Documenti di Didattica
Documenti di Professioni
Documenti di Cultura
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
– Deamination
– Formation of urea
Typical first transamination reaction:
COO− COO−
HC NH3+ + C O C O + HC NH3+
(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
HC NH3+ + C O C O + HC NH3+
(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
12
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
13
•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]:??????????????????????
Thank You