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Amino Acid Breakdown:
No storage form of Amino Acids, therefore excess need to
be converted to other forms to be used as energy or stored
as glycogen/fat.
CH2N CH
O
OH
R
Disposal of Nitrogen
Atom (Urea)
Recycling of the
Carbon Skeleton
a-ketoglutarate
Aminotransferase
B6
Flow of Nitrogen:
In tissues (e.g Muscle), most amino acids transfer their
a-amino group to Glutamate
Aminotransferase
The N is then transferred from Glutamate
to Pyruvate, producing Alanine.
Pyruvatea-ketoglutarate
Four of the amino acids,
Glycine, Lysine, Threonine
and Serine are directly
deaminated.
Serine
Dehydratase
Glutamine Synthetase
[ ]
NH3 released from Glycine/Lysine/Threonine/Serine
is incorporated into Glutamine
In sum:
During amino acid breakdown, the a -amino Nitrogen gets
incorporated as the a-amino group in Alanine or the amide group
in Glutamine.
Alanine and Glutamine are then released to the circulation.
Flow of Nitrogen:
Alanine and Glutamine released by peripheral tissues are
taken up by the Liver.
The Nitrogen on Alanine is transferred to a-ketoglutarate
to produce Glutamate
Aminotransferase
a-ketoglutarateGlutamate
Glutamate has two fates important for disposal of waste N.
1) Conversion to a-ketoglutarate by Glutamate Dehydrogenase
to release NH3
2) As N donor in the transamination of oxaloacetate to Aspartate
[ ]
Glutamate dehydrogenase
1) Conversion to a-ketoglutarate by Glutamate Dehydrogenase
to release NH3
2) As N donor in the transamination of oxaloacetate to Aspartate
O
Glutamate a-ketoglutarate
NH2
Oxaloacetate Aspartate
Aminotransferase
B6
O O
HO-C-CH2-C-C-OH
O O
HO-C-CH2-CH-C-OH
Glutamine is hydrolyzed by Glutaminase to release NH3
Glutaminase
NH3
Nitrogen flow in Liver
Alanine Glutamate Aspartate
NH3
NH3Glutamine
Net reaction:
HCO3 + NH3 + 2 ATP
(CO2 + NH4)Carb-Phos + 2 ADP + Pi
Carbomyl Phosphate Synthetase I
Glutamate
Carbomyl Phosphate Synthetase I
HCO3 + NH4
+
N-Acetyl Glutamate
CH3-C-NH-CH-C-OH
O
O
O
C-OH
CH2
CH2
Allosteric:
Argininosuccinic
acidemia
Citrullinuria
Arginase Deficiency
Hyperammonemi
a:
Type I
Type II
Metabolic Diseases of the Urea Cycle
Disorders present in infants:
Symptoms: Lethargy, swelling of the brain
leads to mental retardation/brain damage
Diagnosis: Low blood urea nitrogen (BUN) levels
-high levels of ammonia in the blood
elevated circulating glutamine
-other metabolites that accumulate depend on
the specific enzyme defect
Most common form: Hyperammonemia Type II
caused by Ornithine Transcarbamylase deficiency
Elevated Carb-P levels in this deficiency cause
secondary problems in pyrimidine metabolism
Metabolic Diseases of the Urea Cycle
Treatment:
Long term, dietary restriction.
Low protein diet. Supplemented with Arginine
Short term
Dialysis
Administration of Nitrogen “scavengers”
e.g. Phenylacetate
Treatment of Hyperammonemia with Phenylacetate:
taking advantage of metabolism