51. Urea cycle

Question 1

Sources of ammonia

Answer 1

Deamination reaction by GDH (glu–> alpha-keto + NH3) or glutaminase (gln –> glu + NH3).
Glycine –> CO2+NH3 by glycine synthase/cleavage complex.
From purines and pyrimidine catabolism.
Dietary amines and monoamies (hrms, NTs).

Question 2

Ammonia in liver

Answer 2

In periportal cells, AA, NH3 and gln are converted to urea and glu.
Some NH3 that leaks to perivenous cells are used to convert glu back to gln.

Question 3

Urea cycle

Answer 3

1. NAGS
2. CPS-1
3. OTC.
4. ASS
5. ASL
6. A-1

Question 4

Urea cycle: mitochondria

Answer 4

1. NAGS converts glu+acetyl coa –> NAG. NAGS is upregulated by arginine.
2. CPS-1 converts CO2+NH3 into carbamoyl P. CPS-1 is upregulated by NAG.
3. OTC converts carbamoyl P + ornithine –> citrulline.

orhitine transporter 1 (ORNT-1) is coupled anti-porter that transports 1 ornithine into mito for every citrulline transported out of mito.

Question 5

Urea cycle: cytosol

Answer 5

4. Citrullin + Aspartate –> argininosuccinate (by argininosuccinate synthetase + ATP)
5. Argininosuccinate –> arginine + fumerate by argininosuccinate lyase.
6. Arginine + H2O –> Urea + ornithine (by arginase).

Question 6

Citrulline-NO cycle

Answer 6

Arginine + NADPH –> citrulline + NO.

If urea cycle is disrupted, arginine production goes down and results in HTN.

Question 7

Hyperammonemia.

Answer 7

Results from disrupted urea cycle.

OTC defect is 55% but any of the 6 enzymes can be disrupted. OTC is the only X-linked.

Question 8

Hyperammonemia: 1. NAGS deficiency

Answer 8

AR.

NAG can also be deficient if not enough acetyl-CoA

Question 9

Hyperammonemia: 2. CPS-1 deficiency

Answer 9

AR

HA develops as early as 1st day of life.

Question 10

Hyperammonemia: 3. OTC deficiency

Answer 10

X-linked.
Accumulation of carbamoyl P leaks to cytosol and converted to orotic acid by CPS-2.
Also accumulates as ornithine, glutamate and ammonia.
Heterozygous females and some males have variable age of onset and clinical sx.

Question 11

Hyperammonemia: 4. argininosuccinate synthetase deficiency

Answer 11

AR.
Citruline accumulates but not aspartate.
Onset 1-2 days of life but can be later.

Question 12

Hyperammonemia: 5. argininosuccinate lyase deficiency

Answer 12

AR.
Argininosuccinate and all other IM builds up except aspartate.
Arginonosuccinate aciduria.
Abnormally fragile hair.

Question 13

Hyperammonemia: 6. Arginase deficiency

Answer 13

AR
Arginine accumulates but not NO.
Argininemia and mild hyperammonemia.
Neonates are usually asymptomatic but can present with CNS.

Question 14

Hyperammonemia treatments.

Answer 14

Lactulos: promotes bacterial growth that uses ammonia.
Sodium Benzoate: combines with glycine to form hippuric acid (more excretable). by reducing glycine, more glycine can be made, clearing ammonia.
Sodium phenylacetate or phenylbutyrate: conjugates with glu to form phenylacetylglutamine (excretable).
Arginine: supplies urea cycle with ornithine and NAG, and supports NO synthesis.
Citrulline: for OTC deficiency.