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Lysosomal Degradation
Lysosomes contain around 50 hydrolytic enzymes
including a variety of proteases.
Degrades proteins with KFERQ sequence. If you
have a protein with this sequence, it is easily
degraded by the lysosome.
K
Lysine
F
Phenylalanine
E
Glutamic Acid
R
Arginine
Q
Glutamine
Ubuiquitin
A 76-residue monomeric protein known for its
ubiquity and abundance.
If the N-terminal is:
Methionine or Serine cannot be degraded by
Ubiquitin (Retarded)
Aspartic or Arginine faster degradation
(Accelerated)
OVERALL SOURCES AND UTILIZATION OF AMINO ACIDS
2 sources of CHONs in the body:
1. Exogenous
o Diet after digestion of proteins
amino acids
2. Endogenous
o Amino acids synthesized by the liver,
which are the NON-essential amino acids
o Degradation of tissue proteins (protein
turnover) contributes to amino acid
pool
Functions of Amino Acids
1. The most important function of amino acids is for
you to use them to synthesize all the proteins that
you need (enzymes, hemoglobin, collagen,
plasma proteins, etc).
2. Synthesize essential non-protein nitrogenous
substances (these are not CHONs but needs
amino acids in order to be synthesized).
E.g.
Purines and pyrimidines require Asp, Gly and Gln
Gly gives C4 C5 N7
Gln gives N3 N9
Asp gives N1
Porphyrins need Glycine.
Some Vitamins require amino acids (Folic acid
requires Glu)
Creatine (tripeptide) Lys,Arg, Met
Glutathione Gly, Cys. Glu
PROTEIN DIGESTION
Mouth no enzyme acting on proteins
Stomach pepsin
Small intestines pancreatic enzymes (Trypsin,
Chymotrypsin, Carboxypeptidase, Elastase)
AMINO ACID
Ala
Glu
Asp
Gly
His
ITS CORRESPONDING
KETO ACID
Pyruvate
Alpha ketoglutarate
Oxaloacetate
Glyoxylic acid
Uroconic acid
Oxidative Deamination
Enzymes involved:
1. Glutamate dehydrogenase
Converts Glu to alpha ketogluratate
most active enzyme
o Glutamic acid is the MOST ACTIVE amino
acid
Found in almost all parts of the body
When you reverse the reaction, the alphaketoglutarate accepts the amino group to
form back the amino acid
o Alpha-ketoglurate is the MOST ACTIVE
amino group acceptor
2.
3.
2.
Transamination
Major process for removing nitrogen from amino
acids
Transfer of amino group from the original amino
acid to keto acid
*Keto acid is a substance without amino group.
Keto acid + amino group = AMINO ACID
Amino acid Amino group = KETO ACID
Every transamination, there is formation of a new
amino acid
Enzymes for transamination: AMINOTRANSFERASE
or TRANSAMINASES
o When these enzymes are used, new
amino acids can be synthesized
depending on the acceptor of the
amino group.
The usual acceptor is ALPHA-KETOGLUTARATE;
therefore, the usual amino acid formed is GLU.
The transfer of amino group requires a carrier.
Pyridoxal PO4/VitB6 PO4
o PLP
o carrier of the amino group or the coenzyme for transamination
AMMONIA
Slurring of speech
Convulsive seizures
Unconsciousness
Comatose
Death
2.
Glutamine formation
Major means by which the BRAIN detoxifies
ammonia.
BRAIN: most sensitive to ammonia
Once Ammonia reaches the brain, it will
react with the glutamic acid in the brain
Glutamine (through the enzyme Glutamine
synthetase) goes to the kidney once in
the kidneys, it will be converted back to
glutamic acid + NH3 (through the enzyme
Glutaminase) NH3 will go out in the urine.
There are vitamins with glutamic acid (e.g.
Glutafoss). There is no need to take in these
because the body can already synthesize
Glu unless you have a disease that consumes
that consumes Glu.
4.
Urea formation
Major means by which the LIVER detoxifies
ammonia.
Most ACTIVE way of detoxifying NH3
Form majority of NH3 in the liver
Aspargine formation
Asn formation is comparable to
formation by just changing Glu to Asp
Gln
REACTION 1:
Mitochondria
2 ATPs, CO2, NH3 and H2O reacts to form
Carbamoyl phosphate
ENZYME: Carbamoyl phosphate synthetase 1
(CPS1)
CPS 1
Urea Cycle
Mitochondria
Requires an activator
(N-AGA
or
N-Acetyl
Glutamic Acid)
CPS 2
Pyrimidine Metabolism
Cytosol
Does
not
require
activator
an
REACTION 2:
Ornithine reacts with carbamoyl PO4 to form
Citrulline
The ornithine that reacted with carbamoyl PO4
came from the Cytosol
ENZYME: Ornithine Transcarbamoylase
REACTION 3:
Citrulline will go out into cytosol and reacts with
one more NH3, entering as Aspartic Acid to form
Argininosuccinate
Note: the 2nd ammonia that will be detoxified
enters as aspartic acid.
ENZYME: Argininosuccinate Synthetase
REACTION 4:
Argininosuccinate is cleaved to Fumarate and
Arginine
Arginine is still an essential amino acid despite
that it can be synthesized by the body. Strictly
speaking, Arginine should be termed as SEMIESSENTIAL because it can be synthesized by the
body and yet, it should be provided in the diet; it
can both non-essential and essential.
ENZYME: Arigininosuccinase
Q: Why is Arginine considered semi-essential?
A: Because it can be synthesized by the body
through the urea cycle and yet, you have to
provide it in the diet because the arginine that is
synthesized in the urea cycle cannot be used for
CHON synthesis because it is immediately
converted to urea and ornithine. The Arginine
used for CHON synthesis should be provided in
the diet.
REACTION 5:
Arginine is converted to Urea and Ornithine
ENZYME: Ariginase
For every turn of the urea cycle, you are detoxifying
2 MOLES of Ammonia.
comes out in the urine
Is solid (increases specific gravity of urine)
Considered to be a diuretic (increases the
volume of urine)
CHON diet
urea
excretion
urine
sp.gravity &
volume
It will be destroyed
NH3 accumulation
Hyperammonemia
Rate Limiting Steps (Control Points of Urea Cycle):
1. Synthesis of Carbamoyl PO4 with CPS1 (R#1)
2. Synthesis
of
Citrulline
with
Ornithine
transcarbamoylase (R#2)
3. Cleavage of Arginine with Arginase (R#5)
If you want to stimulate/stop the cycle, stimulate/inhibit
the control points.
Q: Do you produce ATP through the urea cycle?
A: NO. ATP is used. This is an endergonic reaction.
Q: How many ATPs are used?
A: 4 ATPS; 2 on the 1st step, 1 on the 3rd step and 1 more
because of the PPi (PPi 2 Pi 1 ATP.
Normally when ATP undergoes degradation or hydrolysis,
the products are ADP+Pi. But when you look at the
hydrolysis of ATP in the urea cycle, there is ATP + AMP +
PPi (pyrophosphate). The PPi should be converted to 2 Pi
in order for the reaction to be complete. And that will
yield 1 more ATP.
AMMONIA INTOXICATION
H1: Hyperammonemia
Because the urea cycle stops there will be
Increase in ammonia
H2: Hyperornithinemia
Ornithine cannot enter so it will accumulate in
the blood
H3: Homocitrullinuria
Because the urea cycle cannot
Citrulline will come out of the urine.
proceed,
ENZYME DEFICIENT
Carbamoyl PO4 synthetase
Ornithine
transcarbamoylase
Argininosuccinate
synthetase
Argininosuccinase
Arginase
Give LEVULLOSE/LACTULOSE
Excretion in urine
In
the
presence
of
the
enzyme
Glutamate
dehydrogenase + NH3, that can be converted to
Glutamic acid.
Glutamate dehydrogenase is a very active enzyme that
is present in almost all parts of the body. Therefore, it is
also present in the brain. If all the glutamic acids are used
up, it will convert alphaketoglutarate + NH3 (in the
presence of Glutamate dehydrogenase) to Glumatic
Acid.
But Alpha-ketoglutarate is taken from the Krebs cycle
(major ATP producing pathway) deplete Krebs cycle
of alpha-ketoglutarate Krebs cycle stops no ATP
production No ATP in the brain coma.
Q: What is the immediate cause of coma when you have
a severe liver disease?
A: depletion of alpha-ketoglutarate in the Krebs cycle.
Q: How to prevent the coma?
A: Prevent the depletion of alpha-ketoglutarate by giving
alpha-ketoglutarate to the patient. But there is no
preparation of a-ketoglutarate that can be given to the
patient because it is corrosive to the veins. So you give
GLUTAMIC ACID.
A-ketoglutarate is depleted because there is
shortage of Glutamic acid.
If there is an external source of glutamic acid,
then there is no need to give a-ketoglutarate.
All the previously mentioned interventions are all
supportive treatments and do not treat the actual cause
of the disease.
Main treatment: TREAT THE CAUSE! (give external
Glutamic Acid)
What will happen to the other product, KETO ACID?