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Protein metabolism
Protein digestion:
A) In stomach:
passage of food into stomach stimulates gastric mucosa to secret a
polypeptide hormone called: Gastrin which has the following actions:
1- stimulate the chief cells of gastric mucosa to secret the inactive
zymogen “pepsinogen”
2- stimulates the parietal cells of gastric mucosa to secret HCl which
activates pepsinogen into pepsin which activates more
pepsinogen”autoactivation”
Pepsin is an endopeptidase, partially hydrolyse the ingested proteins
into polypeptides.
HCl
Pepsin
Pepsinogen
Auto activation
pepsin
Pepsinogen
Pepsin
B) In small intestine (Action of pancreatic enzymes): Pancreas secret several
proenzymes into duodenum. The release and activation of pancreatic zymogens is
mediated by the secretion of cholecystokinine and secretin (GIT hormones).
Activation of pancreatic zymogens: The pancreatic zymogens are: trypsinogen,
chymotrypsinogen and pro-carboxypeptidases (A and B). Enteropeptidase
(formerly called enterokinase) converts trypsinogen into active trypsin which then
activates more trypsinogen and the other proenzymes i.e activates
chymotrypsinogen into chymotrypsin and pro-carboxypeptidase into
carboxypeptidase. These enzymes hydrolyze polypeptides into oligopeptides.
enteropeptidase
Trypsinogen
trypsin
trypsin
Trypsinogen
trypsin
Chymotrypsinogen
trypsin
chymotrypsin
Other enzymes secreted into intestinal
lumen are:
1- Amino peptidase: which hydrolyse Nterminal of amino acid to give free amino
acids, dipeptides and tripeptides.
2-Dipeptidases and Tripeptidases:
Hydrolyze dipeptides and tripeptides into
free amino acids. So the final product of
digestion is amino acids.
NB:
Carboxypeptiases
and
aminopeptidase are called exopeptidases
as they hydrolyze protein at C-terminus
and N-terminus, respectively. Pepsin,
trypsin
and
chymotrypsin
are
endopeptidases
Amino acids are absorbed by the intestinal mucosa and transported via blood stream.
Once enter blood, amino acids rapidly enter cells. Liver and kidney take up the largest
portion.
Amino acid degradation
Most of absorbed dietary amino acids are catabolized by 2 subsequent steps:
1- Removal of α-amino group: α-amino group is removed in the form of ammonia
(NH3). This occurs in most amino acids by transamination followed by oxidative
deamination of the resulting glutamate.
2- Breakdown of carbon skeleton.
Removal of α-amino group:
Transamination: is the transfer of α-amino group from α-amino acid to α-keto acid
to yield α-keto acid of the original amino acid and a new amino acid.
The enzymes that catalyze
transamination are called
transaminases or
Aminotransferases.
which
need
coenzyme
pyridoxal phosphate (PLP)
General reaction is:
In most transamination reactions, the α-keto acid is α-ketoglutarate.
The most common examples on transaminases are:
1- Alanine Aminotransferase (ALT) or called Glutamate-Pyruvate
Transaminase (GPT):
ALT
2- Aspartate Aminotransferase (AST) or called: Glutamate Oxaloacetate
Transaminase (GOT).
AST
Clinical significance of aminotransferases:
Aminotransferases are normally intracellular enzymes, and found only in low levels in
plasma. The presence of elevated plasma levels of aminotransferases indcates damage
of cells rich in these enzymes. e.g. ALT and AST are present in liver, so their elevation
in blood indicate liver cell damage such as in hepatitis, toxic injury, cirrhosiss,……
Glutamate produced from transamination is oxidatively deaminated by the enzyme
glutamate dehydrogenase yielding ammonia and regenerating α-ketoglutarate that
is used in additional transamination reactions.
The produced ammonia is toxic to CNS (neurotoxic) and it must be removed.
Disposal routes of NH3 OR Removal of ammonia:
1- excreted with urine.
2- react with glutamate yielding glutamine by the enzyme glutamine synthetase
this reaction occurs primarily in brain, muscles and liver. This reaction is the
main disposal route of ammonia in brain
3- Used in formation of urea in liver. It is the most important disposal route of
ammonia.
Urea cycle or urea synthesis
Site:
urea is synthesized in the liver
by 5 enzymes.
Steps : see handout
for detailed steps
cytoplasm
Notes on urea cycle:
1- Urea cycle involves 5 steps The first two reactions occur in Mitochondria while
the steps 3,4 and 5 occur in Cytoplasm).
2- The rate limiting step in the cycle is the first reaction which is the formation of
carbamoyl phosphate from CO2 and NH3 in the presence of carbamoyl phosphate
synthetase I (CPSI) which is the rate limiting enzyme in the synthesis.
3-CPSI absolutely depends on the presence of N-acetyl glutamate which act as
allosteric activator for the enzyme.
4- Ornithine and citrullin are two basic amino acids used in urea synthesis, but not
enter in protein synthesis.
What are the sources of N- and C atoms in urea?
Fate of urea:
1- diffuse from liver, transported in blood to kidney and excreted with urine
2- a portion diffuse from blood to intestine and cleaved by bacterial urease into
ammonia and CO2. Ammonia passes with stool.
Hyperammonemia:
1- Genetic (hereditary hyperammonemia):
Due to deficiency of one of the 5 enzymes of urea cycle (particularly CPSI) leading to
increased level of ammonia during the first week of birth leading to mental retardation
Precaution: limiting protein in diet
2) Acquired hyperammonemia
- Is most commonly due to liver disease, especially in last stage where the capacity of
live to synthesize urea is decreased
Symptoms of hyperammonemia:
Neurotoxic effects on CNS leading to:
- Tremors , slurring of speech, blurring of vision, behavioral changes and cerebral
edema
-At very high levels: coma and death
- A hyperammonemic coma occurs when serum ammonia concentrations are greater
than 300 μmol/L and is a medical emergency requiring immediate treatment designed
to prevent irreversible brain damage.