Transcript Protein mteabolism

Amino acid degradation
Most of absorbed dietary amino acids are catabolized by 2 subsequent
steps:
I- 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.
II- Breakdown of carbon skeleton:
Carbon skeleton (R side chain) is degraded to give either energy or some
compounds in the body
I- Removal of α-amino group:
The removal of amino group takes place in two steps which are
Transamination (that produce glutamate) followed by oxidative
deamination of the produced glutamate to give ammonia.
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 indicates 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,……
Oxidative deamination of the glutamate:
Glutamate produced from transamination is oxidatively deaminated
by the enzyme glutamate dehydrogenase (GDH) yielding
ammonia and regenerating α-ketoglutarate that is used in additional
transamination reactions.
GDH is oxidoreductase enzyme that catalyze the oxidative deamination of
glutamate (using NAD or NADP) and catalyze the reversal reduction reaction
using NADH (or NADPH)
The produced ammonia is toxic to CNS (neurotoxic) and it must be
removed.
Ammonia (if increased) will react with α-ketoglutarate in the
presence of glutamate dehydrogenase enzyme (GDH) and therefore
interfere with Kreb’s cycle by consuming α-ketoglutarate .
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 of urea cycle
1) Ammonia reacts with CO2 and 2ATP in mitochondria to form
carbamoyl phosphate in the presence of carbamoyl phosphate
synthestae I.
2) Carbamoyl phosphate combines with ornithine to produce
citrulline which is then diffuse to cytoplasm
3) Aspartat e, carrying the second nitrogen atom of urea, enters the
cycle by condensing with citrulline to form argininosuccinate.
4) Argininosuccinate is cleaved to fumarate and arginine.
5) Arginine is further hydrolyzed to yield urea and regenerate the
ornithine
 Urea cycle involves 5 steps:
The first two reactions occur in
Mitochondria while the steps 3,4 and 5 occur in Cytoplasm).
 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.
 Regulation of urea cycle:
Carbamoyl phosphate synthetase-I is absolutely activated by Nacetylglutamate.
 Energy used for urea cycle: 3ATP
 Overall reaction:
CO2 + NH3 + aspartate + 3ATP
→ Urea +fumarate
 Sources of nitrogen atoms in urea formation:
One nitrogen is derived from ammonia, the second is derived from aspartate
The carbon of urea is derived from CO2
 Fate of urea:
1- diffuse from liver, transported in blood to kidney and excreted with urine.
Urea is used as kidney function test, increased blood urea
indicate renal disease.
2- a portion diffuse from blood to intestine and cleaved by bacterial urease into
ammonia and CO2. Ammonia passes with stool.
Hyperammonemia
High ammonia decrease α-ketoglutarate and interfere with Kreb’s
cycle so decrease ATP production
α-ketoglutarate + NH3 + NADH (or NADPH)
NAD(P)
Ammonia toxicity in brain:
low ATP
COMA (a symptom of high ammonia)
→ glutamate +
Hyperammonemia:
1) Genetic (hereditary hyperammonemia):
Due to deficiency of one of the 5 enzymes of urea cycle leading to
increased level of ammonia during the first week of birth leading to
mental retardation.
Examples:
a. Type I: Carbamoyl phosphate synthetase deficiency
b. Type II: Ornithine transcarbamoylase deficiency
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.