinase and PDH phosphatase are part of the PDH complex and act on
Phosphorylation through PDH kinase inhibits E1, while dephosphorylation
through PDHphosphatase activates E1
PDH kinase is activated (which leads to inactivation of E1) by ATP, acetyl-
CoA, andNADH
PDH kinase is inhibited (which leads to activation of E1) by pyruvate
PDC defciency has two typical presentations:
1. Metabolic (lactic acidosis as pyruvate is shunted to lactate)
2. Neurological (hypotonia, poor feeding, lethargy, seizures, mental retardation)
less Most common form is caused by mutations in the X-linked E1 gene
Even though the E1 mutation is X-linked, it still afects females due to critical role of
the enzyme in the nervous system considered X-linked dominant
Key feature: gray matter degeneration with brainstem necrosis and capillary
Treatment: very few forms respond to cofactor supplementation with thiamine
Ketogenic diets (high fat, low carbohydrate, adequate protein) have minimal
Citric Acid Cycle
Basic Sciences Biochemistry Cellular Energy
7 questions

Citric Acid Cycle: central catabolic pathway used to generate energy through the
oxidization of acetate (derived from carbohydrates, fats, and proteins) into CO
For each turn, the cycle produces 1 GTP, 3 NADH, 1 FADH
, and 2 CO
less 1 NADH 3 ATP equivalents
2 ATP equivalents
However, because of the energy expenditure required to shuttle NADH and FADH to
theETC, each turn through the citric acid cycle yields:
3 NADH x 2.5 7.5 ATP equivalent
x 1.5 1.5 ATP equivalent
1 GTP 1 ATP equivalent
For a total of 12 potential and 10 actual ATPs
The citric acid cycle (tricarboxylic acid cycle or Krebs cycle) takes place in the
mitochondrial matrix
Citrate synthase catalyzes the transfer of a 2-carbon acetyl group from acetyl-
CoA tooxaloacetate, forming the 6-carbon molecule citrate
less Citrate synthase is inhibited by ATP, NADH and succinyl CoA and stimulated
by insulin
Strongly exergonic step, regulatory point in the cycle
Aconitase catalyzes the isomerization of citrate into isocitrate
less Fluoroacetate (a metabolic poison) inhibits the enzyme aconitase
Isocitrate dehydrogenase catalyzes the oxidative decarboxylation of isocitrate to -
less NAD+ NADH, 1
molecule of CO
is released
Key regulatory step that is stimulated by ADP (low energy state) and inhibited
by ATP andNADH (high energy state)
The -ketoglutarate dehydrogenase complex converts -ketoglutarate to succinyl-
less NAD+ NADH, 2
molecule of CO
is released
Regulatory step, regenerates a 4-carbon chain (CoA excluded) and requires
many coenzymes, including vitamins B1, B2, B3, CoA, and lipoic acid
Note: the same cofactors are required in the pyruvate dehydrogenase complex.
-ketoglutarate dehydrogenase is inhibited by NADH, succinyl
CoA, ATP and GTP
Succinyl-CoA synthetase converts succinyl-CoA to succinate and CoA
less Substrate level phosphorylation: GDP + P
The succinate dehydrogenase complex catalyzes oxidation of succinate to fumarate

Mitochondrial fumarase converts fumarate to malate
Malate dehydrogenase oxidizes malate to oxaloacetate, and the cycle can begin
less NAD+ NADH
Electron Transport Chain
Basic Sciences Biochemistry Cellular Energy
1 question

Electron transport chain: uses NADH and FADH2 electrons (from glycolysis,
pyruvate dehydrogenase complex, and the citric acid cycle) to form a proton gradient,
coupled to oxidative phosphorylation, that drives the production of ATP
less The ETC (electron transport chain) is composed of 5 multi-enzyme
complexes, numbered I-V, that accept and donate electrons while molecular oxygen,
O2, is the fnal electron acceptor
Mobile electron carriers, such as cytochrome c and coenzyme Q, shuttle
electrons between various enzyme complexes of the ETC
Primary NADH electron transport system: malate-aspartate shuttle, which
transportsNADH electrons to complex 1 in the mitochondria.
Less commonly used NADH electron transport system: glycerol-3-phosphate
Theoretically: 1 NADH yields 3 ATP and 1 FADH2 yields 2 ATP (because
FADH2 electrons are transferred to complex II, a lower energy level than NADH)
However, since NADH from glycolysis needs to be transported into the mitochondria
and the mitochondrial membrane "leaks" protons, the actual yields are smaller
As electrons fow through the ETC, protons (H+) are pumped into the
mitochondrial inter-membrane space this creates an electrochemical proton
ATP Synthase (Complex V): uses the electrochemical proton gradient
created by theETC to pump protons (H+) back into the mitochondrial matrix to
produce ATP from ADPand Pi
Toxins that disrupt any component of the ETC disrupt the aerobic production
of ATP tissues that depend highly on aerobic respiration, such as the CNS and
the heart are particularly afected
less Amobarbital (known as amytal) and rotenONE bind to NADH dehydrogenase
(complex 1) directly inhibit electron transport
Antimycin A binds to cytochrome c reductase (complex III) directly inhibits electron
Carbon monoxide and Cyanide bind to Cytochrome C oxidase (complex IV)
directly inhibit electron transport
Oligomycin (a macrolide) inhibits ATP synthase (complex V) by blocking its
proton channel
2,4-Dinitrophenol and doses of aspirin increase the permeability of the
inner mitochondrial membrane proton gradient and oxygen consumption
heat generated instead of ATP (explains the fever generated following toxic doses of
Thermogenin in brown fat is an uncoupling agent that disrupts the proton
gradient used to generate heat in animals
HMP hunt (Pentose phosphate path!ay)
Basic Sciences Biochemistry Cellular Energy
4 questions

HMP Shunt: a 2 phase pathway consisting of an oxidative (irreversible) phase
andnonoxidative (reversible) phase that uses available glucose-6-phosphate to
mainly produce NADPH and ribose-5-phosphate
less Both phases occur in cytosol
ATP is not used or produced!
Key reactions:
1) Glucose-6-Phospate Ribulose-5-Phospate + 2 NADPH
*Enzyme: Glucose-6-Phosphate Dehydrogenase
2) Ribulose-5-Phosphate Ribose-5-Phosphate + G3P + F6P
*Enzyme: Transketolase
Oxidative phase: key enzyme is G6P dehydrogenase (G6PD), the rate-limiting
enzyme; all steps of the oxidative phase are irreversible and are used to
generate NADPH for reductive biosynthetic pathways
less NADPH is used to reduce glutathione, a coenzyme for glutathione
peroxidase which prevents oxidative damage by converting H
O. This is
especially important in RBCs
Increased in tissues that consume NADPH in reductive pathways like adipose
tissue for fatty acid synthesis, gonads and adrenal cortex for steroid synthesis, liver
for fatty acid and cholesterol synthesis, and glutathione reduction inside RBCs
Nonoxidative phase: key enzyme is transketolase (thiamine-dependent); all
steps arereversible and are used to convert sugars to produce ribose-5-phosphate
and intermediates for glycolysis and gluconeogensis
less Pentose sugars like ribose-5-phosphate are used for nucleotide synthesis
Fructose-6-phosphate and glyceraldehyde 3-phosphate (products of the non-
oxidative phase) are used as substrates for glycolysis in fed state, and intermediates
in gluconeogenesis in the fasting state
G6PD defciency: hemolytic anemia when RBCs are exposed to oxidative stress
because of inadequate NADPH production leading to less anti-oxidant activity of
less Causes of oxidizing stress: infections, fava beans, drugs (e.g. sulfonamides,
dapsone, primaquine)
Transmitted in X-linked recessive fashion with a predominance in Asia, the
Mediterranean, and Africa (disease provides protection against Plasmodium
falciparum malaria)
On a peripheral smear look for Heinz bodies (inclusions in RBCs composed
of denaturedHemoglobin) and degmacytes (bite cells) (result of splenic
macrophages removing Heinz bodies)
Mono"Disaccharide Meta#olic Disorders
Basic Sciences Biochemistry Cellular Energy
4 questions

Hereditary fructose intolerance: autosomal recessive defciency of aldolase B,
which cleaves fructose 1-phosphate to 3-carbon molecules.
less A defciency in aldolase B leads to accumulation of phosphorylated fructose
available phosphate levels drop gluconeogenesis is blocked
Symptoms: hypoglycemia, vomiting, jaundice, and cirrhosis
Patients usually asymptomatic until challenged, in infancy, with fructose
Treatment: avoid intake of fructose or sucrose (combination of glucose and
Essential fructosuria: autosomal recessive, benign condition resulting from defect
in hepatic fructokinase
less Fructose can not be phosphorylated, so it is unable to be sequestered in the
cell elevated serum fructose levels fructosuria
Classic galactosemia: autosomal recessive defciency in GALT (galactose-1-
phosphate uridyl transferase), which converts galactose-1-phosphate to glucose-1-
less Absence of GALT leads to galactose-1-phosphate accumulation toxic
All states mandate neonatal screening because lactose (i.e. milk) is
metabolized to glucose and galactose
Symptoms: poor growth, hepatic dysfunction (jaundice, coagulopathy,
hepatomegaly), ascites, cataracts, mental retardation
These infants also have an risk for E. coli septicemia.
Treatment: galactose-free diet
Galactokinase defciency: autosomal recessive defciency in galactokinase, which
phosphorylates galactose to make galactose-1-phosphate
less Accumulation of galactose galactosemia galactosuria
Galactosemia cataracts because the lens of the eye contains aldose
reductase, which converts galactose to galactitol, an osmotically active alcohol
Lactase defciency: age-related or hereditary lactose intolerance due to
expression of lactase (a brush-border enzyme) or transient expression following
less Symptoms: osmotic diarrhea, bloating/cramps
Treatment: avoid lactose
Sorbitol accumulation: high blood levels of glucose (or fructose or galactose) lead
to osmotic damage from sorbitol accumulation in tissues that lack sorbitol
dehydrogenase cataracts, diabetic retinopathy, and peripheral neuropathy
less Liver, ovaries, and seminal vesicles have both aldose reductase and sorbitol
dehydrogenase (thus, there is no sorbitol accumulation)
Glucose sorbitol (via aldose reductase) fructose via (sorbitol
Schwann cells, lens, retina, and kidneys only have aldose reductase (thus,
there is sorbitol accumulation in hyperglycemic states)
Phenylalanine $ Tyrosine Meta#olism
Basic Sciences Biochemistry Cellular Energy
6 questions

Phenylalanine hydroxylase (PAH): enzyme that converts Phenylalanine to Tyrosine
less In this reaction, tetrahydrobiopterin (BH
), the required cofactor, is converted
to dihydrobiopterin (BH
is converted back to BH
via the enzyme dihydrobiopterin reductase
Tyrosine is a precursor for many catecholamines, neurotransmitters, melanin
and thyroid hormones
Phenylketonuria (PKU): autosomal recessive defects in the enzyme phenylalanine
hydroxylase (PAH)
less Phenylalanine accumulates and leads to the following symptoms:
- neurologic defects (e.g. seizures and mental retardation)
- albinism (tyrosine required for melanin synthesis)
- "musty odor" to their sweat & urine (due to accumulated phenylalanine conversion
to phenylketones)
Screened for on the 2
or 3
day of life due to presence of maternal enzyme
at birth
Treatment: restrict phenylalanine and aspartame (contains phenylalanine) in
diet and tyrosine intake (becomes an essential amino acid)
Maternal PKU: lack of proper dietary treatment in a pregnant woman with PKU
infant born with microcephaly, congenital heart defects, mental and growth
Malignant PKU: autosomal recessive defects in the enzyme dihydrobiopterin
reductase (called malignant because restricting phenylalanine does not correct
neurological problems)
Note: in malignant PKU, BH
is not converted back to BH
because of a defect in
dihydrobiopterin reductase so DOPA needs to be supplemented in these patients
Tyrosine hydroxylase: enzyme that converts Tyrosine to Di-hydrOxy-PhenylAlanine
less (BH4) is a necessary co-factor for the enzyme tyrosine hydroxylase. (BH4) is
also a co-factor for phenylalanine hydroxylase.
Tyrosinase: similar to tyrosine hydroxylase in that it converts Tyrosine to DOPA, but
this enzyme has further catalytic activity that results in the production of melanin
from DOPA
less Autosomal recessive defects in tyrosinase or albinism: absence of melanin
in hair (white hair), eyes (photophobia), and skin (increased risk of UV related skin
Homogentisic acid dioxygenase (HGD): enzyme that is part of the degradative
pathway of tyrosine into fumarate
less The catabolic process involves homogentisate (or alkapton) as an
Congenital defciency of HGD (or alkaptonuria), autosomal recessive
disease with the following symptoms:
- homogentisate excreted in urine (if the urine is left standing it will turn black)
- homogentisate also polymerizes and deposits in joints joint arthritis, ankylosis,
and arthralgias (toxic to cartilage)
- dark connective tissue (called ochronosis)
- brown hyper-pigmented sclera
%ranched&chain 'etoaciduria (Maple yrup
(rine Disease)
Basic Sciences Biochemistry Cellular Energy
1 question

Branched chain ketoaciduria (maple syrup urine disease): autosomal
recessive defect in the branched-chain -ketoacid dehydrogenase complex (BCKD)
less The BCKD complex catalyzes the breakdown of Isoleucine, Leucine,
and Valine
Mnemonic: I Love Vermont maple syrup from trees with branches
Defective BCKD accumulation of branched chain amino acids in the blood
and the brain irreversible neurological damage
Symptoms typically present in the frst few days of life (days 4-7) and include
poor feeding, vomiting, poor weight gain, lethargy, and maple syrup odor to the urine
Isoleucine: characteristic maple syrup odor of the urine
Leucine: readily crosses the blood-brain barrier and is responsible for the
neurological symptoms
Treatment: restrict amino acid intake, and a small number of patients respond
to thiamine (vitamin B
) supplementation
)ipoprotein Complexes and
Basic Sciences Biochemistry Cellular Energy
1 question

Lipoprotein complexes are composed of cholesterol, TGs (triglycerides), and
phospholipids and apolipoproteins.
less Lipoprotein complexes include: chylomicrons, VLDL, IDL, LDL, and HDL
Apolipoproteins are proteins that bind to lipids; they have various functions:
less ApoA-I activates LCAT
ApoB-100 is the sole protein component of LDL
ApoB-48 lacks the LDL-receptor binding sequence that ApoB-100 has. It is a
component of chylomicrons.
ApoC-II activates lipoprotein lipase (LPL) in capillaries
ApoE mediates chylomicron and IDL uptake in the liver.
*lucose Transport
Basic Sciences Biochemistry Cellular Energy
5 questions

All GLUT transporters work via facilitated difusion
GLUT1: most cell types including RBCs and brain
GLUT2 (bidirectional): pancreatic islet cells, liver, renal tubular cells, small intestine
less Low afnity and high capacity isoform liver needs to be
glycogen/glucose reservoir, but shouldnt compete with other tissues
This should look similar to glucokinase (low afnity or K
and high capacity or
) because it has a similar tissue distribution
GLUT3: neurons, testes, and the placenta
GLUT4: adipose tissue and striated muscle (skeletal and cardiac)
less Insulin regulates insertion of GLUT4 transporters into cell membrane in
response to high glucose levels
Basic Sciences Biochemistry Cellular Energy
3 questions

Acetoacetate, -hydroxybutyrate, and acetone are the ketones produced during
ketogenesis: Produced by liver for use in the brain and heart.
less Most other tissues can use fatty acids, but brain cannot. The liver lacks the
enzymes to use ketones
During hypoglycemia, fatty acids are sent to the liver for oxidation acetyl-CoA
less The rate limiting enzyme in the formation of ketones is HMG-CoA synthase.
Ketone utilization: If the ketone is acetoacetate, this is converted (via multiple steps)
to 2 acetyl-CoA molecules that enter the TCA cycle
less If the ketone is -hydroxybutyrate, it is converted back to acetoacetate, then
2 acetyl-CoA
Ketones are excreted in urine. Acetone, from spontaneous decarboxylation of
acetoacetate, causes the "fruity odor" detected on breath during ketoacidosis
Diabetic ketoacidosis: insulin (mostly in Type I diabetes) leads to ketone
production because cells are unable to utilize serum glucose without insulin (
glucose in cells oxaloacetate is shunted into gluconeogenesis stops
the TCA cycle acetyl CoA is shunted into ketogenesis)
Methylmalonic and Propionic Acidemia
Basic Sciences Biochemistry Cellular Energy
3 questions

Methylmalonic acidemia and Propionic acidemia: autosomal recessive disorders
of enzymes in the pathway that converts propionyl CoA to succinyl CoA (process that
produces energy or glucose from odd-chain fatty acids or certain amino acids)
less Pathway: propionyl CoA methylmalonyl CoA succinyl CoA
Propionyl CoA carboxylase: enzyme that catalyzes the conversion of
proprionyl CoA to methylmalonyl CoA (defciency of this enzyme leads to propionic
Methylmalonyl CoA mutase: enzyme that catalyzes the conversion of
methylmalonyl CoA to succinyl CoA, requiring vitamin B12 as a cofactor (defciency
of this enzyme leads to methylmalonic acidemia)
Symptoms of both include: ketosis, metabolic acidosis, vomiting, lethargy,
poor feeding, neutropenia, and developmental/neurological complications
Propionic acidemia levels of propionic acid in the blood
Methylmalonic acidemia levels of propionic acid and levels of methylmalonic
acid in the blood
Need to rule out vitamin B
defciency with methylmalonic acidemia because
some neurologic symptoms are reversible
Treatment for both: low-protein diet (specifcally intake of methionine, valine,
threonine, isoleucine, and odd-chain fatty acids because they are all broken down
into propionyl CoA) and carnitine supplementation (improves -oxidation of fatty
Hemoglo#in (H#)
Basic Sciences Biochemistry Cellular Energy
6 questions

Tetramer (4 subunits); each subunit polypeptide has a heme molecule at its center
and each heme molecule can carry 1 oxygen molecule

Hemoglobin A (adult):

Hemoglobin A2 (adult):

Hemoglobin F (fetal):

elevated in sickle-cell disease patients
Hemoglobins oxygen dissociation curve is sigmoidal: the tetramer fips between 2
less Deoxy or T (Taut) form: low O
Oxy or R (Relaxed) form: high ( 300x) O
When 2 O
molecules are bound to the T form, conformation switches to R
and all 4 sites can be flled
The T to R shift occurs under conditions of high oxygen tension (i.e. the
lungs) and the R to T shift occurs under conditions of low oxygen tension.
Lung: High O
oxygenated Hb.
Tissues: Low O
deoxygenated Hb (Bohr efect: CO
and/or H
stabilizes deoxygenated conformation).
4 factors cause O
dissociation (T form favored):
less 1) pH: relative acidic environment, like peripheral tissues
2) CO
: produced by cellular metabolism
3) 2,3-DPG (diphosphoglycerate, the same as bisphosphoglycerate):
stabilizes the T conformation, produced by glycolysis
4) temperature
These factors shift the O
dissociation curve to the right a higher
pressure is needed to maintain the same level of hemoglobin saturation
Myoglobin has a similar structure/sequence, but is a monomer doesnt exhibit
cooperative binding
transport: CO
is converted to H
by carbonic anhydrase
(carbonic acid) dissociates to bicarbonate and a proton; the H
binds to
hemoglobin and thus has no efect on serum pH
Allosteric inhibition: CO
also binds at the hemoglobin chain N terminus,
favoring the deoxy Hb form
Carbon monoxide: CO is a competitive inhibitor with 200x afnity for heme
compared to O
less Carboxyhemoglobin is bright red and poisoned patients are commonly
described as having a cherry-red appearance to their skin
Iron in Hb is usually in the Fe
(ferrous), reduced state
less Methemoglobinemia: oxidation to the Fe
(ferric) state leads to decreased
afnity of O
at these heme sites; however, at other non-oxidized heme sites, there is
a compensatory increase in afnity leading to a left shift of the oxygen-
dissociation curve
Normally, oxidation is prevented via a reductive enzyme pathway (HMP shunt)
in RBCs
Drugs that cause
methemoglobinemia: Metoclopramide, Procaine, Nitrites, Antimalarials,Sulfonamides
, Dapsone.
Can be easily remembered with mnemonic: A Methemoglobinemic Patient
is Not AlwaysSomething Deadly.
Treatment: methylene blue
Cyanide poisoning: CN
preferentially binds to Fe
and inactivates cytochrome c
oxidasein the electron transport chain stops cellular respiration
less Nitrites can be used to convert Hb to methemoglobin methemoglobin then
binds the CN
use sodium thiosulfate to chelate this CN
and yield thiocyanate
renally excreted
Methemoglobinemia decreases the patients O
carrying capacity, but
methemoglobinemia can be managed whereas arrested cellular respiration is
AM (&Adenosyl Methionine)
Basic Sciences Biochemistry Cellular Energy
1 question

SAM (S-Adenosyl Methionine): the primary methyl donor of the body
less Helps methylate DNA
After donating its methyl group, SAM is hydrolyzed to homocysteine and
adenosine; regeneration of methionine from homocysteine requires folate and
vitamin B12
+atty Acid ,xidation
Basic Sciences Biochemistry Cellular Energy
5 questions

In the cytosol, long chain (> 14 C) free fatty acids are converted to fatty acyl-CoA
by fatty acyl CoA synthetase. This step activates the fatty acid for transport into the
Because the inner mitochondrial membrane is impermeable to CoA, the carnitine
shuttle system is required to transport the fatty acyl CoA into the mitochondrial
less Step 1:
Enzyme: CAT-I (carnitine acyl transferase I) on the outer mitochondrial membrane
Reaction: Fatty acyl-CoA + carnitine fatty acyl carnitine + free CoA
CoA remains in the cytosol, and fatty acyl carnitine can now pass through the inner
mitochondrial membrane.
Step 2:
Enzyme: CAT-II on the inner surface of the inner mitochondrial membrane
Reaction: Fatty acyl carnitine + CoA (already in the mitochondrial matrix) fatty acyl
CoA + free carnitine
Fatty acyl CoA stays in the mitochondrial matrix for further metabolism, and carnitine
leaves the matrix to be used again in the shuttle.
Carnitine defciency decreased ability to utilize long chain fatty acids as a
fuel source. Can be due to environmental (e.g. malnutrition) or genetic factors
(e.g. CAT-I defciency).
Symptoms: Muscle aches and fatigue following exercise, free fatty acid levels in
the blood, hypoketotic hypoglycemia.
Treatment: Diet high in carbohydrates and medium and short chain fatty acids, low
in long chain fatty acids.
Malonyl-CoA, an intermediate in fatty acid biosynthesis, inhibits this shuttle
system to prevent newly synthesized fatty acids from entering the degradation
pathway, and thus prevent a futile synthesis-degradation cycle
Medium and short chain fatty acids directly enter the mitochondrial matrix without
need for a special transport.
less In the mitochondrial matrix, fatty acyl-CoA synthetase activates short/medium
chain fatty acids to fatty acyl-CoA molecules.
MCADD (medium-chain acyl-CoA dehydrogenase defciency): MCAD is a
enzyme required for complete oxidation of medium length fatty acids. Defciency
inability to oxidize fatty acids with <12 carbons.
Presents with symptoms of hypoglycemia.
Treatment: Avoid prolonged fasting, carbohydrate and protein intake, fat intake.
Inside the mitochondria, fatty acyl-CoA with an even number of carbons undergo
successive rounds of oxidation, yielding acetyl-CoA, and NADH & FADH
less Acetyl-CoA enters the citric acid cycle.
NADH and FADH~2~ are used in the electron transport chain.
Oxidation of fatty acids containing an odd number of carbons Acetyl-
CoA and Propionyl-CoA
less Because Propionyl-CoA Succinyl-CoA, it is the only part of fatty acids that
Ketogenesis occurs when there is a high rate of fatty acid oxidation forming Acetyl-
less When the liver is overloaded with Acetyl-CoA ketone bodies form
The 2 main ketone bodies are acetoacetate and -hydroxybutyrate
Acetoacetate undergoes spontaneous decarboxylation to form acetone
Ketones are generally used in 2 ways:
1) Extrahepatic tissues can convert ketone bodies Acetyl-CoA
2) Because ketone bodies are volatile, they are readily exhaled by the lungs (Note:
This is why diabetics in DKA have fruity smelling breath)
Regulation o- *lycolysis
Basic Sciences Biochemistry Cellular Energy
5 questions

Regulation points indicate places where intermediates can be shunted in and out of
glycolysis. Examples:
1. Shunting into glycolysis: Glycogenolysis produces G6P that enters the glycolytic
pathway after the 1st regulated reaction.
2. Shunting out of glycolysis: DHAP can be turned into glycerol-3-phosphate
instead ofGADP. Glycerol-3-phosphate is then shunted into triglycerides synthesis.
There are 3 key regulated glycolytic enzymes: Hexokinase/glucokinase, PFK-1 and
pyruvate kinase
Hexokinase: Inhibited by G6P and not induced by insulin
Glucokinase: Not inhibited by G6P but is induced by insulin
Remember glucokinase is induced by insulin.

Hexokinase: High afnity ( K

), low capacity ( V

Glucokinase: Low afnity ( K

), high capacity ( V
GLUcokinase is a GLUtton with an insatiable V
PFK-1 activity is by AMP and F2,6BP and by acetyl-CoA, citrate, and ATP
less PFK-2/FBPase-2 (phosphofructokinase-2/Fructose bisphosphatase-2) is a
bifunctional enzyme:
1. PFK-2 synthesizes F2,6BP (fructose-2,6-bisphosphate) from F6P, the same
substrate from which F1,6BP is synthesized
2. FBPase-2 reverses the reaction, by dephosphorylating F2,6BP to form F6P
F2,6BP is the most potent activator of PFK-1
High glucose levels insulin dephosphorylation of PFK-2/FBPase-2
activatesPFK-2 activity while simultaneously inhibiting FBPase-2 activity F6P
converted to F2,6BP stimulates glycolysis by activating PFK-1
Low glucose levels glucagon cAMP and pKA activity
phosphorylation of PFK-2/FBPase-2 activates FBPase-2 activity while
simultaneously inhibiting PFK-2 activity F2,6BP converted to F6P decrease
in PFK-1 activity inhibits glycolysis
Pyruvate kinase activity is by F1,6BP and PEP, while allosterically inhibited
by ATP and alanine
less Low glucose leads to glucagon levels cAMP and pKA activity
causing phosphorylation and inactivation of pyruvate kinase allows PEP to enter
*lycogen torage Diseases
Basic Sciences Biochemistry Cellular Energy
7 questions

Glycogenoses (glycogen storage diseases): autosomal recessive enzyme
defects that result in either decreased glycogen breakdown (eg, Pompes) or
increased glycogen synthesis (eg, von Gierkes) accumulation of glycogen within
the cytoplasm (except Pompes, where glycogen accumulates in lysosomes) of cells
in one or more tissues organ dysfunction
less Mnemonic: If you have Very Poor CArbohydrate Metabolism, dont eat
that Hersheys bar!
Type 1: Von Gierkes
Type 2: Pompes
Type 3: Coris
Type 4: Andersens
Type 5: McArdles
Type 6: Hers
Type I (von Gierkes): defcient glucose-6-phosphatase (liver, kidney) defective
glycogenolysis and gluconeogenesis severe fasting hypoglycemia (seizures,
hypoxic brain damage)
less Normal glycogen structure
Hepatorenomegaly glycogen accumulates in liver and kidney because
excess G-6-P stimulates glycogen synthesis and inhibits glycogenolysis
Hyperlipidemia skin xanthomas and VLDL
Hyperuricemia free phosphate due to G6-Pase defect
AMP AMP degraded to uric acid uric acid predisposes to gout
Fasting lactic acidosis lactate uric acid excretion by kidneys
Ingestion of galactose or fructose no increase in blood glucose
Administration of glucagon, epinephrine, or other gluconeogenic stimulus
no increase in blood glucose
Type II (Pompes): defective lysosomal -1,4-glucosidase enzyme is
responsible for digesting glycogen glycogen deposits accumulate in lysosomes
less Lysosomal -1,4-glucosidase is responsible for only ~3% of glycogenolysis,
so defects dont cause hypoglycemia
Organs most afected are those that store glycogen (liver, heart, skeletal
Left ventricular hypertrophy leads to outfow tract obstruction and cardiac
Mortality in infantile form due to cardiac failure from massive cardiomegaly
death before age 2
Mnemonic: Pompes trashes the Pump (heart)
Type III (Coris): defective -1,6-glucosidase (glycogen debrancher enzyme)
fasting hypoglycemia milder than Type I (von Gierkes), normal blood lactate levels
less Glycogen molecules have shorter outer branches single glucose residue
Glycogenolysis is defective but gluconeogenesis is still functional.
Presents with hepatomegaly in infancy
Type IV (Andersens): defective -4,6-glucosidase (glycogen branching
less Inability to form branches accumulation of long, insoluble glycogen chains
hepatosplenomegaly and cirrhosis
Causes infantile cirrhosis failure to thrive and hypotonia usually fatal
Type V (McArdles): defective skeletal muscle glycogen phosphorylase
unable to break down glycogen glycogen in muscle muscle
cramps/weakness with exercise can lead to myoglobinuria
less Still form normal glycogen molecules
McArdles = Muscle phosphorylase
Type VI (Hers): defcient Hepatic glycogen phosphorylase gluconeogenesis
but no glycogenolysis fasting hypoglycemia (mild) and hepatomegaly/cirrhosis
less Hers = Hepatic phosphorylase
As with Type V (McArdles), glycogen structure is normal
Early childhood presentation of hepatomegaly and growth retardation
hepatomegaly may improve with age
+amilial Dyslipidemias"Hyperlipidemias
Basic Sciences Biochemistry Cellular Energy
4 questions

In 1967, Dr. Donald S. Fredrickson developed a classifcation of lipoprotein
abnormalities, depending on the pattern of lipoprotein electrophoresis. Collectively,
they are called dyslipoproteinemias, but most have a more descriptive, colloquial
name. Lipid Digestion & Metabolism and the role of each Lipoprotein Complexes and
Apolipoproteins are not included in this topic.
Type I dyslipoproteinemia, or more commonly hyperchylomicronemia, is
characterized by a defciency in lipoprotein lipase (LPL) or a mutation in ApoC-II.
The inheritance pattern of hyperchylomicronemia is autosomal recessive.
less Due to defective LPL or ApoC-II, the chylomicrons cannot be cleared from the
blood. Lab fndings include increased serum chylomicrons, triglycerides, and
The clinical fndings include chylomicron-induced
acute pancreatitis,hepatosplenomegaly, and eruptive/pruritic xanthomas.
There is no increased risk of atherosclerosis.
Type IIa dyslipoproteinemia, or more commonly familial hypercholesterolemia, is
characterized by an absence of or a decrease in competent LDL receptors. The
inheritance pattern is autosomal dominant.
less Due to defective LDL receptor, LDL cannot be cleared from the blood. Lab
fndings include increased serum LDL and cholesterol leading to increased risk
of atherosclerosis and coronary artery disease.
Patients develop tendon xanthomas, classically on the Achilles heel and,
less commonly, elbow.
Patients develop corneal arcs (a.k.a., arcus senilis, arcus senilis corneae),
which is gray or white arcs of lipid deposits visible at the edge of the cornea. Note:
This is also seen is other dyslipidemias.
Cholestyramine and other drugs that bile salt synthesis from cholesterol
cholesterol concentration within hepatocytes LDL receptor expression
cholesterol removal from circulation.
Statins de novo synthesis of cholesterol increases LDL receptor expression
Prevalence: heterozygotes = 1/500 (cholesterol > 300 mg/dL); homozygotes =
(cholesterol > 700+ mg/dL)
Heterozygotes (1 in 500) have total serum cholesterol around 300 mg/dL.
Homozygotes (very rare) have total serum cholesterol 700 mg/dL or greater and
have poor prognosis due to myocardial infarction before age 20.
Type IIb dyslipoproteinemia, or more commonly familial combined hyperlipidemia,
is characterized by decreased LDL receptor and increased ApoB. The mechanism
is not fully elucidated. The inheritance pattern is autosomal dominant.
less Due to decreased LDL receptor and increased ApoB, the characteristics lab
fndings areincreased serum LDL, VLDL, and triglycerides (<1000 mg/dL).
Familial combined hyperlipidemia afects 1% of the population.
Type III dyslipoproteinemia, or more commonly, dysbetalipoproteinemia, is
characterized by a mutation in ApoE. The name dysbetalipoproteinemia comes from
the broadening of the beta band, which contains increased
chylomicrons/VLDL/IDL/LDL, on lipoprotein electrophoresis.
less Due to defective ApoE, chylomicrons and and IDL cannot be cleared from the
blood. The lab fndings include increased serum IDL, cholesterol, and triglycerides
and decreased serum HDL.
Presents with tuberoeruptive xanthomas and peripheral vascular disease.
Tuperoeruptive xanthomas, as the name suggests, are large grapelike nodules that
appear infamed and coalesce.
Responsive to dietary changes and cholesterol lowering drugs (statins).
Type IV dyslipoproteinemia, or more commonly hypertriglyceridemia, is
characterized byincreased VLDL production. The inheritance pattern is autosomal
less Due to hepatic overproduction of VLDL, the characteristic lab fndings
are increased serum VLDL and triglycerides.
Patients present with pancreatitis.
Type V dyslipoproteinemia is characterized
by increased VLDL production anddecrease lipoprotein lipase production.
less The lab fndings are increased serum chylomicrons and VLDL.
The high yield dyslipoproteinemias are hyperchylomicronemia (Type I
dyslipoproteinemia),hypercholesterolemia (Type IIa dyslipoproteinemia),
and hypertriglyceridemia (Type IV dyslipoproteinemia).
Abetalipoproteinemia (also known as Bassen-Kornzweig syndrome) is
characterized by microsomal triglyceride transfer protein (MTTP) defciency. MTTP is
essential for synthesis and secretion of beta-type apolipoproteins (e.g., ApoB-48 and
ApoB-100). The inheritance pattern is autosomal recessive.
Due to inefective MTTP, there is reduced chylomicron and VLDL synthesis
and secretion.
Reduced chylomicron and VLDL synthesis leads to severely reduced
absorption of dietary fats and fat-soluble vitamins. Accumulation of lipids within
enterocytes can be seen on intestinal biopsy.
Clinical fndings present in the frst few months of life and include failure to
gain weight and grow, steatorrhea, abnormal star-shaped red blood cells
(acanthocytosis), ataxia, and night blindness.
Basic Sciences Biochemistry Cellular Energy
2 questions

Synthesis occurs in liver, intestines, adrenal glands, reproductive organs.
Rate-limiting step is catalyzed by HMG-CoA reductase.
less HMG-CoA reductase converts HMG-CoA to mevalonate.
Pharmacology Correlate:
HMG-CoA reductase is the enzyme targeted by statin drugs, which act by
competitive inhibition.
HMG-CoA reductase expression is inhibited by cholesterol levels.
HMG-CoA activity is by AMP dependent phosphorylation and glucagon.
HMG-CoA activity is by insulin.
ACAT (acylcoenzyme A: cholesterol acyltransferase) esterifes cholesterol inside
the liver (for storage) and intestine (for transport in chylomicrons). Free cholesterol in
the bloodstream is esterifed by LCAT (lecithin-cholesterol acyltransferase):
less LCAT is bound to plasma HDL and LDL. As it esterifes cholesterol in HDL, it
allows HDL to participate in reverse cholesterol transport.
Esterifcation makes the cholesterol more hydrophobic sequestered in the
core of the lipoprotein.
CETP (cholesteryl ester transfer protein) facilitates the transfer of cholesteryl
ester (added by LCAT) from HDL to VLDL, IDL, and LDL in exchange for
SLOS (Smith-Lemli-Opitz-Syndrome) is an autosomal recessive defciency in DHCR-
7 (7-dehydrocholesterol reductase), an enzyme used in the synthesis of cholesterol
cholesterol levels.
Symptoms include abnormal facial features, mental retardation and
characteristics of autism, and congenital malformations.
Treatment: Cholesterol supplementation via synthetic cholesterol or dietary
eforts may help.
Basic Sciences Biochemistry Cellular Energy
9 questions

Gluconeogenesis occurs predominantly in the liver, but enzymes are also found in
the kidney and intestinal epithelium
less Muscle cells cannot participate in gluconeogenesis because they lack
Consumes 6 ATP equivalents (4 ATP and 2 GTP) per glucose at a time when
energy is already low (starvation, prolonged anaerobic respiration) and often occurs
concurrent with ketosis
The 3 regulated steps of glycolysis are essentially irreversible, so diferent enzymes
are required to regenerate glucose. Recall that the 3 irreversible steps of glycolysis
less 1) Glucose G6P
2) F6P F1,6BP
3) PEP pyruvate
These reactions are irreversible using glycolytic enzymes; however,
using diferentenzymes, gluconeogenesis makes the reverse of the above reactions
energetically possible
Pyruvate to PEP requires 2 enzymes: pyruvate carboxylase and PEP carboxykinase
Pyruvate carboxylase activates biotin (vitamin B7), then transfers CO
activated biotin to pyruvate, yielding OAA (oxaloacetate). This occurs in
the mitochondria
less Biotin activation requires 1 ATP (2 per glucose)
Allosterically stimulated by acetyl-CoA
Note that OAA can also directly enter the citric acid cycle
OAA transported to the cytosol using the malate shuttle
Note: since OAA itself cannot transverse the mitochondrial membrane, it is
frst reduced to malate when malate enters the cytosol, it is converted back
to OAA by malate dehydrogenase
PEP carboxykinase converts the OAA to PEP in the cytosol
less 1 GTP is consumed in this reaction (2 per glucose)
Glycolytic enzymes are used in reverse, until F1,6BP is reached
Fructose-1,6-bisphosphatase dephosphorylates F1,6BP to F6P in the cytosol
The fnal reaction occurs in the smooth endoplasmic reticulum, when G6P is
dephosphorylated into glucose by glucose-6-phosphatase sequestration of this
enzymes assures it does not compete with hexokinase during glycolysis
Basic Sciences Biochemistry Cellular Energy
12 questions

Glycogen is a highly branched glucose polymer used as the main storage form of
glucose in the body.
less The linear bonds between glucose molecules in glycogen are -(1,4)
glycosidic linkages; the branching bonds are -(1,6) glycosidic linkages.
Glycogen is synthesized and stored primarily in the cytoplasm of hepatocytes
and skeletal muscle cells.
Glycogen can provide energy for about one hour of exercise, depending on
Glycogen synthesis is the creation of a large glucose polymer. The synthesis of
glycogenrequires energy in the form of ATP and UTP.
less The frst step in glycogen synthesis uses ATP to make glucose-6-phosphate
(G6P) from glucose.
The enzyme that converts glucose to glucose-6-phosphate is
either hexokinase orglucokinase.
Hexokinase and glucokinase both catalyze the same reaction (glucose
glucose-6-phosphate). The diference is that glucokinase is found in liver and
pancreas cells and becomes active at higher levels of glucose, while hexokinase is
found in most cells and efciently uses low levels of glucose.
In the second step of glycogen synthesis, glucose-6-phosphate is mutated
to glucose-1-phosphate (G1P).
less The enzyme that mutates glucose-6-phosphate to glucose-1-phosphate
In the third glycogen synthesis step, glucose-1-phosphate + UTP UDP-glucose +
less The enzyme for the conversion of glucose-1-phosphate to UPD-glucose
is UDP-glucose pyrophosphorylase.
The rate-determining step of glycogen synthesis is the addition of UDP-glucose to a
pre-existing glycogen chain by glycogen synthase.
less The enzyme that catalyzes the addition of UDP-glucose to an existing
glycogen molecule is glycogen synthase. Glycogen synthase adds UDP-glucose in
an -(1,4) glycosidic linkage.
Glycogen synthase is activated by insulin and glucose and inhibited by
glucagon and epinephrine.
In cases where there is not already a pre-existing glycogen molecule, glycogenin is
needed. Glycogenin is an enzyme that self-catalyzes the attachment of the frst
few UDP-glucose molecules to itself. Glycogenin remains at the center of the
glycogen molecule.
Branching enzyme makes branch points in a linear glycogen molecule using -1,6
glycosidic bonds, about every 10 glucosyl residues.
Glycogenolysis is the breakdown of glycogen. The end result is free glucose (liver)
or glucose-6-phosphate (muscle).
The frst (and rate-determining) step of glycogenolysis is: Glycogen + phosphate
glycogen (less 1 residue) + glucose-1-phosphate.
less The enzyme that catalyzes the rate-determining step of glycogenolysis
is glycogen phosphorylase.
Glycogen phosphorylase is activated by epinephrine, glucagon, AMP, and
calcium and inhibited by insulin and ATP.
Glucagon and epinephrine activate glycogen phosphorylase in a G-protein
Adenylyl Cyclase cAMP Protein Kinase A phosphorylase kinase pathway.
Calcium activates glycogen phosphorylase via a calcium-calmodulin complex
in muscle so that glycogenolysis is coupled with muscle contraction.
Insulin deactivates glycogen phosphorylase by activating a protein
phosphatase that dephosphorylates glycogen phosphorylase.
The next step in glycogenolysis is that glucose-1-phosphate is converted to glucose-
less Glucose-1-phosphate is converted to glucose-6-phosphate in glycogenolysis
by the enzyme phosphoglucomutase.
The glucose-6-phosphate may then be used in glycolysis, the HMP shunt, or
converted to free glucose (liver).
Glucose 6-phosphatase removes the phosphate from glucose-6-phosphate to
create free glucose.
less In the liver, glucose 6-phosphatase is expressed, which leads to free glucose
being made from glucose-6-phosphate and sent into the bloodstream. In muscle,
however, glucose-6-phosphatase is NOT expressed, which means that glucose-6-
phosphate is trapped in muscle cells for their own use.
When 4 glucose residues are left on a branch (also known as a limit
dextrin), debranching enzyme moves 3 residues to the end of another branch,
leaving one residue with alpha-1,6 linkage. The debranching enzyme then
hydrolyzes this remaining residue to yield one free glucose molecule.
Basic Sciences Biochemistry Cellular Energy
7 questions

Heme synthesis starts in mitochondria with succinyl-CoA from the citric acid cycle.
All the steps in heme synthesis are as follows (Steps critical to know for Step 1 are
less -aminolevulinate acid(ALA) is synthesize from glycine and succinyl-
CoA via the enzyme ALA synthase in the mitochondrial matrix.
ALA porphobilinogen via the enzyme ALA dehydratase in the cytosol
Porphobilinogen hydroxymethylbilane via the enzyme
porphobilinogen deaminase (aka uroporphyrinogen I synthase)
Hydroxymethylbilane uroporphyrinogen III via the enzyme
uroporphyrinogen III synthase
Uroporphyrinogen III coproporphyrinogen III via the enzyme
uroporphyrinogen decarboxylase
Coproporphyrinogen III protoporphyrinogen III via the enzyme
coproporphyrinogen oxidase
Protoporphyrinogen III protoporphyrin IX via the enzyme
protoporphyrinogen oxidase
Protoporphyrin IX combines with Fe 2+ heme via the enzyme
ferrochelatase in the mitochondrial matrix
The frst and last 3 steps of heme synthesis occur in mitochondria, the rest occur in
the cytosol.
ALA synthase has important regulation:
-Activated by P450 inducers
-Inhibited by hemin, glucose
-Requires vitamin B6 as a cofactor
Disruption at 4 points in the pathway leads to accumulation of intermediates
Acute intermittent porphyria: autosomal dominant defect of PB-deaminase
less Characterized by attacks of peripheral/autonomic neuropathies with
intermittent, symptom free periods. It is unclear how porphyrin intermediates cause
these symptoms.
Symptoms can include abdominal pain (severe and several days' duration),
seizures, tachycardia, hypertension, coma, dark or reddish-brown urine,
and psychiatric manifestations (e.g. depression).
Porphyria cutanea tarda: autosomal dominant defect of UROD (uroporphyrinogen
less 80% of cases are acquired, 20% genetic (autosomal dominant).
Episodes are precipitated by hepatotoxic agents (e.g. EtOH, hepatitis)
Initial symptoms: fragile skin that blisters with minimal sun exposure. Patients
may also present with pink or dark colored urine, but this is more commonly seen
with Acute Intermittent Porphyria.
Pharmacology Correlate:
Barbiturates (and other inducers) induce the P450 system consumption of heme
loss of heme's negative feedback on ALA synthase (the rate limiting step of
heme biosynthesis) accumulation of heme intermediates.
Accumulation of these intermediates causes acute exacerbations of porphyrias.
Lead poisoning: symptoms primarily via inhibition of ALA dehydrogenase (also
called ALAdehydratase or PBG synthase) but also inhibits ferrochelatase
less Causes microcytic anemia
Inhibition of ALA dehydratase accumulation of ALA; if ferrochelatase is
inhibited, protoporphyrin IX accumulates.
Symptoms can closely mimic those of acute intermittent porphyria, or can be
more subtle (loss of developmental milestones, temperamental lability). Lead
poisoning in children encephalopathy, seizures, mental deterioration.
Heme Degradation: Heme biliverdin unconjugated bilirubin, transported to liver
(rea Cycle
Basic Sciences Biochemistry Cellular Energy
3 questions

Urea cycle: series of reactions that occur in the liver in order to convert toxic
ammonia (product of amino acid catabolism) to urea (molecule with two amine
less Failure of the urea cycle (mainly genetic vs. cirrhosis) leads to
hyperammonemia, which can lead to hepatic encephalopathy.
Symptoms of hyperammonemia include:
Neurological symptoms: fapping hand tremor, ataxia, intellectual impairment,
seizures, behavioral changes, eventual coma and death if not corrected
Excess ammonium (NH
) depletes -ketoglutarate (-ketoglutarate + NH

glutamate), which leads to inhibition of the TCA cycle
Treatment for hyperammonemia: limit protein intake or administer benzoate or
phenylbutyrate to ammonia levels
The frst step, the conversion of CO
and ammonia to carbamoyl phosphate, is rate-
less Enzyme: carbamoyl phosphate synthetase I
Allosteric Activator: N-acetyl-glutamate
This step consumes 2 ATP
This step takes place in the mitochondria
The ammonia in this reaction provides the 1
amine groups in urea
Note: HCO
+ NH
is equivalent to CO
+ NH
+ H
The carbamoyl moiety is transferred to the non-proteinogenic amino
acid ornithine to formcitrulline
less Takes place in mitochondria, then Citrulline is transported into the Cytoplasm
Enzyme: ornithine transcarbamylase
Most common inherited urea cycle disorder is a defciency of ornithine
transcarbamylase (X-linked recessive unlike the other urea cycle enzyme
defciencies which are autosomal recessive)
X-linked disorder more common in males .
Signs and symptoms of ornithine transcarbamylase defciency:
- often evident in the frst few days of life (but may appear later)
- orotic acid in blood and urine (excess carbomyl phosphate converted to orotic
acid, a pyrimidine synthesis intermediate)
- BUN (no urea produced due to enzyme defciency)
- symptoms of hyperammonemia (should be distinguished from orotic aciduria which
has orotic acid with no hyperammonemia)
Aspartate condenses with citrulline to form argininosuccinate

The reaction is catalyzed by the cytosolic enzyme argininosuccinate


The amine group on aspartate provides the 2

amine found in urea

Requires the cleavage of ATP AMP + PP

Arginosuccinate is cleaved into arginine and fumarate by argininosuccinate lyase
less Fumarate malate oxaloacetate
(this series of reactions occurs in the cytosol and generates a reduced NADH)
Oxaloacetate is converted to aspartate by transaminases, ensuring that the
fow of nitrogen into the cycle is maintained
Arginase I catalyzes hydrolysis of arginine to yield urea and regenerate ornithine
Pyruvate 'inase De/ciency
Basic Sciences Biochemistry Cellular Energy
4 questions

Autosomal recessive mutations of PKLR gene pyruvate kinase defciency,
which is characterized by three things: 1. Chronic hemolysis 2. increased levels of
2,3-BPG and 3. Lack of Heinz bodies
less 1) Chronic hemolysis (both extravascular hemolysis and intravascular
hemolysis occur)
2) levels of 2,3-BPG (2,3-bisphosphoglycerate, also known as 2,3-DPG, or
2,3-diphosphoglycerate) oxygen afnity of hemoglobin
3) Lack of Heinz bodies within RBCs on peripheral blood smearvs. G6PD
defciency, a disease in which Heinz bodies are characteristic fndings
Mature RBCs have no mitochondria RBCs rely entirely on anaerobic glycolysis .
for ATPproduction. Pyruvate kinase defciency levels of ATP, which leads to:
less Na/K ATPase activity Na
accumulates intracellularly, drawing water
along with it osmotic fragility, swelling, and intravascular hemolysis of RBCs
Swelling causes RBCs to lose their biconcave shape chronic
extravascular hemolysis in the spleen
Patients can survive on reticulocytes (still have organelles and can still perform
oxidative phosphorylation) and 2,3-DPG levels (allows an easier release of oxygen
from an already low number of RBCs)
In laboratory testing, addition of ATP to an afected RBC sample will prevent
Basic Sciences Biochemistry Cellular Energy
2 questions

Energy of ATP (the primary currency of cellular energy) is released when two high-
energy phosphate bonds are hydrolyzed to form ADP or AMP and free phosphate
One molecule of glucose that undergoes glycolysis produces two molecules of
pyruvate, withnet production of 2 molecules of ATP and 2 molecules of NADH
less Energy investment phase: the conversion of glucose to F1,6BP (fructose-1,6-
bisphosphate) requires 2 ATP
Energy production phase: degradation of F1,6BP to 2 molecules of pyruvate
yields 4 ATPand 2 NADH
Glycolysis does not require oxygen but under anaerobic conditions,
converting pyruvate to lactate oxidizes NADH to NAD
, allowing glycolysis to continue
Aerobic respiration yields 30-32 ATP per glucose
less This can be confusing because theoretical calculations yield 36-38 ATP per
glucose; however, pyruvate, ADP, and phosphate need to be transported into the
mitochondria and this requires energy
Cysteine Meta#olism
Basic Sciences Biochemistry Cellular Energy
4 questions

Cysteine: synthesized from homocysteine and serine, requiring pyridoxine (B6) as
a coenzyme
Homocystinuria: several diferent enzyme defects (all forms are autosomal
recessive) that lead to elevation of homocysteine
Classical homocystinuria (most common cause of
homocystinuria): defciency of cystathionine synthase can be treated with
methionine and cysteine intake with supplementation of B12 and folate
Decreased afnity of cystathionine synthase for pyridoxal phosphate
can be treated with high does of pyridoxal phosphate (vitamin B6) to overcome the
decreased afnity
Homocysteine methyltransferase defciency: defect in the enzyme
responsible for the regeneration of methionine from homocysteine
Methylenetetrahydrofolate reductase (MTHFR) defciency: defect in the
enzyme that catalyzes the conversion of 5,10-methylenetetrahydrofolate to 5-
methyltetrahydrofolate, a cosubstrate for homocysteine remethylation to methionine
Clinical fndings include: mental retardation, atherosclerosis leading to
vascular thrombosis, long thin extremities with eunuchoid features (reminiscent of
Marfan's habitus), lens dislocation, and osteoporosis
Note: patients with Marfan's syndrome usually have a lens that is dislocated in an up-
and-out direction, while patients with homocystinuria have lens dislocation in a down-
and-in direction
Acquired homocysteinemia: seen in both B
and folate defciency (both are
needed for the remethylation of homocysteine to methionine)
less Homocysteine is thought to promote atherosclerosis explaining vascular
disease in patients with homocystinuria and elevated cardiovascular disease risk in
people with B
or folate defciency
Cystinuria: defect in cystine transport proteins in renal proximal tubule and small
intestine urine levels of cystine
less Cystine precipitates in acidic (less than pH 7.5) urine patients sufer from
recurrent cystine renal stones (cystine staghorn calculi)
Hexagonal or benzene crystals in the urine are pathognomonic of cystinuria
Same amino acid transporter is responsible for the dibasic amino acids
(ornithine, lysine, and arginine)
Mnemonic is COAL Cysteine, Ornithine, Arginine, Lysine
Treatment: hydration and alkalization of the urine using potassium citrate or
)ipid Digestion $ Meta#olism
Basic Sciences Biochemistry Cellular Energy
5 questions

Dietary fat in the intestinal lumen stimulates the secretion of bile and pancreatic
enzymes bile emulsifes dietary lipids increases the surface area available
for pancreatic enzymatic digestion.
less Pancreatic lipase, colipase, and cholesterol esterase degrade lipids into 2-MG
(monoglyceride) + FAs (fatty acids) + cholesterol which are absorbed by intestinal
epithelial cells, then re-esterifed into TGs (triglycerides) and CEs (cholesterol esters)
and packaged into chylomicrons.
Chylomicrons contain:
1. TGs (90% of chylomicron)
2. CEs
3. Fat-soluble vitamins and other lipids
4. ApoB-48 (an apolipoprotein specifc to chylomicrons and chylomicron remnants)
apoB-48 is a truncated form of apoB-100 that lacks the C-terminal LDL receptor
Chylomicrons are secreted by intestinal epithelial cells (due to apoB-48) and
circulate in the lymphatics before entering the venous bloodstream via the thoracic
duct. (Recall: the thoracic duct empties into the venous system at the junction of the
left subclavian vein and left internal jugular vein.)
After entry into the venous circulation, chylomicrons pick up apoC-II and apoE from
circulating HDL
less apoC-II activates LPL (lipoprotein lipase), which releases FFAs (free fatty
acids) and glycerol FFAs are subsequently taken up and stored within peripheral
tissues (adipose, muscle) while glycerol is taken up by the liver.
The remaining glycerol and cholesterol in the chylomicron are delivered to the
liver and ApoC is returned to HDL apoE permits uptake of remnants (eg,
chylomicron remnants,VLDL remnants (ie, IDL)) by the liver
Excess fatty acids and carbohydrates are converted by the liver into TGs
hepatocytes subsequently package TGs + apoB-100 to form VLDL (very low-
density lipoprotein) apoB-100 allows the secretion of VLDL from the liver into
the bloodstream.
less Like chylomicrons, VLDL entering the bloodstream picks up apoC-II and apoE
from circulating HDL
Again, LPL (lipoprotein lipase) releases free fatty acids into peripheral tissues,
convertingVLDL to IDL (intermediate-density lipoprotein). IDL is synonymous
with VLDLremnants.
Note: VLDL cannot be directly converted into LDL. On the other
hand, IDL (VLDLremnants) can either be converted into LDL by hepatic lipase and/or
lipoprotein lipase, orIDL can be taken up by the liver.
Presence of apoB-100 and apoE on IDL allows liver to endocytose the IDL (via
apoB-100/apoE receptor)
less Alternatively, LPL and/or hepatic lipase may continue to remove TGs
from IDL, convertingIDL into LDL
LDL is the primary carrier for cholesterol (needed for plasma membranes)
apoB-100 (the only apolipoprotein component of LDL) mediates the
endocytosis of LDLvia interaction with cell-surface apoB-100 receptors
(LDL receptors)
HDL is synthesized de novo in the liver and intestines and secreted into the
bloodstream carrying apoA-I, apoC-II and apoE. HDL has 3 functions:
less 1. Pick up and sequester cholesterol in the periphery. HDL contains apoA-I
which activates LCAT (lecithin-cholesterol acyltransferase,
aka PCAT (phosphatidylcholine-cholesterol acyltransferase)).
LCAT esterifes cholesterol to HDL, allowing HDL to take cholesterol in the
bloodstream and return it to the liver via reverse cholesterol transport.
2. Transport this esterifed and sequestered cholesterol acquired from
peripheral tissues and deliver it to the liver and other steroidogenic tissues (eg,
adrenals, ovaries, testes).
3. Carry and donate apoC-II and apoE to chylomicrons and VLDL.
Cholesterol-rich HDL is endocytosed by the liver via the interaction between
apoE on HDLand apoE receptors on hepatocytes.
Note: The cholesterol from cholesterol-rich HDL may also be delivered directly into
the cells of other tissues via scavenger receptors (eg, SR-B1) which do not mediate
endocytosis of HDL, however the specifc mechanisms of such scavenger receptor-
mediated cholesterol uptake pathways remain incompletely elucidated.
RCT (reverse cholesterol transport): process by which HDL carries cholesterol to the
liver for excretion.
less 1. Transfer of cholesterol from peripheral cells to HDL is mediated by the
protein ABCA1. Hereditary defect in the ABCA1 gene leads to a condition called
Tangier disease, which is characterized by complete absence (homozygotes) or
markedly decreased levels (heterozygotes) of serum HDL.
2. Esterifcation/sequestration of cholesterol in HDL occurs by LCAT, as
described above.
3. Cholesterol-rich HDL is endocytosed by the liver via the interaction
between apoE onHDL and apoE receptors on hepatocytes.
The protein SR-B1 also causes cholesterol transfer from HDL to hepatocytes, though
not through endocytosis of HDL.
4. In the liver, cholesterol may be converted to bile and excreted.
CETP (cholesterol ester transfer protein) catalyzes the transfer of cholesterol
from HDL toVLDL, and TGs from VLD to HDL CETP activity is linked to increased
cholesterol levels and coronary artery disease.
Basic Sciences Biochemistry Cellular Energy
4 questions

Occurs in the cytosol and has 2 phases: preparatory (requires ATP) and payof
Preparatory phase:
1) Hexokinase converts glucose to G6P (glucose-6-phosphate)
less Simple phosphorylation reaction consumes1 ATP
"Reason" its done: G6P formation efectively intracellular glucose
concentrations thereby driving more glucose into the cell
In the liver and pancreas, a high capacity isoenzyme, glucokinase
sequesters excess glucose in the liver
2) G6P is isomerized to F6P by phosphoglucose isomerase
less Fully reversible reaction: its driven forward by low F6P concentrations (see
next step)
3) F6P is phosphorylated at the C1 site F1,6BP (fructose-1,6-bisphosphate)
less This second phosphorylation destabilizes the molecule its being prepared
to be split in 2
While the biochemical names can be challenging to remember, if you keep
the "reasons" for these reactions in mind itll be easier to learn the names:
Since this is a simple phosphorylation reaction, the enzyme is a kinase.
Since it acts on a phosphorylated fructose molecule: phosphofructokinase-1
This step is irreversible and rate-limiting.
4) The unstable F1,6BP is split to yield two molecules of the 3-
carbon GADP (glyceraldehyde 3-phosphate)
less In reality, fructose is split into GADP + DHAP (dihydroxyacetone phosphate),
but DHAP is rapidly isomerized to GADP
The enzyme that splits F1,6BP is aldolase. Three aldolase isozymes exist (A,
B, and C; located in muscle, liver/kidney, and brain, respectively).
Clinical Correlates
- Defects of aldolase B lead to hereditary fructose intolerance
- Defects of aldolase A presents with hemolytic anemia and rhabdomyolysis following
febrile illness
Payof phase: (remember that each step occurs twice for each glucose molecule
because 2GADP are created from each F1,6BP)
5) GADP is dehydrogenated and phosphorylated, forming 1,3BPG (1,3-
less The dehydrogenation of GADP by glyceraldehyde-3-phosphate
dehydrogenase yields a hydrogen that is used to reduce NAD
Yields 2 NADH per glucose (1 per GADP)
The phosphorylation uses inorganic phosphate as a substrate,
not ATP or GTP
6) 1,3BPG is dephosphorylated, yielding 3PG (3-phosphoglycerate because 1,3-
bisphosphoglycerate loses 1 phosphate group)
This yields 2 ATP per glucose (1 per 1,3BPG)
7) 3PG becomes 2PG (2-phosphoglycerate). 2PG
becomes PEP (phosphoenolpyruvate)
8) PEP is dephosphorylated to become pyruvate; the enzyme is pyruvate kinase
less This yields 2 ATP per glucose (1 per PEP)
+atty Acid ynthesis
Basic Sciences Biochemistry Cellular Energy
3 questions

The frst step in de novo fatty acid synthesis is transportation of acetyl-CoA through
the inner mitochondrial membrane via the citrate shuttle.
Recall that the inner mitochondrial membrane is impermeable to acetyl-CoA.
less Citrate synthase catalyzes the condensation of oxaloacetate + acetyl-CoA
Citrate enters the cytosol, and is subsequently cleaved to oxaloacetate + acetyl-CoA.
During well fed states, isocitrate dehydrogenase (from the citric acid cycle)
is inhibited byATP and NADH citrate is free to move into the cytosol and undergo
fatty acid synthesis.
Anabolic synthesis of fatty acids involves repeated condensation reactions with
less Step 1:
Enzyme: Acetyl-CoA carboxylase
Reaction: Acetyl-CoA + CO
This step requires biotin and ATP.
Step 2:
Enzyme: Fatty acid synthase
Reaction: Acetyl-CoA + malonyl-CoA a 4-carbon saturated fatty acid.
This step requires NADPH.
The fatty acid chain is lengthened by 2 carbons with each addition of malonyl-
CoA (which comes from acetyl-CoA).
Fatty acid synthesis cant produce linoleic and linolenic acids these are essential
fatty acids
less These fatty acids are eicosanoid precursors
Eicosanoids include prostaglandins, prostacyclins, thromboxanes,
Amino Acid Derivatives
Basic Sciences Biochemistry Cellular Energy
4 questions

The derivatives of tryptophan are serotonin, melatonin, and NAD and NADP.
less Serotonin synthesis from tryptophan requires BH4 and vitamin B
cofactors. Serotonin is acetylated by acetyl CoA then methylated by S-
adenosylmethionine (SAM) to produced melatonin, a hormone in the sleep/wake
Niacin (Vitamin B3), a necessary functional group of NAD and NADP, can be
synthesized from tryptophan; however, the bodys primary source of niacin is dietary.
A lack of proper dietary niacin leads to pellagra.
Histamine is a derivative of the amino acid histidine.
less The decarboxylation of histidine produces histamine. Histamine is a
vasodilator and bronchoconstrictor and a neurotransmitter that stimulates the
secretion of hydrochloric acid (HCl) in the stomach.
Some of the derivatives of arginine are creatine, and nitric oxide.
less Creatine phosphate is a short term energy reservoir primarily used during the
early stages of muscular exercise.
NO is an important vasodilator, synthesized from arginine via nitric oxide
synthase (NOS).
The derivatives of glutamate are -aminobutyric (GABA) and glutathione (GSH).
GABA, an inhibitory neurotransmitter, is synthesized by the decarboxylation of
GSH is a tripeptide, -glutamylcysteinylglycine, consisting of glutamate,
cysteine, and glycine.
See Heme and Phenylalanine & Tyrosine Metabolism for information on other amino
acid derivatives.
0ucleotide ynthesis
Basic Sciences Biochemistry Cellular Energy
2 questions

Purine bases are synthesized starting with the activation of Ribose-5-phosphate
by PRPPsynthetase to create 5-Phosphoribosyl-1-pyrophosphate (PRPP).
less Through a series of reactions (10 total), the following molecules react
with PRPP to form Inosine 5-monophosphate (IMP): glutamine, glycine, formyl-
tetrahydrofolate, a second glutamine, CO
, aspartate, and a second formyl-
IMP is converted to adenosine monophosphate (AMP) or guanine
monophosphate (GMP).
The synthesis of AMP requires GTP and Aspartate, and the synthesis
of GMP requiresATP and Glutamine.
Clinical Correlate: Mycophenolic acid is a reversible inhibitor
of IMP dehydrogenase, an enzyme required for GMP synthesis from IMP. The drug
efects rapidly proliferating cell types, such as immune cells, for treatment of
autoimmune diseases as well as prevention of transplant rejection.
AMP and GMP are phosphorylated to ADP/GDP or ATP/GTP and used in
energy-requiring processes or RNA synthesis. Ribonucleotide reductase reduces the
ribose base of ADP and GDP to dADP and dGDP, respectively, then dADP and
dGDP phosphorylated to dATP and dGTP for use in DNA synthesis. Ribonucleotide
reductase only works on diphosphate nucleotide.
Pyrimidine synthesis begins with the formation of carbamoyl phosphate from
Glutamine and CO2 via the enzyme carbamoyl phosphate synthetase II. Note that
this is diferent from carbamoyl phosphate synthetase I used in the urea cycle.
less Following three additional reactions orotic acid is formed. Orotic acid
formation requires aspartate and glutamine.
Catalyzed by UMP synthase (also known as orotate
phosphoribosyltransferase and oritidine 5-decarboxylase), a bifunctional enzyme,
orotic acid reacts with PRPP followed by a decarboxylation yielding Uridine 5-
monophosphate (UMP).
UMP is phosphorylated to UTP, then in a reaction with glutamine, UTP is
converted toCTP. UTP and CTP are used in RNA synthesis.
Similar to dADP and dGDP synthesis, CDP is reduced by ribonucleotide
reductase then phosphorylated to dCTP and used for DNA synthesis.
Clinical Correlate: Hydroxyurea inhibits ribonucleotide reductase decreasing
deoxyribonucleotide synthesis and, in turn, DNA replication and is used in treatment
of chronic myelogenous leukemia (CML).
Thymidylate synthase, which requires methylene tetrahydrofolate as a
cofactor, methylates dUMP to produce thymidine monophosphate (dTMP). dTMP is
phosphorylated to dTTP and used in DNA synthesis.
Clinical Correlate: 5-furouracil (5-FU) irreversibly inhibits thymidylate
synthase and is used in treatment of breast and colon cancers.
Clinical Correlate: Methotrexate (MTX), a folate analogue, competitively
inhibits dihydrofolate reductase, an enzyme required for activation of methylene
tetrahydrofolate and is used as an anticancer drug.
Clinical Correlate: Trimethoprim (TMP) inhibits bacterial dihydrofolate
reductase and is used as an antibiotic drug.
Respiratory %urst
Basic Sciences Biochemistry Cellular Energy
1 question

Respiratory burst, or oxidative burst, is the rapid release of reactive oxygen species
(ROS) by immune cells such as neutrophils to kill phagocytosed microbes and is the
most efective mechanism of killing microbes.
For simplicity the respiratory burst can be divided into 2 groups of 3
reactions, Activationand Neutralization.
Activation is a series of reactions that converts molecular oxygen (O
) to
hypochlorite, or bleach, in phagolysosomes to destroy the phagocytosed microbes.
less Membrane bound NADPH oxidase converts molecular oxygen (O
) to
superoxide radical (O
) (Step 1). Defciency of NADPH oxidase leads to Chronic
Granulomatous Disease(CGD)
The immune system of patients with CGD can use hydrogen peroxide (H
produced by the invading pathogen and continue with the activation process but they
are at risk of recurrent infection by catalase positive organisms which neutralizes the
they produce.
Some examples of catalase positive species are S.
aureus, Aspergillus, Pseudomonas, and Candida.
Superoxide dismutase then converts superoxide radical (O
) to hydrogen
peroxide (H
) (Step 2).
Hydrogen peroxide (H
) can either get converted by myeloperoxidase to
hypochlorite (HOCl
), or bleach, as the fnal product of the activation and
dependent killing or become neutralized (Step 3).
Neutralization is needed because hydrogen peroxide is a reactive oxygen species
and is harmful the host cell.
less Glutathione peroxidase requires selenium to function and is used to
neutralize hydrogen peroxide by oxidizing glutathione. (Step 4)
Glutathione reductase then reduces glutathione by oxidizing NADPH (Step
Glucose-6-phosphate dehydrogenase (G6PD) then
reduces NADP to NADPH as part of the oxidative phase of HMP Shunt (Pentose
phosphate pathway (Step 6).
+ructose1 *alactose1 or#itol1 and )actose
Basic Sciences Biochemistry Cellular Energy
2 questions

Fructose is a monosaccharide that is found in sucrose (glucose + fructose), honey
and corn syrup etc and its metabolism occurs mainly in the liver. It enters epithelial
cells by GLUT 5 facilitated difusion and is converted to glycolysis and
gluconeogenesis intermediates.
less Fructose enters glycolysis/gluconeogenesis by frst being phosphorylated
byfructokinase to fructose-1-phosphate. Clinical correlation: Essential Fructosuria is
an autosomal recessive defect in fructokinase.
Fructose-1-phosphate is then cleaved by aldolase B (the rate limiting
enzyme) to dihydroxyacetone-phosphate and glyceraldehyde both of which are
intermediates in glycolysis and go on to make pyruvate. Clinical
correlation: Hereditary Fructose Intolerance is an autosomal recessive defciency of
Aldolase B is found in liver while aldolase A is in other tissues. Both of these
enzymes participate in glycolysis.
Galactose is a monosaccharide sugar that is a C-4 epimer of glucose.
less Principally there are 2 enzymes involved in the metabolism of galactose, they
are galactokinase (GAL-K) and galactose-1-phosphate uridyltransferase (GAL-T).
Note there are also UDP-galactose-4-epimerase (GAL-E) and mutarotase (GAL-M)
which are involved in the process but dont need to be mentioned.
Dietary galactose enters glycolysis/gluconeogenesis by frst being
phosphorylated to galactose-1-phosphate by galactokinase. This enzyme is present
in many tissues but is most active in the liver. Clinical correlation: A defciency of
galactokinase leads to non-classical galactosemia, a rare and mild galactosemia.
The galactose in galactose-1-phosphate is then transferred to UDP-glucose
bygalactose-1-phosphate uridyltransferase to yield UDP-galactose and glucose 1-
phosphate. UDP-galactose is then converted back to UDP-glucose by GAL-E and
the cycle repeats. Clinical correlation: A defciency of galactose-1-phosphate
uridyltransferase leads to the most common genetic disease Classic Galactosemia, a
severe disorder.
Sorbitol is the alcohol counterpart of glucose. Aldose reductase converts glucose
to sorbitol using NADPH.
less Sorbitol is then converted to fructose by sorbitol dehydrogenase using
Both aldose reductase and sorbitol dehydrogenase are present in liver,
ovaries and seminal vesicles.
Some tissues such as Schwann cells, retina, kidneys, and lens only have
aldose reductase, so these tissues are at risk for accumulation of sorbitol causing
osmotic damage such as peripheral neuropathy retinopathy and cataracts. These
symptoms are seen with chronic hyperglycemia in diabetes.
Lactose is a disaccharide sugar thats found in milk. Its a combination
of glucose andgalactose.
less It is cleaved in the small intestine by the brush border enzyme, lactase, and
absorbed as glucose and galactose to be metabolized in their respective pathways.
Clinical correlation:Lactase defciency is mainly due to age dependent decline of the
Loss of brush borders due to gastroenteritis, autoimmune disease or
congenital lactase defciency (rare) can also lead to lactose intolerance.
Basic Sciences Biochemistry DNA & RNA
4 questions

A nucleotide is made up of a nitrogenous base, 5-carbon sugar, and one or more
phosphate groups. A nucleoside is just a nitrogenous base and 5-carbon sugar, no
phosphate groups.
less The deoxyribonucleic acid (DNA) 5-carbon sugar is 2-deoxy-ribose and
the DNApyrimidines are cytosine and thymine; DNA does not use uracil. The
ribonucleic acid (RNA) 5-carbon sugar is ribose and the RNA pyrimidines are
cytosine and uracil; RNAdoes not use thymine.
Guanine has a ketone. Thymine has a methyl. Deamination of cytosine
makes uracil.
The nitrogenous pyrimidines (1 cyclic ring, see image)
are Cytosine, Thymine, andUracil. Mnemonic: CUT the PY (pie).
The nitrogenous purine bases (2 cyclic rings, see image) are Adenine
and Guanine. Mnemonic: Pur e A s G old.
When dsDNA is formed, adenine pairs with thymine, and guanine pairs with cytosine.
less G-C pair has 3 H-OH bonds
A-T pair has 2 H-OH bonds
The adenine-thymine (A-T) bond consists of 2 hydrogen bonds; the guanine-
cytosine (G-C) bond consists of 3 hydrogen bonds. A higher content of G-C bond
increases the melting point of DNA.
De novo synthesis of both purines and pyrimidines involves PRPP (Phosphoribosyl
Purine synthesis: requires glycine, aspartate, and glutamine
less PRPP + glutamine + aspartate + glycine = IMP
IMP is converted into the ribonucleotides AMP or GMP. These can be
converted to ADPand GDP by adenylate and guanylate kinases, respectively.
Nucleoside diphosphate kinase, which has broad specifcity,
convert ADP and GDP to ATPand GTP.
Pyrimidine synthesis: orotic acid (aka orotate) + PRPP = OMP
OMP UMP UDP. UMP + glutamine CDP (ribonucleotides). dTDP is
made from dUMP.
Last step of nucleotide synthesis: ribonucleotides (ADP, GDP, UDP, CDP) are
converted toDNA (deoxyribonucleotides) by ribonucleotide reductase
Clinical Correlate: Inability to convert orotic acid to UMP orotic aciduria.
less Autosomal recessive defect in UMP synthase (a bifunctional enzyme,
including orotic acid phosphoribosyltransferase and orotidine-5-phosphate
Presents with megaloblastic anemia that is not responsive to iron, folate or
vitamin B
supplementation. If not corrected, causes developmental/intellectual
Treated with lifelong uridine supplementation.
Basic Sciences Biochemistry DNA & RNA
5 questions

Called "transcription" because both DNA and RNA are nucleic acids, as opposed
to translation, in which the genetic code in nucleic acids is translated into amino
3 types of RNA: ribosomal RNA, messenger RNA, and transfer RNA
less rRNA is still transcribed from DNA, but isnt translated instead, it plays
several key roles in ribosomes, including recognition and positioning of tRNA and
It also catalyzes peptidyl transferase activity of 60S subunit.
rRNA comprises 80% of eukaryotic RNA
mRNA is the transcript of DNA
tRNA has 1 amino acid bound to its 3 end; matches amino acids with mRNA
codons during translation
Start codon: AUG (or rarely GUG)
AUG inAUGurates protein synthesis
less In eukaryotes, AUG Met. In prokaryotes, AUG formylMet (fMet)
Stop codons: UGA, UAA, UAG
UGA=U Go Away
UAA=U Are Away
UAG=U Are Gone
less Also known as nonsense codons since mutations into these codons cause
chain termination
Transcription is controlled via 4 cis-acting elements: promoters, enhancers,
silencers/operators, and response elements
less Promoters are where RNA polymerase and transcription factors (TFs) bind to
initiate transcription (often located 25 to 50 bases upstream of the gene, and often
contains A-T rich sequences of TATA or CAAT boxes)
Enhancers also bind TFs, and can signifcantly the rate of transcription (can
be located upstream, downstream, or a distance from the gene)
Silencers repress transcription when repressors, a subset of TFs, bind to
them (known as operators in prokaryotes)
Response elements bind specifc TFs (e.g. heat shock response element,
estrogen response element) and modulate transcription
Eukaryotic RNA polymerases I, II, and III
less RNAP I transcribes rRNA (most abundant)
RNAP II transcribes mRNA
-amanitin (deadly toxin found in certain mushrooms): inhibits RNAP II liver
damage when ingested
RNAP III transcribes tRNA (shortest RNA)
"Rampant, Massive, Tiny": RNAP I transcribes the most abundant
type rRNA, RNAP II transcribes the longest type mRNA, RNAP III transcribes the
shortest type tRNA
Prokaryotic RNAP is made of 5 subunits and can synthesize all the 3 kinds of RNA
RNA polymerases do not require primers
less Prokaryotic RNAP binds directly to promoters
Eukaryotic RNAPs require TFs (pre-initiation complex) to direct transcription
Basic Sciences Biochemistry DNA & RNA
4 questions

Short, between 75 and 90 nucleotides
Secondary structure: cloverleaf. Tertiary structure: "L" shaped.
less The "bottom" of the cloverleaf houses the anti-codon, which pairs with mRNA
codons when brought together in a ribosome
The 3 end has a CCA sequence that is recognized by aminoacyl-tRNA synthetase,
the enzyme responsible for "charging" the tRNA with an amino acid
less In the 3D image, the CCA is shown in orange
Aminoacylation (aka "charging") covalently bonds an amino acid to the 3 end of the
less There is 1 aminoacyl-tRNA synthetase per amino acid, so each aminoacyl-
tRNA synthetase recognizes multiple tRNAs
(Remember the genetic code is degenerate so there are several diferent tRNAs that
recognize codes for the same amino acid)
Aminoacylation also gives a phosphate group (hence "charged") that later
provides energy for peptide bond formation; aminoacylation converts ATP AMP (2
phosphate bonds)
Aminoacyl-tRNA synthetases proofread before & after charging; if the wrong amino
acid is on the tRNA, the covalent bond is hydrolyzed
Wobble hypothesis: Prokaryotes typically express 40-50 tRNAs, but there are 61
codons the 3rd position isnt as critical to pairing between the 3 codon of mRNA
and the 5 anticodon of tRNA and is allowed some "wobble"
Purine alvage
Basic Sciences Biochemistry DNA & RNA
2 questions

There are two pathways for synthesis of purines: de novo and salvage. Purine
salvage is the process of recycling purines acquired from normal cell turn-over, or
obtained in the diet, and converting them into nucleoside triphosphates that can be
used again in the body.
less The three free purine bases are adenine, guanine, and hypoxanthine.
The primary enzymes involved in purine salvage are HGPRT (hypoxanthine-
guanine phosphoribosyltransferase) and APRT (adenine phosphoribosyltransferase).
In addition to purine bases, salvage enzymes require the substrate PRPP.
Purine salvage is separated further into two separate pathways: 1) guanine
and hypoxanthine salvage, and 2) adenine salvage.
Guanine and hypoxanthine salvage
less Guanine is converted to GMP via the enzyme HGPRT.
Guanine + PRPP GMP + PP (pyrophosphate)
Hypoxanthine is converted to IMP via the enzyme HGPRT.
Hypoxanthine + PRPP IMP + PP
Adenine salvage
less Adenine is converted to AMP via the enzyme APRT.
Adenine + PRPP AMP + PP
For information on de novo purine synthesis see Nucleotide Synthesis. For more
information on diseases that result from defciencies in these pathways, like Lesch-
Nyhan syndrome that results from a defect in hypoxanthine-guanine phosphoribosyl
transferase (HGPRT), seeDisorders of Nucleotide Metabolism.
D0A Replication
Basic Sciences Biochemistry DNA & RNA
1 question

Prokaryotic replication: only 1 ORI (origin of replication)
Eukaryotic replication: multiple ORIs
less DNA replication is semiconservative: each resulting dsDNA has 1 strand from
the parent and 1 new strand
Process of prokaryotic replication:
less Helicase: unwinds DNA at the replication fork
SSBP (single-strand binding protein): prevents DNA from reverting to
duplex form (re-annealing) remember the strong hydrogen bonds between
nucleotide bases
Gyrase (a topoisomerase type II enzyme): introduces negative supercoils,
thereby relaxing positive supercoils that form during helicase unwinding
DNA Primase: synthesizes a short RNA segment on the ssDNA template
(no DNApolymerase can start synthesis w/o a DNA or RNA primer)
DNA Polymerase III (the main prokaryotic polymerase):
adds DNA nucleotides to the hydroxyl group on the 3 end of the new strand (53
DNA Pol III also has a 35 proofreading ability w/ exonuclease function to
correct mistakes
DNA polymerase I: when DNA Pol III reaches the "prior" RNA primer on the
lagging strand, this enzyme degrades the primer and flls in
appropriate DNA nucleotides DNAligase then closes any remaining breaks in the
new strand
Process of eukaryotic replication (similar, but some enzymes have diferent names &
less DNA Pol : acts as a DNA primase, elongates the primer w/
20 DNA nucleotides, after which DNA Pol takes over
DNA Pol : analogous to DNA Pol III, also w/ 35 exonuclease
Telomerase: reverse transcriptase enzyme with intrinsic RNA template that
synthesizesDNA at 3' end of linear chromosome, in order to prevent shortening
during lagging strand template DNA synthesis
Stem cells and cancer cells upregulate telomerase activity no shortening of
chromosomes increased replicative ability
D0A Repair
Basic Sciences Biochemistry DNA & RNA
4 questions

Nucleotide excision repair: NER enzymes recognize bulky distortions in the shape
of theDNA double helix
less Important in removal of UV-induced damage (i.e. thymine dimers) and
autosomal recessive defects in this enzyme cause xeroderma pigmentosum, with
death by melanoma & squamous cell carcinoma
this is another sub-concept
Multi-protein complex nicks an oligonucleotide segment including the
damaged bases DNAP or replaces the nucleotides and ligase seals the
Base excision repair: corrects single depurinated, or otherwise damaged bases,
with the use of special N-glycosylase enzymes
less Adenine and guanine can spontaneously undergo depurination, and cytosine
can deaminate to uracil
These errors are detected by DNA glycosylases that are specifc to the injury, e.g.
the uracil DNA glycosylase only recognizes uracil in DNA, a 3-methyl adenine is
detected only by alkyladenine DNA glycosylase
The glycosylases create an AP (apurinic and apyrimidinic) site by removing
the nitrogenous base without interrupting the phosphodiester backbone. This site is
recognized by AP endonucleases which then excises the abasic sugar
DNA Pol I (prokaryotic) or DNA Pol (human) then replaces the damaged
base DNAligase seals the new DNA strand
Mismatch repair (G-T or A-C pairs): daughter strand identifed by lack of methylation
less These genes are so key that inheriting 1 defective copy high risk for cancer
(e.g.HNPCC, inherited in an autosomal dominant fashion in which a mismatch-repair
gene causes a microsatellite repeat replication error to go unfxed)
There are two methods of correcting double strand DNA breaks: homologous
recombination and non-homologous end joining
less Homologous recombination: occurs normally during meiosis, utilized to
repair double strand breaks
Damaged strands are matched to non-damaged strands DNA Pol flls in damaged
strand using the new non-damaged strand as a template
Non-homologous end joining: broken ends of two DNA strands are brought
together by a group of proteins and joined without checking for homology
signifcant potential for error and mutations (conserved throughout all kingdoms of
This process can use short DNA sequences of overhang to determine homology, but
homology isnt required (i.e. no overhang sequences)
Inefective double strand repair leads to ataxia-telangiectasia.
Disorders o- 0ucleotide Meta#olism
Basic Sciences Biochemistry DNA & RNA
4 questions

A defect in purine nucleoside phosphorylase (PNP) results in accumulation of dGTP
and dATP, particularly in lymphoid tissues, which is toxic for cells.
Clinically, there is reduced T cell numbers, lymphopenia, neurologically
problems including mental retardation and muscle spasticity, and autoimmune
A defect in adenosine deaminase (autosomal recessive) results in accumulation
of ATP and dATP, similar to PNP defciency. Clinically, there is decreased T-, B-, and
natural killer cells with marked lymphopenia.
less ADA defciency leads to severe combined immunodefciency disease ( SCID ).
A defect in UMP synthase (autosomal recessive) results in an inability to properly
synthesize pyrimidines and leads to excretion of large amounts of orotic acid
(hereditary orotic aciduria).
less Clinically, there is megaloblastic anemia and poor growth. The condition does
not improve with vitamin B12 or folic acid administration.
In contrast to orinithine transcarbamylase defciency, which presents with
hyperammonemia and increased orotic acid excretion, hereditary orotic aciduria
shows no hyperammonemia.
Oral uridine administration allows for a source of proper pyrimidine synthesis.
Lesch-Nyhan syndrome results from a defect in hypoxanthine-guanine
phosphoribosyl transferase (HGPRT). It is X-linked recessive and results in faulty
purine salvage.
less Purines are instead converted to uric acid, leading to hyperuricemia
and gout .
Clinically, patients present with mental retardation and self-mutilation, and
less frequently with aggression, gout, and choreoathetosis (involuntary movements).
D0A structure
Basic Sciences Biochemistry DNA & RNA
2 questions

Phosphodiester bonds connect nucleotides in a 3-5 direction
Chromatin is the complex of DNA, RNA, and histones that comprise chromosomes
less Heterochromatin: sterically inaccessible, condensed, and transcriptionally
inactive (HeteroChromatin is Highly Condensed)
Euchromatin: sterically accessible, uncondensed, and transcriptionally active
(Echromatin is Expressed)
Clinical Correlate: A Barr Body is the inactive X chromosome in a female
somatic cell. It is composed of heterochromatin.
Nucleosome: 1 histone octamer + 2 loops of dsDNA = nucleosome core and the
"bead" in the beads on a string model
less Histone octamer (core histones): 2 each of H2A, H2B, H3, and H4
Adjacent nucleosome cores are linked by intervening DNA associated with
H1, 1 of the other 5 histones (this is the "string" part of beads on a string model)
DNA is acidic (negatively charged) while histones are primarily lysine and
arginine (positively charged)
Acetylation (negative charge) of positively charged histones weakens
the DNA-histone bonds and makes DNA accessible to transcription factors
and RNA polymerases
Basic Sciences Biochemistry DNA & RNA
3 questions

Transition vs. transversion:
In a transition, a purine is substituted for a purine or a pyrimidine is substituted for a
In a transversion, purine pyrimidine or pyrimidine purine.
Order of increasing severity: silent missense nonsense
Silent: mutation that yields the same amino acid (often a base change in the
position of a codon yields the same amino acid due to tRNA wobble)
less Amino acid mutations in other positions can also lead to silent mutations
because the genetic code is degenerate (the exception is methionine, which is only
encoded by AUG)
Missense: mutation that creates a change in the amino acid
less Conservative: a type of missense mutation that yields a new amino acid with
a similar chemical property as the original amino acid (e.g. hydrophobic)
Nonsense: mutation that creates an early stop codon protein is truncated
(Its early, stop the nonsense!)
Frameshift: deletion or addition of any number of nucleotides not divisible by 3, that
causes all downstream codons to change
less Occurs because the genetic code is commaless & non-overlapping (read
from a single starting point in a continuous string)
Post&transcriptional processing
Basic Sciences Biochemistry DNA & RNA
6 questions

Occurs in eukaryotes. 3 main forms: 5 capping, 3 poly-adenylation, and splicing
In prokaryotes, transcription occurs in cytoplasm right next to translation (prokaryotes
have no nucleus), whereas in eukaryotes transcription occurs in nucleus, the mRNA
is processed, then shipped to cytoplasm for translation
less The RNA produced by RNAP II is actually called hnRNA (heterogeneous
nuclear RNA) until processing has occurred
5 capping adds a 7-methylguanosine to the 5 end of the transcript
less The cap protects the transcript from ribonucleases and is involved in initiating
translation of mRNA
Poly (A) polymerase adds the 3 poly-A tail, as many as 200 adenines (does not
require a template)
less The poly-A tail facilitates the mRNAs exit from the nucleus and is also thought
to protect the transcript from 35 exonuclease activity
Splicing removes introns (non-coding segments); the remaining exons are re-joined
to form a single transcript
less Introns go out; exons are expressed
Splicing is catalyzed by the spliceosome and snRNPs (small nuclear
ribonucleoproteins nuclear b/c all of this occurs in the nucleus)
Alternative splicing allows multiple proteins to be translated from a single transcript
(e.g. antibodies); some exons are discarded in a controlled fashion
2illiams yndrome
Basic Sciences Biochemistry Genetics
1 question

Williams syndrome (Williams"Beuren syndrome) is a genetic disorder resulting
from the deletion of approximately 26 genes from chromosome 7q11.23.
less The majority of cases are due to random events at fertilization. If someone
with Williams syndrome has a child, there is a 50% chance it will be passed to that
One of the deleted genes is ELN (encodes the protein elastin), which may
contribute to many of the symptoms.
Afects approximately 1 in 10,000 live births.
Williams syndrome has a variable clinical presentation.
less Facial features: Distinctive elf-like features. Includes wide mouth, full lips,
short fat nose, full cheeks, and wide-spaced teeth.
Cognitive defcits: Most are developmentally delayed, though patients show
a wide range of mental capacity from severe mental retardation to normal
Some have ADD, anxiety and other psychiatric disorders.
Supravalvular aortic stenosis (SVAS): Narrowing of the aorta to varying
degrees. Sometimes requires surgical intervention.
Williams syndrome patients are known to be overly friendly.
less Despite mental disability, patients are often very talkative and interested in
other people.
Little to no fear of strangers.
Hardy&2ein#erg *enetics
Basic Sciences Biochemistry Genetics
4 questions

Both allele and genotype frequencies in a population remain constant if 4 conditions
are met:
less 1) No mutations
2) No selection for a genotype
3) The population is large and mating is random (to prevent genetic drift)
4) No migration
Allele prevalence: p+q=1
less p is the frequency for allele A
q is the frequency for allele B
Genotype prevalence: p
+ 2pq + q
= 1
= frequency of AA genotype (homozygote)
2pq = frequency of AB genotype (heterozygote)
= frequency of BB genotype (homozygote)
If allele A is X-linked recessive:

The A genotype frequency in males = p The A phenotype also = p

The A genotype frequency in females = p

the A phenotype in females also
= p
Founder efect occurs when a small number of people break of the original
population leading to a change in allelic frequency within the new group.
less The frequency of alleles in the founders of the new group is not representative
of the allele frequency found in the original population. This can lead to two diferent
1) An allele thats rare in the original group is more common in the founders
increased expression of recessive traits.
2) An allele found in the original population is rare in the founders decreased
expression and potential loss of that allele in future generations.
Trisomy 34
Basic Sciences Biochemistry Genetics
3 questions

Edwards syndrome
Second most common (after Downs): 1 in 3000
95% of conceptuses with trisomy 18 die before birth
Only 5-10% of live births survive beyond frst year of life
less High mortality due to cardiac, renal, and CNS defects (severe mental
retardation, central apnea); patients are prone to sepsis
Physical fndings: rocker-bottom feet, clenched hands, micrognathia, low-set ears
5563375 Deletion yndrome
Basic Sciences Biochemistry Genetics
2 questions

CATCH-22: microdeletion of central portion of chromosome 22
Cleft palate
Abnormal facial features
Thymic aplasia T-cell dysfunction/defciency
Cardiac defects: tetralogy of Fallot, VSD, many others
Hypocalcemia: due to hypoparathyroidism
22 q11.2 deletion
less Chromosome 22
Also known as DiGeorge Syndrome, velocardiofacial syndrome. Involves
developmental defect in third and fourth pharyngeal pouches.
'ey *enetic Terms
Basic Sciences Biochemistry Genetics
3 questions

Allelic Heterogeneity
less Diferent mutations in the same gene cause similar phenotype.
Examples are Duchennes and Beckers muscular dystrophy
less Disease severity increases in successive generations.
Age of onset decreases in successive generations.
Codominant Alleles
Both alleles share dominance and the phenotype of both is expressed.
2 most commonly cited examples are ABO blood groups and -1-antitrypsin
Dominant-Negative mutation
less The product of the mutant allele actually inactivates the product of the normal
gene. Thus, the mutation exerts a dominant efect.
less A term referring to maternal mitochondrial DNA that is present in both
mutated and wild type forms. As such, there is inconsistent expression of the disease
among patients.
less Selective methylation of maternal vs paternal allele results in diferent
phenotypes of disease.
Most important examples are on chromosome 15 Prader-Willi Syndrome
(paternal) & Angelmans syndrome (maternal).
Incomplete Penetrance
less Mutant phenotype is not expressed in all individuals containing mutation.
Examples include cancer caused by Rb mutation and HNPCC.
less Refers to the tendency of two diferent genes on the same chromosome to
segregate together during recombination. The genes appear to be linked.
The closer two genes are, the more likely they are to remain linked.
Loss of Heterozygosity (LOH)
less Heterozygous at a locus with one deleterious and one normal allele.
Mutational event in the healthy allele homozygous for deleterious allele.
Seen in tumor suppressor genes. Cancer develops when second allele
becomes mutated.
less Cells in the body contain diferent genes.
Germline mosaicism occurs when the germ cells contain a diferent genetic
makeup than the somatic cells.
Should be considered when there is a mutation present in the ofspring that is
not present in the parents.
Phenotypic Heterogeneity
less Mutations in the same gene cause diferent phenotypes
less The mutation of one gene causes several phenotypic efects.
Uniparental Disomy
Instead of receiving one copy of a chromosome from each parent, child
receives 2 copies from one and none from the other.
Uniparental disomy is another cause of Prader-Willi and Angelmans
Maternal chromosome 15 disomy Prader-Willi syndrome
Paternal chromosome 15 disomy Angelmans syndrome
Variable Expression
less Severity of disease is diferent among individuals
8nheritance $ Pedigree Analysis
Basic Sciences Biochemistry Genetics
6 questions

It is important to understand how to read and interpret a pedigree.
less Squares/circles in the same horizontal line represent individuals from the
same generation.
A circle and square joined by a horizontal line represents mating.
Individual connected by a vertical line to someone from the previous
generation is the child of that person .
Autosomal dominant: Only one allele required for expression. Manifests in every
less If a parent is a carrier, each child has a 50% chance of inheriting the trait.
Afects males and females equally
Autosomal recessive: Two alleles required for expression. Skips generations, both
parents must be carriers if neither are homozygous.
less Afects males and females equally
X-linked recessive: No father-to-son transmission; sons of heterozygous mothers
have 50% chance of being afected
less In women, X chromosomes are randomly inactivated in each cell female
carriers are rarely symptomatic (however, they can be)
X-linked recessive traits are extremely more common in males
X-linked dominant: All daughters of an afected father (only 1 X chromosome) are
Codominance: Both alleles are expressed. ABO blood group is a classic example.
Mitochondrial inheritance: only transmitted via mother
Afects male and female ofspring of an afected mother equally
Mitochondrial Diseases
Basic Sciences Biochemistry Genetics
2 questions

Mitochondria provide the cell with energy in the form of ATP, primarily through
oxidative phosphorylation and the Krebs cycle.
less Mitochondrial diseases are particularly damaging to tissues that use oxygen
dependent energy production pathways, such as the brain, heart, skeletal muscles,
liver and kidney.
Inheritance patterns for mitochondrial diseases are unique compared to other
heritable diseases.
less Upon fusion of sperm and egg, the egg supplies the mitochondria of the
newly formed zygote mitochondrial diseases are inherited from the
mother if mutation afects a gene in mitochondrial DNA.
Some mitochondrial proteins are encoded by nuclear DNA. Diseases from mutations
in nDNA genes do not follow a maternal inheritance pattern but rather are transferred
in an autosomal recessive fashion.
When the zygote and other stem cells divide, there is random distribution of
mitochondria to daughter cells potential for uneven distribution of mutated
mitochondria. As a result, some tissues have normal mitochondria whereas others
may have diseased mitochondria. Result is a large variety of afected tissues,
disease severity, and subsequent clinical presentations. This principle is known
as heteroplasmy.
Threshold Efect: There must be a minimum amount of mutated
mitochondrial proteins in a cell for that cell to be diseased. This number may be as
high as 90%, and depends on the tissue.
There are symptoms typical of most mitochondrial diseases.
less Lactic acidosis due to decreased oxidative phosphorylation, even though
plasma and tissue oxygen levels are normal.
Hypotonia and muscle disease due to decreased muscle ATP levels.
Often presents with classical ragged red fbers in muscle histological specimens.
This is due to increased numbers of mitochondria, and other cellular changes, in
muscle cells in an attempt to produce more ATP.
Ophthalmoplegia due to extraocular muscle damage.
There exists a wide range of age of onset. The time it takes to accumulate
malformed proteins and reach the threshold level is variable.
Children with earlier onset of mitochondrial diseases often have brain atrophy.
There are an increasing number of specifc mitochondrial diseases, with many
overlapping signs and symptoms.
less For all of the diseases below, deletion of mtDNA maternal inheritance.
LHON (Lebers hereditary optic neuropathy)
less Defect in NADH dehydrogenase progressive loss of central vision and
Though inherited through mitochondrial DNA, for unknown reasons afects
males more than females.
Kearns-Sayre Syndrome
less Presents with PEO (progressive external opthalmoplegia), pigmentary
retinopathy, cardiac conduction defects. Onset is generally before age 20.
MERRF (myoclonic epilepsy with ragged red fbers)
less Presents with ragged red fbers, myoclonic epilepsy, cerebellar ataxia.
MELAS (mitochondrial encephalopathy, lactic acidosis, stroke-like episodes)
less Stroke-like events, muscle weakness, short stature.
Repeated stroke-like events can lead to long-term damage. Stroke symptoms are not
confned to specifc vasculature regions.
Onset is in childhood or early adulthood.
Cri&du&chat yndrome
Basic Sciences Biochemistry Genetics
3 questions

Partial deletion of the short arm of chromosome 5
Afected infants have a characteristic, high-pitched cry like the meowing of kittens
less In French, "cri-du-chat" means "cry of the cat"
Other features:
less Microcephaly
Facial abnormalities
Mental retardation
Basic Sciences Biochemistry Genetics
3 questions

Imprinting refers to the non-random expression of genes in a parent of origin
preferential manner: Genes are inherited from both parents, but only one copy,
paternal or maternal, is expressed.
less The inactive copy of the gene is silenced through methylation. Methylation
associated with genetic imprinting occurs in the germ line cells prior to fertilization.
Paternal methylation patterns are distinct and diferent from maternal
methylation patterns
Two classic syndromes result from spontaneous loss (deletions, unbalanced
translocations, uniparental disomy) of locus 15q11-13 on one chromosome.
Loss of the paternal alleles at 15q11-13 expression of only maternal alleles, some
of which are already silenced through methylation Prader-Willi syndrome
less Loss of Paternal alleles Prader-Willi syndrome
Sx: obesity, mental retardation, neonatal hypotonia (hallmark feature), genital
Loss of the maternal alleles at 15q11-13 expression of only paternal alleles (some
already silenced through methylation) Angelman syndrome
less Loss of Maternal alleles AngelMan syndrome
Sx: Inappropriate laughter, seizures, mental retardation, ataxia
Trisomy 39
Basic Sciences Biochemistry Genetics
2 questions

Patau syndrome
Trisomy 13 (Patau syndrome) is the least common and most severe of the autosomal
less Median survival: < 3 days
Physical fndings:
less Trisomy 13 results in holoprosencephaly (failure of proper forebrain
Rocker-bottom feet
Cleft lip and palate
Heart defects: PDA, VSD, ASD, dextrocardia
:&)in;ed Recessive Disorders
Basic Sciences Biochemistry Genetics
1 question

Mnemonic: For X-linked recessive
disorders, Be Wise, Fools GOLD Heeds Silly Hope
less Brutons Agammaglobulinemia
Fabrys disease
G6PD defciency
Ocular albinism
Note: Oculocutaneousalbinism is diferent than ocular albinism.
Oculocutaneous albinism is caused by an autosomal recessive mutation of the
tyrosinase enzyme.
Duchennes (and Beckers) muscular dystrophy
Hunters Syndrome
SCID (severe combined immunodefciency)
Hemophilia A and B
Note: Although a rare occurrence, female carriers can be afected by X-linked
recessive disorders due to non-random or preferential inactivation of an X
chromosome in each cell
Trinucleotide repeat disorders
Basic Sciences Biochemistry Genetics
6 questions

Diseases characterized by unstable and abnormal expansions of DNA-triplets
Number of repeats accumulates in successive generations more severe
symptoms occur earlier in life (example of anticipation)
less Anticipation is notable in many trinucleotide repeat disorders, but especially
Huntingtons, Fragile X, Friedreichs ataxia, and myotonic dystrophy
Fragile X Syndrome: 200 or more CGG repeats in the FMR1 gene on the X
less X-linked dominant inheritance
Associated with large testes (macro-orchidism), large jaw, large ears and
mental retardation.
Huntingtons Disease: > 35 CAG repeats in the Huntingtin gene on chromosome 4
less Autosomal dominant, symptoms develop at 20 to 50 years of age
S/Sx: Progressive dementia, chorea (dance-like motions), caudate atrophy.
See Huntingtons disease.
Friedreichs Ataxia: > 100 GAA repeats in the FXN gene on chromosome 9
less Autosomal recessive inheritance
Myotonic Dystrophy: > 50 CTG repeats of the gene for myotonic dystrophy protein
kinase on chromosome 19
less Autosomal dominant inheritance
Autosomal Dominant Disorders
Basic Sciences Biochemistry Genetics
1 question

Autosomal dominant disorders result from mutations of genes on autosomal
less Development of an autosomal dominant disorder requires inheritance of one
mutation to develop the disease.
The mutation often afects structural genes.
Homozygous dominant phenotypes are typically lethal, while heterozygous
phenotypes are typically less severe than autosomal recessive diseases.
Phenotypes are often pleiotropic.
Men and women are afected equally, and have an equal likelihood of passing
the gene to ofspring, since the mutations occur on autosomal chromosomes.
When analyzing a pedigree, look for afected people in each generation.
Below is a list of autosomal dominant disorders:
less Achondroplasia (see Bone Formation).
Autosomal-Dominant Polycystic Kidney Disease (see ADPKD)
Familial adenomatous polyposis (see Colorectal Cancer)
Familial hypercholesterolemia (hyperlipidemia type IIa). See Familial
Hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome).
Review Benign Vascular Tumors.
Hereditary spherocytosis. Review Hemolytic Anemias.
Marfan syndrome, see Fibrillin.
MEN syndromes (multiple endocrine neoplasias). Review MEN.
Neurofbromatosis type 1 (von Recklinghausens disease).
Review Phakomatoses (Neurocutneous Syndromes).
Neurofbromatosis type 2 (review Phakomatoses (Neurocutneous
Tuberous Sclerosis (review Phakomatoses (Neurocutneous Syndromes))
von Hippel-Lindau disease (review Malignant Tumors of the Urinary Tract and
Huntington disease (See Huntington Disease)
)arge Chromosomal De-ects
Basic Sciences Biochemistry Genetics
2 questions

Translocations occur during recombination and involve an exchange of genetic
material between two separate chromosomes.
less Most translocations are harmless. Chromosome segments are in diferent
places, but there is not interruption of genetic material.
Disease results when the translocation interrupts (is within) a gene.
Robertsonian translocations are a specifc type of translocation that involves
fusion of the long arms of two acrocentric chromosomes.
Acrocentric chromosomes are those whose short arms are extremely small and hard
to observe.
There are several examples of disease states caused by translocations:
less Down syndrome usually occurs due to maternal meiotic non-disjunction, but
some cases are due to a robertsonian translocation extra chromosome 21
attached to chromosome 14.
Burkitt lymphoma is due to translocation between chromosomes 8 and 14,
Various leukemias due to fusion of proteins from separate chromosomes
unregulated activity of those proteins uncontrolled growth.
t(9;22) chronic myelogenous leukemia
t(15;17) acute promyelocytic leukemia
t(12;21) acute lymphoblastic leukemia
Chromosomal inversions, as the name suggests, is the inversion or reversal of a
segment of a chromosome. Inverted segment remains within the original
less Pericentric inversion involves the centromere.
Mnemonic: perIcentric Involves the centromere.
Paracentric inversion does not involve the centromere.
Mnemonic: paracentric acentric does not involve the centromere.
As with translocations, inversions only cause a disease or syndrome if the
break points of the inversion are within a gene.
Trisomy 53
Basic Sciences Biochemistry Genetics
6 questions

Trisomy 21 or Down syndrome is the most common chromosomal disease
less Incidence with maternal age:
- If mother is younger than 30, < 1:1000
- If mother is 35, 1:400
- If mother is 40, 1:105
Due to meiotic nondisjunction, ~90% maternal nondisjunction (correlates w/ maternal
less A gamete has an extra chromosome 21 (total of 24 chromosomes)
Average life expectancy: 50 years, but patients develop Alzheimers-type symptoms
around age 40
Prenatal screening (quad screen): AFP (-fetoprotein), hCG, urine
unconjugated estriol, inhibin A. Can also look for nuchal translucency on
Physical fndings:
less Flat nasal bridge
Oblique eye fssures
Single palmar fold ("simian crease")
Short neck ("webbed neck")
Brushfeld spots - white or dark colored spots seen on anterior surface of the
Trisomy 21 patients have an increased risk of multiple complications:
less Congenital cardiac defects: Atrial septal defect, endocardial cushion defect.
GI disorders: Duodenal atresia/stenosis, Hirschsprung disease, celiac
Trisomy 21 patients have weaker immune systems risk of infections
All leukemias, including ALL (acute lymphoblastic leukemia) and AML (acute
myeloid leukemia).
Duchenne<s muscular dystrophy
Basic Sciences Biochemistry Genetics
4 questions

Gene: Dystrophin, on X-chromosome rarely afects girls
less 1 in 3500 boys
The dystrophin links the actin cytoskeleton of smooth, cardiac and skeletal
muscle cells to the extracellular matrix.
Disease phenotype requires mutations at the reading frame level (deletion,
Clinical course: pelvic muscle weakness that ascends
less Look for calf muscle pseudohypertrophy (large calves that are weak) from
muscle replacement with fbrofatty tissue (muscle biopsy for diagnosis)
Patients will use upper extremities to help them stand up when lying down
due to proximal lower extremity weakness: Gower maneuver
Beckers muscular dystrophy: same gene is mutated, but symptoms are less severe
Autosomal Recessive Disorders
Basic Sciences Biochemistry Genetics
2 questions

Cystic fbrosis: A defect in a transmembrane chloride channel results in thickened
mucus secretions, severely afecting function of the pancreatic, pulmonary, and
reproductive systems.
less Most common lethal genetic disease in whites
Gene: CFTR (a chloride channel) on chromosome 7
Diagnosis: + family history, clinical fndings, and sweat test showing
chloride ion in the sweat (due to absorption)
Defective gene results in chloride secretion in lungs, pancreas, liver and GI
tract (causing mucous viscosity) and chloride absorption in the skin, making the
skin taste salty (positive sweat test)
Bacteria stick to viscid mucous and arent cleared infammation, infection
Respiratory tract recurrent Pseudomonas and Staph pneumonias, chronic
bronchitis, bronchiectasis
Pancreas pancreatic insufciency (steatorrhea, malabsorption). Intestinal
tract meconium ileus, obstructive cirrhosis (from bile viscosity)
Mutations in CFTR can cause congenital bilateral absence of the vas
deferens male infertility
Tay-Sachs Disease: A lysosomal storage disease afecting the CNS and normal
growth and development.
less Gene: Hexosaminidase A GM2 ganglioside accumulates in neurons
Characterized by CNS degeneration: mental retardation, amaurosis
(blindness), macular cherry red spot
For other lysosomal storage diseases, see Lysosomal storage diseases.
Phenylketonuria, Alkaptonuria, see Phenylalanine & Tyrosine Metabolism.
Maple syrup urine disease (MSUD). See Branched-chain Ketoaciduria.
Glycogen storage diseases.
+8H (+luorescent in situ hy#ridi=ation)
Basic Sciences Biochemistry Molecular Biology
2 questions

Cytogenetic technique that localizes specifc sequences on chromosomes, hence "in
Fluorescent probes that are complementary to the target sequence are synthesized.
The photo shows probes complementary to the bcr-abl gene
Probes are hybridized to chromosomes in interphase or metaphase
cD0A (Complementary D0A)
Basic Sciences Biochemistry Molecular Biology
1 question

Complementary DNA (cDNA) is DNA generated from an mRNA template
less Accomplished using a reverse transcriptase
cDNA is synthesized from a mature mRNA (post-transcriptional modifcations
are completed and since DNA is more stable than RNA, scientists prefer to store a
library of cDNA rather than mature mRNA)
Because cDNA is made from mRNA, it does not have intron sequences which have
been spliced out of the RNA during processing.
PCR (Polymerase chain reaction)
Basic Sciences Biochemistry Molecular Biology
2 questions

Exponentially copies a desired DNA sequence
less 1) DNA is heated to denature the strands
2) DNA primers are added to the sample, and the sample is cooled
to anneal the primer to some of the sample
3) Taq DNA polymerase (or another heat stable DNAP) elongates the primer,
generating a new copy
The process is repeated; every cycle doubles the number of copies. (8 cycles =
>ectors $ Cloning
Basic Sciences Biochemistry Molecular Biology
2 questions

Cloning: The production of recombinant DNA that can self-perpetuate
Vector: Carrier for the recombinant DNA of interest
less Includes plasmids, BAC (bacterial artifcial chromosomes), viruses (e.g.
Plasmids as vectors in cloning:
less Commercially available plasmids containing multiple cloning sites can be
Restriction enzymes are used to insert the recombinant DNA of interest into
the plasmid
Competent cells (e.g. E. coli) are then used to take up the plasmid. This
process is known as transformation.
Plasmids replicate independently of bacterial replication, unless integrated
into bacterial chromosomal DNA, and can thus be purifed.
In addition to the gene of interest, most plasmids also contain a selection
marker such as a gene for antibiotic (e.g. Ampicillin) resistance to help screen cells.
The bacteria are then grown in selective medium and only cells containing the
plasmid (and thus gene of interest and selection marker) will proliferate.
D0A e6uencing
Basic Sciences Biochemistry Molecular Biology
1 question

DNA sequencing is a method that combines the use of PCR-like amplifcation of the
gene with a mixture of normal deoxynucleotides and fuorescently labeled
less 1) PCR is used to amplify the DNA sample
2) Nucleotides include normal deoxynucleotides (dNTPs). Additionally,
fuorescent dideoxynucleotides (ddNTPs) are available in solution at a much lower
concentration and are randomly incorporated into elongating DNA chains.
Because ddNTPs lack a 3-OH their incorporation terminates DNA elongation
generation of diferent length sequences. The fnal nucleotide is visible due to
fuorescent tag.
3) The varying length DNA chains are electrophoresed and the sequence can
be read
Basic Sciences Biochemistry Molecular Biology
3 questions

Molecular biology technique that checks for the presence of a specifc sequence of
nucleotides or protein in a sample (usually encased in a gel)
Southern Blot: DNA
less 1) DNA samples are separated (via electrophoresis) on a gel
2) The separated DNA is transferred to a flter
3) The DNA is exposed to a labeled DNA probe that anneals to its
4) The labeled probe is visualized, locating the DNA sample of interest
Northern Blot: RNA
less Same as Southern blot, except the sample is RNA, not DNA
The probe remains DNA
Western Blot: Protein
less Similar to the other types of blot, but protein-specifc antibodies are used for
After proteins are electrophoretically separated and transferred to a flter,
a primary antibody (specifc to the protein of interest) is applied
Excess primary antibody is washed of, and secondary antibody (enzyme-
linked, e.g. horseradish peroxidase) is applied. Secondary antibody recognizes and
binds to the primary antibody.
Finally, an appropriate substrate is added to visualize the bands of interest
The western blot is the confrmatory test in a presumed HIV infection.
(ELISA is the screening test).
Southwestern blot: DNA and protein interactions
less Used to study the interaction of DNA with DNA-binding proteins, such as
proteins that regulate transcription.
1) Proteins are separated (via electrophoresis) on a gel
2) Proteins are transferred to a flter
3) Proteins are exposed to radiolabeled known DNA sequences
4) Proteins that bind that sequence will bind the DNA, which can then be
visualized on a flm
Basic Sciences Biochemistry Molecular Biology
1 question

DNA microarray is a glass chip that contains an arrangement of several sample
genes. They are used to measure gene expression in any given cell by taking
advantage of the fact that mRNA (and thus cDNA) binds to its parent DNA.
less DNA oligonucleotides with known sequences are synthesized by machines
and immobilized on the grid.
mRNA from the cell of interest is isolated and used to construct a cDNA
library, which contains fuorescent tags. This forms the mobile probe.
The mobile probe can consist of cDNA, mRNA or DNA.
The fuorescent probe is then incubated on the immobilized sequences and
allowed to hybridize.
The more sample that binds, the greater the degree of fuorescence
represents higher gene expression.
Used to simultaneously profle gene expression of diferent tissues and diseases.
R0Ai (R0A 8nter-erence)
Basic Sciences Biochemistry Molecular Biology
2 questions

dsRNA is always cleaved by human cells presumed to be an antiviral strategy.
This can be exploited to knock out a specifc gene at the mRNA level:
less RNAi uses a naturally occurring mechanism by which small, double-
stranded RNA(dsRNA) guides an enzyme complex that
destroys complementary RNA.
This causes downregulation of gene expression in a sequence-specifc manner.
The dsRNA is processed into 21"23 nt dsRNA which is known as siRNA
(small interferingRNA).
This step is carried out by the enzyme Dicer.
The siRNA then recognizes and binds the complementary strand of mRNA.
With the help of RISC (RNA-induced silencing complex), the target mRNA is
degraded and the gene is efectively silenced.
Alcohol meta#olism
Basic Sciences Biochemistry Nutrition
3 questions

Basic alcohol metabolism (low alcohol concentrations) occurs in hepatocytes and
converts ethanol to acetate.
less In the cytosol, ethanol is oxidized by alcohol dehydrogenase (ADH) to form
acetaldehyde and NADH. The limiting reagent is NAD
. ADH works via zero-order
Acetaldehyde enters the mitochondria and is oxidized by acetaldehyde
dehydrogenase (ALDH) to form acetate and NADH.
Most of the acetate enters the bloodstream, converted to acetyl-CoA by
acetyl-CoA synthase in extrahepatic tissues and used to generate cellular energy.
Methanol, another form of alcohol, is highly toxic, since it is metabolized to
formaldehyde. Ingestions leads to a metabolic acidosis with an increased anion gap.
Methanol formaldehyde (highly toxic) formic acid
The NADH generated from basic alcohol metabolism increases
ratio, which inhibits many important dehydrogenase reactions,
leading to acute and chronic alcohol toxicities.

Both reactions require NAD

, converting it to NADH

Pyruvate is reduced to lactate producing lactic acidosis.

Pyruvate + NADH Lactate + NAD

Oxaloacetate is reduced to malate, which inhibits the TCA cycle. Acetyl-CoA

is then shunted into ketone production leading to ketoacidosis.
Oxaloacetate + NADH Malate + NAD

Pyruvate and oxaloacetate depletion leads to inhibition of gluconeogenesis

and stimulation of fatty acid synthesis, which results in hypoglycemia.

Dihydroxyacetone phosphate is reduced to glycerol 3-phosphate, which

further stimulates fatty acid synthesis.
Dihydroxyacetone phosphate + NADH Glycerol 3-phosphate + NAD

Chronically, protein synthesis is impaired preventing assembly and secretion

of VLDL, causing triglycerides to accumulate in the liver resulting in hepatic fatty
change(hepatocellular steatosis) seen in chronic alcoholics.
Clinical correlation: Fomepizole inhibits ADH and is used as an antidote for
methanol or ethylene glycol poisoning. Disulfram (Antabuse) inhibits ALDH leading
to increased acetaldehyde concentrations and hangover symptoms. It is used in
treatment of chronic alcoholism.
During acute high level alcohol ingestion, alcohol along with NADPH are oxidized
bycytochrome P450 to acetaldehyde and NADP. Cytochrome P450 are present in
the smooth endoplasmic reticulum and have a relatively high Km explaining why
they are only active during high alcohol concentrations.
Ethanol + NADPH + O
Acetaldehyde + NADP + H
less The cytochrome P450 superfamily that metabolized alcohol are part of
the microsomal ethanol system (or MEOS). They have the ability to metabolize 10-
20% of the ethanol to acetaldehyde.
Since the NADH/NAD
is not afected, the toxicities of basic alcohol
metabolism are not seen; however, increased acetaldehyde can cause hepatic and
extrahepatic tissue damage, P450 enzymes can produce reactive oxygen
species also causing cellular damage, and alcohol can divert P450 metabolism of
certain drugs (e.g., barbiturates) leading to drug toxicities.
Basic Sciences Biochemistry Nutrition
1 question

Biological roles of zinc:
less Found in >100 enzymes, serves as a structural ion in transcription factors
("zinc-fnger" motif)
Also plays roles in signal transduction, nucleic acid metabolism, apoptosis
Defciency is usually of nutritional etiology, e.g. bariatric surgery
less Sx: Alopecia, skin lesions, diarrhea
Inherited zinc defciency: acrodermatitis enteropathica (very rare autosomal
recessive disorder)
8nsulin and *lucagon
Basic Sciences Biochemistry Nutrition
10 questions

Insulin is the major anabolic hormone of the body. Glucagon, whose actions
antagonize those of insulin, is the major catabolic hormone of the body.
Insulin is a peptide hormone consisting of an A chain and a B chain linked by two
disulfde bonds.
Insulin is produced in pancreatic cells in the islets of Langerhans.
less Insulin is frst synthesized as preproinsulin.
The signal sequence of preproinsulin directs the nascent peptide to the rough
endoplasmic reticulum (rER).
Proinsulin is formed when the signal peptide is cleaved in the rER.
It is also in the rER that the nascent insulin peptide folds into its native
conformation and the disulfde bonds are formed.
Proinsulin is then transported to the Golgi, where it is cleaved to insulin
and C-peptide.
Insulin and C-peptide are stored in secretory granules until exocytosis is
Increased glucose concentration inside -cells is the primary stimulus for insulin
less Glucose enters the pancreatic cell through the GLUT2 (insulin-independent)
transporter by facilitated difusion. For more about the various glucose transporters,
see https://med.frecracker.me/topics/1229
Inside the cell, glucose is oxidized in glycolysis to ATP, which closes ATP-
sensitive potassium channels on the plasma membrane.
Closure of these potassium channels leads to membrane depolarization.
The depolarization opens voltage-gated [Ca2+] channels, leading to [Ca2+]
Increased intracellular [Ca2+] leads to exocytosis of insulin secretory vesicles,
causing increased insulin in the blood.
Insulin has a short half-life of about fve minutes. Because of its longer half-
life, C-peptideis a good indicator of insulin production and secretion.
Insulin release occurs in two phases.
less The frst phase is rapid and comes from insulin that has already been
synthesized and is stored for quick release.
The second phase of insulin release is dependent on new synthesis of insulin.
Insulin exerts its efect by binding to the extracellular domain of a tyrosine kinase
The activated intracellular domain of the tyrosine kinase receptor
phosphorylates theinsulin receptor substrate-1 (IRS-1) protein.
IRS-1 plays a key role in insulin signal transduction by activating
the Phosphoinositide-3 kinase (PI-3 kinase) pathway and the MAPK pathway.
The PI-3 kinase pathway is responsible for the fusion of vesicles containing
the GLUT4transporter into the membrane of myocytes and adipocytes. Thus, the PI-
3 pathway leads to increased glucose uptake by myocytes and adipocytes. For more
about insulin-dependent and independent glucose transport,
see https://med.frecracker.me/topics/1229
The MAPK pathway regulates gene expression of genes increasing cell
growth and DNAsynthesis.
Finally, the insulin signal is terminated when the insulin-receptor complex is
endocytosed and degraded.
For more about the stimulation, inhibition, and efects of insulin,
Glucagon is a 29 amino-acid peptide hormone.
Glucagon is cleaved from a larger peptide chain in pancreatic -cells of the islets of
The main stimulus for glucagon release is hypoglycemia. The exact mechanism of
glucagon release is still being elucidated.
Glucagon binds to the extracellular side of a G-protein coupled receptor. For more
information on G-protein coupled receptors,
see http://med.frecracker.me/topics/3489.
less The signal is amplifed through an adenylyl cyclase cAMP Protein
Kinase A pathway.
The end result of glucagon signaling is an increase in blood glucose.
+at solu#le vitamins
Basic Sciences Biochemistry Nutrition
5 questions

Vitamins A,D,E,K are fat soluble vitamins that are transported in chylomicrons, and
stored in liver or adipose tissue. Therefore defciencies of fat soluble vitamins can
occur any time fat malabsorption occurs, for example:
- IBD (infammatory bowel disease e.g., Crohns disease, Ulcerative colitis)
- tropical sprue
- pancreatic insufciency
- resected ileum
Vitamin A: functions as a component of visual pigments and in cell diferentiation
less Source: cod liver oil, egg yolks, and dairy products
Vitamin A is used in the treatment of measles.
Defciency: night blindness, squamous metaplasia leading to skin
abnormalities (follicular hyperkeratosis), eye abnormalities (Bitot's spots buildup of
keratin debris in conjuctiva), lung abnormalities (bronchitis, pneumonia)
Excess (result of eating bear liver or isotretinoin therapy): increased
intracranial pressure (papilledema, convulsions), liver toxicity (vitamin A is stored
in the liver), bone pain
Medical uses: tretinoin (all-trans retinoic acid, acid form of vitamin A) topical
medication used for mild acne and psoriasis, also used in APML (acute
promyelocytic leukemia, aka M3 subtype of AML) to induce maturation of leukemic
Before oral isotretinoin (cis retinoic acid) is prescribed for severe cystic acne,
women must have a pregnancy test because high doses of Vitamin A are highly
teratogenic (birth defects include cleft palate, cardiac abnormalities, low IQ scores
and extremely high risk for spontaneous abortions)
Vitamin D2 (ergocalciferol, found in plants) and vitamin D3 (cholecalciferol):
increases intestinal absorption of calcium and phosphorous and renal absorption of
less Source: liver, egg yolk, saltwater fsh, and vitamin D fortifed foods, D3 made
by skin after sunlight exposure (although some foods are now fortifed w/ synthetic
Endogenous vitamin D is produced by photoconversion of 7-
dehydrocholesterol to vitamin D3 in sun-exposed skin (most important source)
Next, vitamin D is hydroxylated in the liver to produce calcidiol (25-
hydroxycholecalciferol) by the P450 system
Calcidiol is then hydroxylated to the active form, calcitriol (1,25-
dihydroxycholecalciferol) in the kidneys by the enzyme 1--hydroxylase
Causes of vitamin D defciency:
- Renal failure (most common cause): defciency of 1--hydroxylase
- Inadequate exposure to sunlight: decreased synthesis of vitamin D3
- Fat malabsorption: cannot reabsorb fat soluble vitamins
- Chronic liver disease: unable to carry out frst hydroxylation of vitamin D3
- Enhanced liver cytochrome P450 system (e.g. alcohol, phenytoin, barbiturates):
increased conversion of 25-hydroxycholecalciferol into inactive metabolite
- Primary hypoparathyroidism: need PTH to enhance activity of 1--hydroxylase
- Type 1 vitamin D-dependent rickets: defciency of 1--hydroxylase
- Type 2 vitamin D-dependent rickets: defciency of vitamin D receptors
Defciency: rickets in children (craniotabessoft skull, rachitic rosaryexcess
osteoid in epiphysis, defective growth plates causing growth retardation, bowed
legs),osteomalacia in adults (pathologic fractures, excess osteoid, bowed legs)
Excess (taking megadoses of vitamin D or medical causes such as
sarcoidosis): hypercalcemia, renal calcium stones
Vitamin E: antioxidant and scavenger of free radicals that protects polyunsaturated
fats and fatty acids in cell membranes from lipid peroxidation and protects LDL from
less Source: abundant in fruits, vegetables, and grains
Defciency (rare): primarily occurs in children with cystic fbrosis and
abetalipoproteinemia (hemolytic anemia, peripheral neuropathy, posterior column
degeneration, retinal degeneration, myopathy)
Excess (taking megadoses of vitamin E): decreased synthesis of vitamin K-
dependent coagulation factors in the liver, thereby working synergistically with
Vitamin K ("Koagulations-Vitamin" in German): gamma-carboxylates glutamate
residues and thereby activates:
- 4 pro-coagulants: clotting factors IX, X, VII, II (prothrombin), ("1972")
- 2 anti-coagulants: protein C, protein S
less Source: green leafy vegetables (supply K
, phylloquinone) and bacterial
synthesis in colon (supply K
, menaquinone).
Neonatal intestines are sterile and breast milk has an inadequate supply of
vitamin K given vitamin K injection at birth to prevent hemorrhagic disease of the
Defciency (broad spectrum antibiotics, warfarin therapy, newborns, fat
malabsorption): prolonged PT (prothrombin time), gastrointestinal bleeding
Excess (rare): hemolytic anemia and jaundice in newborn if mother receives
excess vitamin K
>itamins o- anemia
Basic Sciences Biochemistry Nutrition
2 questions

Both are water soluble: folate & B
Folate: needed for thymine and purine synthesis, especially in states of rapid cell
division (pregnancy, erythropoiesis)
less Defciency neural tube defects & megaloblastic anemia
Some conditions/actions result in an increased need for folate:
- pregnancy and lactation
- smoking
- malabsorption, e.g., celiac disease, alcoholism
Numerous medications can interfere with folate utilization, including the
Metformin (sometimes prescribed to control blood sugar in type 2 diabetes)
Sulfasalazine (used to control infammation associated with Crohns disease,
ulcerative colitis and rheumatoid arthritis)
Triamterene (a diuretic)
Anti-cancer drugs: 5-fuorouracil, methotrexate
Vit B
(cobalamin) is a cofactor for
Methylmalonyl CoA mutase converts methylmalonyl CoA to succinyl CoA
Methionine synthase transfers methyl groups to homocysteine to form
less Synthesized by bacteria (cant be made by plants or animals)
Defciency macrocytic anemia and neuropathy. Occurs only in:
malabsorption,absence of intrinsic factor, or absence of terminal ileum. Vegan diet
has also been linked to B
Peripheral neuropathy: subacute combined degenerationdemyelination of
the dorsal columns leading to loss of pressure/touch/vibratory sense in the
extremities. The lateral corticospinal tract can also be afected, causing UMN type
lesion with spastic paralysis.
Absence of intrinsic factor: can be due to pernicious anemia (atrophic
gastritis) or gastric resection
Absence of terminal ileum: can be damage due to Crohns disease or due to
Diagnosis of folate and B
less Histology: the megaloblastosis caused by folic acid defciency cannot be
diferentiated from that caused by B
defciency; hypersegmented neutrophils may
be seen in both
Laboratory tests may include:
1) Serum folate. Levels <3 g/L indicate defciency. Note that 2-5 % of the
healthy population has folate levels of 2.5 g/L or below, so serum folate cannot be
used to make a defnitive diagnosis.
2) Erythrocyte (RBC) folate. Refects tissue stores of folate. A level of <140
g/L indicates defciency.
3) Serum vitamin B
. Note that patients with subclinical defciency might
have normal B
4) Serum homocysteine. Elevated in both B
and folate defciency
(reference range 5-16 mmol/L)
- levels can also be afected by B
levels, renal insufciency
5) Serum methylmalonic acid (MMA). Sensitive test for B
defciency. Can
be used to diferentiate folate and B
defciency. MMA levels (reference range 70-
270 mmol/L) are elevated in B
defciency only.
Tx: folate or B
less The hematologic sxs of B
defciency can be corrected by folate replacement,
e.g., in the case of a misdiagnosis. However, the neurological sxs will persist.
>itamin C
Basic Sciences Biochemistry Nutrition
3 questions

Ascorbate. Water soluble, cofactor for enzymatic reactions
Anti-oxidant properties, guards against oxidative stress
Vit C serves as a cofactor for prolyl-4-hydroxylase and lysyl hydroxylase, an enzyme
involved in collagen synthesis.
less Stable collagen cannot form without proline and lysine hydroxylation. This
hydroxylation take place in the ER.
Hydroxylation of proline secures the collagen chains in triple helix formation.
The subsequent hydroxylation of lysine is required for cross-linking.
Defciency of lysyl hydroxylase: Ehlers-Danlos Syndrome Type 6
Other roles:
less Cofactor for dopamine hydroxylase (dopamine norepinephrine)
Required for reduction of iron from Fe
, allowing absorption in the
Defciency scurvy.
Malnutrition@ Marasmus and
Basic Sciences Biochemistry Nutrition
5 questions

Top of Form
Bottom of Form
There are three serious forms of energy
malnutrition: kwashiorkor, marasmus and mixed marasmua-kwashiorkor.
less Kwashiorkor and marasmus are distinguished symptomatically primarily
by edema. Patients with kwashiorkor are edematous. Patients with marasmus tend
not to have edema.

Kwashiorkor (Ghanaian word meaning rejected one) is malnutrition
with inadequate protein but adequate carbohydrates.

less The typical presentation of kwashiorkor is a child with a swollen belly due to ascites
(accumulation of fuid in the peritoneal cavity) and an enlarged, fatty liver. Patients
may also have normal or near normal height and weight, anasarca, pitting edema of
the lower extremities, dry, atrophic, peeling skin, dry hair that falls out easily, and
dilated intestinal loops.
Patients with kwashiorkor almost always have anorexia.
In some areas, kwashiorkor presents between ages 1-3 when a child that
received enough protein while breastfeeding is displaced by a new child.
Decreased protein consumption leads to decreased protein production.
Because of the decreased protein production the capillary oncotic pressure
decreases and this leads to tissue edema in kwashiorkor. The following mnemonic
might be useful: You need water towash kwashiorkor has excess water (edema).
The fatty liver in kwashiorkor is due to decreased apolipoprotein synthesis.
Because of decreased apolipoprotein synthesis, fats that would be exported from the
liver by apolipoproteins are trapped.
In contrast to kwashiorkor, which is caused by insufcient protein intake despite
adequate calories, marasmus (from Greek meaning dying away or withering)
results frominadequate protein and overall calories.
less Marasmus presents with broomstick extremities due to muscle
wasting/breakdown for energy production. There is no visible fat and rarely any
edema. A useful memory device for marasmus is: Marasmus causes
extreme Muscle wasting. Patients with marasmus may also present with decreased
height and weight for age, thin, dry skin, bradycardia, hypotension, hypothermia,
redundant skin folds, and thin, sparse hair.

Mixed marasmus-kwashiorkor is a kwashiorkor-type picture (edema, anorexia,
dermatitis) superimposed on a patient already sufering from marasmus, triggered by
an infectious illness.
The treatment of severe energy malnutrition consists of an initial stabilization phase
(frst week), followed by a rehabilitation phase (two to six weeks), and a follow-up
less The stabilization phase of treatment for severe malnutrition includes treatment
of hypoglycemia, hypothermia, and dehydration, as well as initiation of feedings.
There is also evidence for use of empiric antibiotics in this phase. Vitamin
replacement begins as well, with the exception of iron.
Iron is not given during the stabilization phase because of the (negative)
efect of free iron on oxidative stress.
During the rehabilitation phase of treatment for severe malnutrition, feedings
and vitamin supplementation continue, with the addition of iron. Training of the
patient's caregiver to provide adequate follow-up care also begins during this period.
During the follow-up phase of malnutrition treatment, physical and
psychological parameters are monitored.
Basic Sciences Biochemistry Nutrition
2 uestions
" #ram of fat yiel$s % &cal 'hi#hest(
" #ram of protein or car)ohy$rate yiel$s * &cal
B +itamins
Basic Sciences Biochemistry Nutrition
, uestions
-ater solu)le. meta)olic +itamins B" throu#h B/ 'no B*0 a$enine is B* an$ isn1t
consi$ere$ a B +itamin anymore(
2it B" 'thiamine(. one of its $eri+ati+es3 thiamine pyrophosphate3 is a cofactor for se+eral
$ehy$ro#enase en4ymes that 5or& on 6-&etoaci$s 'e7#7 pyru+ate3 6-&eto#lutarate(
8eficiency 9 )eri)eri3 -ernic&e-:orsa&off syn$rome
Beri)eri has a $ry 'neuropathy( an$ 5et 'hi#h output heart failure( component7
-ernic&e-:orsa&off is a syn$rome of -ernic&e1s encephalopathy 'tria$ of confusion3
ophthalmople#ia3 an$ ataxia( an$ :orsa&off1s psychosis 'memory loss3 confa)ulation an$
personality chan#e(7
2it B2 'ri)ofla+in(. &ey component of F;8 an$ F<N
8eficiency 9 an#ular cheilitis 'crac&e$ an#les of the mouth(3 #lossitis
2it B= 'niacin(. precursor for N;8>3 N;83 N;8?3 N;8@ an$ N;8@>
<a$e from tryptophan in a process usin# +itamin B,
8eficiency 9 #lossitis3 pella#ra in se+ere $eficiency '$iarrhea3 $ermatitis3 $ementia(0
occurs in carcinoi$ syn$rome )Ac tryptophan is shunte$ to ma&e serotonin0 prolon#e$
IN> 'isonia4i$( use also can lea$ to niacin $eficiency )Ac it B +it B, le+els7
>artnup $isease. autosomal-recessi+e $efect in intestinal an$ renal transporters for
neutral amino aci$ 9 causes tryptophan excretion in urine 9 lea$s to pella#ra
2it BC 'pantothenic aci$(. nee$e$ to form coen4yme-; 'Co;(3 an essential +itamin
8eficiency '+ery rare( 9 a$renal insufficiency an$ hepatic encephalopathy
2it B, 'pyri$oxine(. acti+e form is pyri$oxal phosphate7 This is a cofactor in
transamination ';STA;DT(3 $eamination3 $ecar)oxylation 'example. #lycine ? succinyl-
Co; 9 aminole+ulinic aci$(7
Nee$e$ for B= synthesis7 @atients ta&in# isonia4i$ reuire supplementation of +itamin
@yri$oxal phosphate is nee$e$ to pro$uce E;B;3 serotonin3 $opamine3 nora$renaline3
an$ a$renaline7
8eficiency 9 peripheral neuropathy an$ con+ulsions 'role in neurotransmitter synthesis(
Toxicity 9 peripheral neuropathy presentin# 5ith )urnin#3 num)ness an$ tin#lin# of the
han$s an$ feet
2it B/ ')iotin(. cofactor in se+eral car)oxylation reactions
@yru+ate 9 oxaloacetate
;cetyl-Co; 9 malonyl-Co;
@ropionyl-Co; 9 methylmalonyl-Co;
8eficiency. $ermatitis3 alopecia7 Biotin $eficiency is rare7 Causes inclu$e excessi+e
consumption of ra5 e## 5hites3 prolon#e$ oral anti)iotic use3 anticon+ulsant use
'phenytoin3 primi$one3 an$ car)ama4epine(3 or )iotin-$eficient parenteral nutrition7
Basic Sciences Biochemistry Nutrition
2 uestions
Cachexia is the loss of )o$y 5ei#ht an$ muscle mass often seen in patients 5ith cancer3
;I8S3 multiple sclerosis an$ other $iseases7
<alnutrition syn$romes such as :5ashior&or an$ <arasmus can also cause cachexia7
Cachexia patients are not tryin# to lose 5ei#ht )ut they ha+e a si#nificant loss of appetite
an$Aor increase$ cata)olic processes 5ith impaire$ ana)olic processes that are li&ely
cause$ )y an un$erlyin# mali#nant $isease7
There is no clear un$erstan$in# for the exact cause of cachexia in the $iseases state$3 )ut
there seems to )e a connection 5ith inflammatory cyto&ines3 such as tumor necrosis
factor-alpha 'nic&name$ cachexin3 TNF-6(3 interferon #amma 'IFN-F(3 an$ interleu&in ,3
'ID-,(3 5hich lea$s to neuroen$ocrine si#nalin# for $ecrease$ ana)olism an$ increase$
@atients 5ith cachexia exhi)its a$ipose loss $ue to increase$ lipolysis3 muscle loss $ue to
increase$ proteolysis an$ $ecrease$ protein synthesis3 an$ sic&ness )eha+iors such as
anorexia3 fati#ue3 an$ $epression7
Some cancer patients 5ho ha+e cancer in$uce$ cachexia as 5ell as those that suffer from
anorexia ner+osa sho5 hi#h plasma le+els of Ehrelin7
Nearly C!G of cancer patients suffer from cachexia7 Don# term mortality an$ uality of
life is impaire$ in con$itions 5ith cachexia7
There is no 5i$ely accepte$ $ru#s to treat cachexia7