Disposal of Amino Acids &

Urea Cycle
Dr Imran siddiqui
MBBS, MPhil
 OVERVIEW OF AMINO ACID METABOLISM

ENVIRONMENT ORGANISM

Bio-
Ingested synthesis Protein
protein
2 3
1
a
AMINO
ACIDS
b
c c Purines
Degradatio Pyrimidines
n Porphyrins
(required)
Carbon
Nitrogen
skeletons
(ketogenic) (glucogenic)
Urea Used for
energy pyruvate
acetoacetate α-ketoglutarate
acetyl CoA succinyl-CoA
fumarate
oxaloacetate
 Amino acid metabolism

• Metabolism of amino acids differs,

but 3 common reactions:

– Transamination

– Deamination

– Formation of urea
Typical first transamination reaction:

The usual AA acceptor is α-ketoglutarate,

producing
GLUTAMATE and the new a-keto acid.

What is produced if oxaloacetate is the

 Example of a Transaminase reaction:

COO− COO−

COO− CH2 COO− CH2

CH2 CH2 CH2 CH2

HC NH3+ + C O C O + HC NH3+

COO− COO− COO− COO−

aspartate α-ketoglutarate oxaloacetate glutamate

Aminotransferase (Transaminase)

(AST/SGOT)
 Aspartate donates its amino group, becoming the
α -keto acid oxaloacetate.
 α -Ketoglutarate accepts the amino group,
becoming the amino acid glutamate.
 COO− COO−

CH2 CH2

CH3 CH2 CH3 CH2

HC NH3+ + C O C O + HC NH3+

COO− COO− COO− COO−

alanine α-ketoglutarate pyruvate glutamate

Aminotransferase (Transaminase)

(ALT/SGPT)
In another example, alanine becomes pyruvate as the amino
group is transferred to α -ketoglutarate.
Most tissues have these enzymes and when tissue is
damaged , such as cells in heart during a myocardial
infarction or in liver diseases, these enzymes are
released into from the cells and lead to increases in
their levels in the blood.
 Deamination reactions
• Amino group (and H) a. Oxidative deamination
removed In order to regenerate the amino
– Forms ammonia (NH3) acceptor, α-ketoglutarate, and to
– Carbon skeleton left can be provide ammonia for re-utilization or
• Oxidised in Kreb’s Cycle disposal it is necessary to deaminate
• used for gluconeogenesis glutamate.
• converted to fatty acid
This is accomplished by the action of
the enzyme glutamate dehydrogenase
(GDH) which is located in the
mitochondrial matrix.
NH3+
H2 H2
−
OOC C C C COO−
glutamate
H
H2O NAD(P)+
NAD(P)H
O
H2 H2
−
OOC C C C COO−
+ NH4+
α-ketoglutarate
Glutamate Dehydrogenase
 Amino acid α
-ketoglutarate NADH + NH4+

α
-keto acid glutamate NAD+ + H2O

Transaminase Glutamate
Dehydrogenase

Summarized above:
The role of transaminases in funneling amino N to
glutamate, which is deaminated via Glutamate
Dehydrogenase, producing NH4+.
 Urea cycle

• Ammonia is toxic
– Readily ionises to
ammonium ion NH4+
• NH4+ converted to urea in
liver (urea cycle)
– Urea contains 2 x NH2

» One from NH4+

O
» One from aspartate
H2N C NH2
• Urea excreted in urine From: Stryer, LS (1988) Biochemistry (3rd Ed). New York: WH Freeman
urea & Co. p500
 O O C NH2
NH3+
Urea Cycle H2N C OPO32− NH

Enzymes in CH2 carbamoyl CH2

phosphate
mitochondria: CH2 citrulline
Pi CH2
1. Ornithine CH2 1
CH2
Trans-
HC NH3+
HC NH3+ COO−
carbamylase Urea Cycle
−
COO CH2
COO−
Enzymes in ornithine ATP 2 HC NH2
cytosol:
4 AMP + PPi
2. Arginino- O H2O
−
COO−
COO
Succinate H2N C NH2 aspartate
Synthase urea H2N NH2+ CH2
C H
3. Arginino- 3 HC N C NH2+
succinase NH COO− NH
4. Arginase. CH2
COO− CH2 arginino-
arginine CH2 succinate
HC CH2
CH2 CH2
CH
HC NH3+ NH3+
COO− HC
COO− fumarate COO−
 Urea Formation
• Occurs primarily in liver; excreted by kidney
• Principal method for removing ammonia
• Hyperammonemia:
• Defects in urea cycle enzymes (CPS, OTC, etc.)
• Severe neurological defects in neonates
• Treatment:
» Stop protein intake
» Dialysis
» Increase ammonia excretion: Na benzoate, Na
phenylbutyrate, L-arginine, L-citrulline

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 Blood Urea Nitrogen
• Normal range: 7-18 mg./dL
• Elevated in amino acid catabolism
• Glutamate N-acetylglutamate
CPS-1 activation
• Elevated in renal insufficiency
• Decreased in hepatic failure

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•Hereditary deficiency of any of the Urea
Cycle enzymes leads to hyperammonemia -
elevated [ammonia] in blood.
•Total lack of any Urea Cycle enzyme is lethal.
•Elevated ammonia is toxic, especially to the
brain.
•If not treated immediately after birth, severe
mental retardation results.
Postulated mechanisms for toxicity of
high
[ammonia]:??????????????????????

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