Protein

Metabolism
Prof Dr. Nesreen Elhelbawy
 In the stomach
• Gastric HCL causes protein denaturation (loss of
the tertiary structure) and the polypeptide chain
unfolded.
Pepsin:
• Secreted by the chief cells of the gastric mucosa as
Protein Digestion the inactive pepsinogen, activated to pepsin by
HCL and by pepsin itself.
• It is an endopeptidase (hydrolyze peptide bonds
within chain).
Rennin:
• It acts on the casein of milk (in infants), changing
it to a paracasein, which is then acted on by pepsin.
In the intestine
• The alkaline pH inhibits the action of pepsin but activates the pancreatic and
intestinal enzymes.
1-The pancreatic secretions contain:
• Endopeptidases: Trypsin, chymotrypsin, and elastase. They are secreted in
inactive forms. Trypsinogen is activated by enterokinase enzyme. Then
trypsin activates them.
• Carboxypeptidase: Exopeptidase, hydrolyzing the carboxy-terminal peptide
bond to liberate single amino acid (AA).
2- The intestinal secretions contain:
• Aminopeptidase: Exopeptidase hydrolyzing the amino-terminal peptide
bonds to liberate.
• Dipeptidases: Complete digestion of dipeptides to free AA.
 Absorption of Proteins

A- Active transport: L-AA are actively absorbed, requiring

energy, B6 vitamin and carrier.

B- Passive transport: D-amino acids are absorbed by

simple diffusion.

N.B. In Celiac disease, protein fragments (larger

molecular size) than AAs are absorbed from the intestine,
causing antigenic reactions.
 Protein turnover
Definition: the continuous degradation and resynthesis of all cellular
proteins.

Each day, humans turn over 1-2% of their total body proteins. 75-80% of the
liberated AAs is reutilized for new protein synthesis. The nitrogen of the
Catabolism remaining 20-25% forms urea and the carbon skeletons are then degraded to
amphibolic intermediates.
of amino Half-life time (t ½): time required to reduce the concentration of a protein
to half its initial value.
acid The alpha- amino nitrogen is excreted as:
nitrogen 1-Ammonia (fish) is toxic compound and must be continuously excreted.

2-Uric acid (birds) is insoluble and excreted as semisolid.

3-Urea (humans) is water-soluble compound and is non-toxic.

 Synthesis of urea is divided into 4 stages
1-Transamination.
2- Oxidative deamination
3- Ammonia transport
4- Reactions of urea cycle.
1-Transamination (removal of the alpha-amino group).

• Most AAs undergo transamination except lysine, threonine, proline and hydroxyproline.

• Reversible reactions catalyzed by aminotransferases (transaminases) and require pyridoxal phosphate

(coenzyme).

• Examples of transaminases: alanine-pyruvate aminotransferase (ALT) and aspartate oxaloacetate

aminotransferase (AST) and glutamate aminotransferase.

• Diagnostic value of plasma aminotransferases: They are normally intracellular enzymes, with the low
levels in plasma (normal cell turnover).

• Elevated plasma levels of aminotransferases indicate damage to cells rich in these enzymes. Plasma AST
and ALT are elevated in liver diseases (viral hepatitis) and non-hepatic disease (myocardial infarction).
2-Oxidative deamination of glutamate
 The α- amino group of glutamate is released as ammonia by:

A- L-glutamate dehydrogenase

It catalyzes deamination of L-Glutamate and require PLP as coenzyme

B- Amino acid oxidases

They remove ammonia from α-amino acids and require flavoproteins as coenzyme.
 Sources of ammonia:
1-Deamination of AAs.
3-
Ammonia 2-Action of intestinal bacteria on dietary protein.

transport
Fate of ammonia:

1- Synthesis of non-essential AAs.

2 – Synthesis of glutamine

by glutamine synthetase present in the kidney and brain.

• In the brain, the major mechanism for detoxification of ammonia is formation of glutamine,

which passes to the kidney.

• In the kidney, glutamine is hydrolyzed by glutaminase producing ammonia (excreted in urine)

and regulate acid-base balance.

3- Synthesis of Urea : ammonia is converted to glutamine and transported to the liver. Liver
 Ammonia intoxication
Mechanism:
• When ammonia reaches high toxic levels in systemic blood (as in hepatic cirrhosis), it
passes the blood brain barrier (BBB).
• Blood glutamate reaching the brain is inadequate for formation of glutamine (to
remove excess ammonia), therefore brain synthesize glutamate from alpha-
ketoglutarate, this will deplete alpha-ketoglutarate and inhibit CAC ↓ ATP
production
• Alpha-ketoglutarate Glutamate glutamine
• ↓ brain glutamate ↓ synthesis of inhibitory neurotransmitter gamma amino
butyrate (GABA) in brain.
• ↑ glutamine level ↑ glutamine outflow from the brain in exchange with
tryptophan inflow to the brain ↑ neurotransmitter serotonin.
• Symptoms: tremors, slurred speech, blurred vision, coma and death
 Urea is the major product of nitrogen catabolism in
humans.
It is synthesized in the liver and excreted in urine.
Site: Reactions (1) and (2) occur in mitochondrial matrix.
Reactions (3), (4) and (5) occur in the cytosol.
Steps:
•Reaction (1): Carbamoyl phosphate is formed from
4- Reactions ammonia and bicarbonate (carbamoyl phosphate
synthetase).
of urea cycle Reaction (2): carbamoyl phosphate and ornithine are
condensed to form citrulline (ornithine transcarbamoylase).
Reaction (3): citrulline and aspartate are condensed to
form argininosuccinate (argininosuccinate synthetase).
Reaction (4): Argininosuccinate is broken down
into arginine and fumarate (argininosuccinate lyase).
Reaction (5): Arginine is broken down into urea and
ornithine (arginase).
• Regulation: control of
the urea cycle involves
carbamoyl phosphate
synthetase enzyme
which is activated by
N-acetylglutamate.
  More than 75% of non-protein nitrogen is excreted as
urea.
 Blood urea level (10-50 mg /dl), Urinary urea level (10-
50 g/dl).
 Causes of abnormal plasma urea:
A)Reduced level: low protein diet, severe liver disease
Plasma and water retention.

urea B)Increased level:

1. Prerenal causes: high protein diet, GIT hemorrhage,
increased protein catabolism (trauma and starvation),
and iatrogenic (urea infusion).
2. Renal causes: reduced glomerular filtration rate
(infections).
3. Postrenal causes: obstruction of urine outflow (benign
prostatic hypertrophy).
 Disorders of urea cycle
Metabolic error
1- Hyperammonemia type I
2- Hyperammonemia type II
3- Citrulinemia
4- Argininosuccinic aciduria
5- Hyperargininemia
• Causes: five inborn errors of
Defective enzyme metabolism (metabolic disorders)
Symptoms: symptoms of
-Carbamoylphosphate synthetase
ammonia intoxication
• Treatment:
-Ornithine transcarbamoylase.
1. Low protein diet to prevent
brain damage.
2. Food intake should be in
-Argininosuccinate synthetase
frequent small meals to avoid
sudden increases in blood
ammonia levels.
- Argininosuccinase
- Liver arginase