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SUBJECT: BIOCHEMISTRY
 
TOPIC: CARBOHYDRATE METABOLISM 3
 
LECTURER: DR. ESPERANZA UY
 
DATE: DECEMBER, 2010
 
 
ALTERNATIVE PATHWAY FOR CARBOHYDRATE -This pathway is used as an alternative when there is a high
METABOLISM (for clearer images, pls. refer to the ppt) demand for NADPH which is required in FATTY ACID
SYNTHESIS

Question: How many ATPs do you need in the conversion of


FRUCTOSE-6-PHOSPHATE to PYRUVATE? TISSUE DISTRIBUTION
Answer: 1 ATP only since we have already bypassed the -Demand for NADPH
major regulatory pathway of glycolysis which is
• Biosynthetic pathways
PHOSPHOFRUCTOKINASE 1
-fatty acid synthesis (liver, adipose, mammary)
- It is not recommended to carbo load on fructose
since it cannot be controlled (Phosphofructokinase -cholesterol synthesis (liver)
regulates the amount that the body requires) -steroid hormone synthesis (adrenal, ovaries, testes)
Question: How many ATPs do you need in the conversion of • Detoxification (Cytochrome P450 system)  liver
SUCROSE to PYRUVATE? (It will come out in the exam.)
• Reduced glutathione as an antioxidant in RBC to
Answer: 3 ATPs. Sucrose is formed by glucose and fructose. maintain the shape of RBC
From glucose to pyruvate, 2 ATPs are needed. For fructose
to pyruvate, 1 ATP is required. In conclusion, 3 ATPs are -preventing hemolysis
required since 2 ATPs are needed for the breakdown of • Generation of superoxide (neutrophils)
glucose and 1 ATP is needed for the breakdown of fructose
**All these conditions will cause an INCREASE in NADPH
demand which can lead to the hexose monophosphate
ALTERNATIVE PATHWAY OF METABOLISM shunt
-Pentose Phosphate Pathway
-Uronic Acid Pathway FUNCTIONS
-Fructose Metabolism -Source of:
-Metabolism of Galactose 1. NADPH + H+  for REDUCTIVE BIOSYNTHETIC
PROCESSES (synthesis of cholesterol, fatty acids, steroid
-Sorbitol Pathway hormones)
-Ethanol Metabolism -more important function
-Hexosamine Formation 2. Pentoses  for nucleotides, nucleic acids and
coenzymes
 HEXOSE MONOPHOSPHATE SHUNT
-aka PENTOSE PHOSPHATE PATHWAY CHARACTERISTICS
-an ALTERNATE ROUTE for glucose oxidation -neither consumes nor produce ATP
-not the main main pathway -that is why it is not the major pathway
-major pathway is GLYCOLYSIS -branches off glycolysis at G6P (common to both glycolysis
and HMP shunt)
-found in the CYTOSOL
-most important molecule in this pathway is GLUCOSE-6-
-active in: liver, adipose tissue, lactating mammary gland,
PHOSPHATE
adrenal cortex and RBC
-glucose should first be converted to glucose-6-
-common among these organs: all are secretory organs,
phosphate before entering the hexose monophosphate
except for RBC
shunt
-5 carbons are produced in this pathway
-GLUCOKINASE in the liver and HEXOKINASE in the
-the 1 carbon will be produced as CO2 muscles  enzymes needed for the conversion of glucose
-the only pathway that produces CO2 in cytoplasm to glucose-6-phosphate

-carbon dioxide is normally produced in the -common enzyme in glycolysis and HMP shunt
mitochondria but in this pathway, the carbon dioxide is in -re-entry is at FRUCTOSE-6-PHOSPHATE
the cytoplasm
-PHOSOHEXOSE ISOMERASE enzyme required for the
-NADPH is important in this pathway (PPP is the major conversion of glucose-6-phosphate to fructose-6-phosphate
source of NADPH in cells)

BIOCHEMISTRY: CARBOHYDRATE METABOLISM 3 Page 1


CHARACTERISTIC DIFFERENCE WITH GLYCOLYSIS NON-OXIDATIVE PHASE
-oxidation utilizes NADP rather than NAD -starts in the ribulose-5-phosphate molecule
-carbon dioxide is a characteristic product of HMP shunt -reversible (can go anywhere)
-only source of carbon dioxide in the cytoplasm -rearrangement of sugars to enter glycolytic pathway
-increase demand for NADP happens where there is an -provides a pathway for recycling excess pentoses
increase in demand for fatty acid synthesis
-NO ATP is generated
IMPORTANT ENZYMES: (refer to the diagram below as well)
1) 3-epimerase
PENTOSE PHOSPHATE PATHWAY HAS 2 PHASES -to convert ribulose-5-phosphate to xylulose-5-phosphate
A. Glucose-6-Phosphate is oxidized and
**epimerase  translocation in only carbon
decarboxylated to a pentose sugar (generates 2
moles of NADPH per G6P oxidized) -irreversible
**GLUCOSE-6-PHOSPHATE  substrate used in HMP 2) Ketoisomerase
shunt -to convert ribulose-5-phosphate to ribose-5-phosphate
-fructose-6-phosphate and glycogen can also be
used as a substrate but they should first be converted
to glucose-6-phosphate 3) Transketolase
B. Interconversions of pentose phosphates lead to -will transfer 2 carbon atoms from xylulose-5-phosphate
intermediates of glycolysis – reversible to ribose-5-phosphate to form glyceraldehyde-3-phosphate
and sedoheptulose-7-phosphate
**FRUCTOSE-6-PHOSPHATE and GLYCERALDEHYDE 
important intermediates of glycolysis -important coenzyme: THIAMIN (Vit. B1)
-important cofactor: MAGNESIUM (Mg+)
OXIDATIVE PHASE -source: unpolished rice
-irreversible ** blocking transketolase activity may lead to pentosuria (a
pentose sugar, usually xylulose, is found in urine
-generates NADPH  2 moles per glucose oxidized
** thiamine deficiency affects sedoheptulose 7 phosphate
-3 reactions  starts with glucose-6-phosphate and results since it affects transketolase activity too
in ribulose-5-phosphate

4) Transaldolase
**3 glucose-6-phosphate molecules are required
-will transfer 3 carbon atoms
-sedoheptulose-7-phosphate is a very unstable
**NADPH producing reactions/ important enzymes needed compound that is why it will be acted upon by
in the oxidative phase: TRANSALDOLASE to form erythrose-4-phosphate and
• Glucose-6-phosphate dehydrogenase fructose-6-phosphate which will then be converted to
glucose-6-phosphate through the enzyme
-coenzyme: NADP PHOSPHOHEXOSE ISOMERASE
-water is also needed to be reduced to NADPH + H
-product: 6-PHOSPHOGLUCONATE **Another TRANSKETOLASE (similar with the transketolase
• 6-phosphogluconate dehydrogenase mentioned above) will act on xylulose-5-phosphate to be
converted to FRUCTOSE-6-PHOSPHATE and
-NADP is required in this step
GLYCERALDEHYDE-3-PHOSPHATE
-decarboxylates 6-phosphogluconate which RELEASES
CARBON DIOXIDE from the cytoplasm
5) Phosphotriose isomerise
-product: ribulose-5-phosphate
-converts glyceraldehydes-3-phosphate to fructose-1,6-
bisphosphate
Question: Why do we need 3 glucose-6-phophate
molecules?
6) Fructose-1,6-bisphosphatase
Answer: To produce 2 fructose-6-phosphate molecules and
1 glyceraldehyde molecule through the interconversion of -also found in GLUCONEOGENESIS because it uses the
the pentoses fructose-1,6-bisphosphate as a substrate
-converts fructose-1,6-bisphosphate to fructose-6-
phosphate
**all the other enzymes are also found in the glycolysis
pathway except the FRUCTOSE-1,6-BIPHOSPHATASE which
is found in the gluconeogenesis pathway

BIOCHEMISTRY: CARBOHYDRATE METABOLISM 3 Page 2


GLUCOSE-6-PHOSPHATE DEFICIENCY
-problem in glucose-6-phosphate dehydrogenase enzyme
-not evident in most cases
-common in the Philippines (usually affects males, while
women are carriers)
-induced by drugs:
 Antimalarials
 sulfa antibiotics
 antipyretics (aspirins,etc.)
-acute haemolytic anemia is due to decreased NADPH
production
-HMP is the major pathway of NADPH production in the red
blood cell (G6PD deficient RBCs = more prone to hemolysis)
-NADPH is responsible for maintaining glutathione in its
reduced state
-reduced glutathione is necessary for the integrity of the
erythrocyte membrane, thus rendering enzyme-deficient
red cells more susceptible to hemolysis by a wide range of
compounds
**1/2 glucose-6-phosphate glyceraldehyde -exposure to anti-malarial drugs (Primaquine) results in
increased cellular production of superoxide and hydrogen
**3 glucose-6-phosphate molecules are required, 6 peroxide (Primaquine sensitivity)
molecules of NADPH + H+ are produced and 3 CO2 from
the cytoplasm are released to have the product, xylulose-5- -other chemicals known to increase oxidant stress
phosphate  irreversible -sulfonamides (antibiotic)
**the reversible process will ultimately produce 2 -aspirin and NSAIDs
molecules of glucose-6-phosphate and 1 molecule of
glyceraldehydes. All of the three molecules will enter the -quinidine and quinine
glycolytic pathway -naphthalene (mothballs)
-entry point GLYCERALDEHYDE-3-PHOSPHATE -fava beans (vicine and isouramil)
DEHYDROGENASE
**defiency in thiamine (VIt.B1)  problem in transketolase
enzyme. This can cause hemolytic anemia and jaundice ROLE OF NADPH IN THE RBC
1.Production of superoxide
2.Hb-Fe2+-O2  Hb-Fe3+ + O2-
OVERALL EQUATION:
3.O2- + 2H2O  2H2O2
Glucose -6- PO4 + 2 NADP+ + H2O ↔
4.Both O2- and H2O2 can produce reactive free radical
ribose -5- PO4 + 2NADPH + 2 H+ + CO2
species, damage cell membranes and cause hemolysis

REGULATION
DETOXIFICATION OF SUPEROXIDE ANION AND HYDROGEN
1.Glucose-6-phosphate dehydrogenase PEROXIDE (H202)
-first step; where regulation acts most -Antioxidant enzymes
-rate limiting step -superoxide dismutase
-most important regulator -glutathione peroxidise
-abundant in the RBC -if the glutathione is in the reduced state, hydrogen
2.Allosteric regulation peroxide will be converted to water

-feedback inhibited by NADPH -glutathione reductase

-increase amounts of NADPH will cease the HMP shunt


-increased NADPH also entails and increased amount
of H ion which decreases intracellular pH (becomes more
acidic); can shrink and wrinkle the cell
3.Inducible enzyme
-induced by insulin
-also found in the glycolytic and glycogenesis pathway
-increased amounts of insulin can induce the HMP shunt
Question: In the formation of lactate from glucose-6-
(since much glucose needs to be distributed)
phosphate, how many ATPs are needed?
Answer: 2 ATPs

BIOCHEMISTRY: CARBOHYDRATE METABOLISM 3 Page 3


 THE URONIC ACID PATHWAY GLUCORONIDES FORMATION
-also encountered in HEME METABOLISM (for more details,
see Bilirubin Conjugation)
-catalyzes the conversion of glucose to glucuronic acid,
ascorbic acid and pentoses
**GLUCORONIC ACID  to conjugate bilirubin so that it
can be more soluble in water
-also an alternative oxidative pathway for glucose
-does not lead to ATP formation GLUCURONIC ACID: PHYSIOLOGICAL SIGNIFICANCE OF
GLUCURONIDE FORMATION
G6P  G1P  UDP-Glucose  UDP- Glucoronic -glucuronide formation is important during detoxification,
Acid Glucoronic Acid  L-Gulonic Acid (a direct steroid excretion, and bilirubin metabolism
Vit. C precursor as well)  3-Keto-L-Gulonic Acid
-the reaction is catalyzed by UDP-glucuronyl transferase,
(+CO2) L-Xylulose Xylitol (usual candy which may take several days to 2 weeks after birth to
component)  D-Xylulose  D-Xylulose-5-P become fully active in humans
-babies are always exposed to the sun to hasten the
**conversion of glucose-6-phosphate to glucose-1- process of bilirubin solubility
phosphate was also encountered in glycogenolysis
**PENTOSURIA  blocks the L-xylulose  xylitol pathway  FRUCTOSE METABOLISM
-causes the presence of xylulose in the urine ESSENTIAL FRUCTOSURIA
**xylulose-5-phosphate will then enter the HMP shunt -fructokinase is deficient in essential fructosuria, a benign
**The L-gulonate has 2 pathways: 1 for the formation of asymptomatic metabolic anomaly; autosomal recessive
xylulose-5-phosphate and the other for the formation of -following intake of fructose, blood and urinary fructose
ascorbic acid. levels of affected individuals are unusually high; however,
-However, the formation of ascorbic acid is not possible 90% of their fructose intake is eventually metabolized
in higher forms of life since the L-gulonolactone 2-
ketogulonolactone pathway is BLOCKED. So in humans, the
only possible route is for it to be converted to xylulose-5-
phosphate which will now enter the HMP shunt
-this means that Vitamin C cannot be produced by the
body and supplements should be taken in to supply the
body with Vit.C
-high amounts of Vit.C in the body can lead to stones

**Fructose can also be a source of glucose through the


enzyme PHOSPHOFRUCTOISOMERASE
**hexokinase is still needed to form fructose-6-phosphate
**Aldolase A used in glycolysis
**Aldolase B  used in fructose metabolism
**Fructokinase  deficient in essential fructosuria
-no formation of fructose-1-phosphate and instead,
fructose from diet will be converted in the glycolysis
pathway (not that significant)
BIOCHEMISTRY: CARBOHYDRATE METABOLISM 3 Page 4
HEREDITARY FRUCTOSE INTOLERANCE GALACTOSEMIA
-deficient aldolase B enzyme; autosomal recessive -inability to transform galactose into glucose
-characterized by severe hypoglycaemia after ingestion of -individuals with this defect are unable to metabolize the
fructose, and prolonged ingestion by affected young galactose derived from lactose (milk sugar) to glucose
children may lead to death metabolites
-fructose-1-phosphate aldolase is deficient and fructose 1- -can lead to cataract formation, growth failure, mental
phosphate accumulates intracellularly retardation or death from liver failure
-causes cataract formation -may be due to deficiency of:
-will eventually go to the glycolytic pathway -GALACTOKINASE  leads to cataract formation
-GALACTOSE-1-PHOSPHATE URIDYLTRANSFERASE
leads to severe disease (liver disease)
**ALDOSE REDUCTASE which is abundant in the lens, liver,
mammary glands and kidneys
-through the NADPH from HMP shunt converts galactose
to GALATITOL which can cause cataracts
-not a significant enzyme, but only becomes important if
galactose levels are very high and a deficiency in
galactokinase
- Aldose Reductase Inhibitors = known side effects are
severe cardiovascular and GIT problems

 METABOLISM OF GALACTOSE
-from LACTOSE
-lactose  glucose + galactose
-abundant in human milk
-UDP-galactose is also formed from free galactose derived
from hydrolysis of lactose in the intestinal tract
-galactose is phosphorylated by galactokinase and ATP to
yield galactose-1-phosphate
-galactose-1-phosphate uridyltransferase froms UDP-
galactose from galactose 1-phosphate displacing glucose
1-phosphate from UDP-glucose

> Classic Galactosemia – more severe than


galactosemia deficiency; patient may die at womb

 SORBITOL / POLYOL PATHWAY


-not found in the liver
-active in those tissues that are not insulin-sensitive
-lens
-peripheral nerves
-renal glomeruli
-maybe involved in the pathogenesis of diabetic cataracts
and diabetic peripheral neuropathy
**1 ATP is required to form GALACTOSE-1-PHOSPHATE -can have effects on the liver, lens and seminal vesicle (can
lead to infertility)
**galactose-1-phosphate uridyl transferase came from
UDP-glucose from GLYCOGENOLYSIS PATHWAY -found in the cytosol
-blocked in galactosemia **NADPH is needed

BIOCHEMISTRY: CARBOHYDRATE METABOLISM 3 Page 5


 METABOLISM OF HEXOSAMINE OR AMINO SUGARS
-another mechanism in diabetic patients
-JUST REMEMBER: from glycogen, glycosaminoglycans,
sialic acid, gangliosides and glycoproteins in the brain can
be formed

COMPLEX POLYSACCHARIDES
-Glycoproteins
-Proteoglycans
**sorbitol dehydrogenase is not a very important enzyme
but only becomes essential if there is an increased amount
of glucose in the body GLYCOPROTEINS
**sorbitol pathway is NOT FOUND IN THE LIVER -conjugated proteins containing one or more saccharides
LACKING A SERIAL REPEAT UNIT and are bound covalently
**active in tissues that are not insulin sensitive
to a protein
**”UNIFYING PATHWAY OF DIABETICS”
-important in the biological functions of the membrane
**sorbitol attracts a lot of water
-constitutes of the mucus
-IMPORTANCE: lubrication and protection of the tissues
Night: Glycogenolysis: Glucose Fasting  inactive sorbitol lining the respiratory, GIT, and female reproductive system
pathway = clear eyesight
-examples: hormones, plasma proteins
Day: Gluconeolysis: Glucose Usage  active sorbitol
pathway = unclear eyesight (due to trapping in lens)
PROTEOGLYCANS
-contains 95% or more of carbohydrates
-carbohydrate chains are called GLYCOSAMINOGLYCANS or
MUCCOPOLYSACCHARIDES
-present in connective tissues
-6 classes:
-chondroitin sulfate
-dermatan sulfate
-keratin sulfate
-heparan sulfate
-heparin
-hyaluronate

GLYCOSAMINOGLYCANS (GAGs)
Common Features
1. GAGs are made up of dissacharide repeating units,
hexosamine and a uronic acid; highly (-) charged
2. they contain sulfate groups linked by ester bonds to
 ETHANOL METABOLISM certain monosaccharides orby amide bonds to the
amino group of glucosamine
Oxidation to acetate in the liver
3. only hyaluronate is not sulphated and is not
-ethanol is oxidized in the liver by CYTOSOLIC ALCOHOL attached to protein
DEHYDROGENASE to acetaldehyde
4. the carboxyls of uronic acids and the sulfate groups
-the acetaldehyde is further oxidized to acetate by contribute to the highly charged nature of GAGs
MITOCHONDRIAL ALDEHYDE DEHYDROGENASE
5. predominantly components of the extracellular
-much of the acetate produced from ethanol leaves the matrices and cell surfaces, and they participate in
liver and is converted by acetyl coA, which can be used to cell adhesion and signalling
provide energy via the TCA cycle
**GAGs are destroyed in diabetic nephropathy
-alcohol will be used for ATP production
-acetyl coA
may also be -------------------------------------END OF TRANX-------------------------------------
formed in the   GOODLUCK ON YOUR EVALUATIONS, BATCH 2014!  
liver and used
as a precursor
for lipid
biosynthesis

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