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