Urea Cycle

Question 1

What are sources of ammonia

Answer 1

liver and kidney: through deamination reaction catalyzed by glutamate dehydrogenase or glutaminase

intestines: formed by action of bacterial urease

free ammonia is generated by catabolism of purines and pyrimidines

dietary amines and monoamines (hormones, NTs) give rise to ammonia by the action of amine oxidase.

Question 2

What are periportal hepatocytes?

Answer 2

abundant ~90%
Blood enters periportal hepatocytes
Have high concentration of enzymes of the urea cycle bc site for urea cycle

Question 3

What are perivenous hepatocytes?

Answer 3

less than 10% of hepatocytes

have high concentrations of glutamine synthetase- takes runaway ammonia, attaches it to glutamate-> glutamine

Question 4

What is urea? Where is it produced?

Answer 4

Urea is the major disposal form of ammonia.

Urea is produced in the liver and transported to the kidney

One of the nitrogens is derived from free ammonia, the other from aspartate.
the carbon and oxygen from CO2.

Question 5

Which reactions of the urea cycle occur in the mitochondria?

Answer 5

The first two

synthesis of carbamoyle phosphate from CO2 and NH3 by carbamoyle phosphate synthetase 1 (CPS1)

ornithine enters the mitochondria and reacts with carbamoyle phosphate- to form citrulline by ornithine transcarbamoylase (OTC) release of Pi

Question 6

Which reactions occur inside the cytoplasm?

Answer 6

citrulline leaves mitochondria and enters the cytosol
reacts with aspartate using arginosuccinate synthase to form arginosuccinate; requires ATP

arginosuccinate lyase -> arginine and fumarate (which leaves)

arginase converts arginine to ornithine; need H2O; UREA IS FORMED

Question 7

What is the citrulline NO cycle?

Answer 7

Arginine can be converted into citrulline using NADPH + H+ + O2
this byproducts are NADP+ and NO

Question 8

Where does the nitrogen in urea come from?

Answer 8

free ammonia and aspartate

Question 9

How is the urea cycle regulated?

Answer 9

N-acetylglutamate is required/an allosteric activator of CPS1 - the rate limiting step of the urea cycle.

Question 10

What is hyperammonemia?

Answer 10

Process of making urea is perturbed
Buildup of NH4+ = toxic

acquired: most often caused by liver disease due to viral infection or alcoholism. Can bring about ischemia and ultimately cirrhosis due to biliary obstruction.

hereditary: 1:30,000
caused by 6 enzyme deficiencies
half of the cases due to OTC deficiency (X-linked)
all other are autosomal recessive

Question 11

NAGS deficiency

Answer 11

becomes deficient if Acetyl CoA is not available
very few cases reported
severe

Question 12

CPS1 deficiency

Answer 12

severe and fatal

hyperammonemia appears as early as the first day of life. Majority of infants die in neonatal period.

Question 13

OTC deficiency

Answer 13

X linked recessive
build up of carbomoyl phosphate-> enter cytosol and participates in pyrimidine synthesis in the presence of CPSII -> orotic aciduria

Question 14

ASS deficiency

Answer 14

arginosuccinate synthase deficiency
build up of citrullate
onset usually between 24 and 72 hours of life. late onset possible

Question 15

ASL deficiency

Answer 15

arginosuccinate lyase deficiency
second most common
leads to arginosuccinic aciduria
abnormally fragile hair (trichorrhexis nodosa) in infants seen as early as 2 weeks

Question 16

A1 deficiency

Answer 16

arginase deficiency
least frequent; relatively mild hyperammonemia
usually asymptomatic but can present with spastic diplegia, diplegia or quadriplegia, intellectual impairment, recurring vomiting, delayed growth and seizures

Question 17

How do you treat hyperammonemia?

Answer 17

Lactulose
sodium benzoate
sodium phenylacetate or phenylbutyrate
arginine
citrulline

Question 18

Lactulose

Answer 18

dosage: oral administration 10 g/d
what it does: colonic acidifier that reduces ammonia. promotes bacteria growth in colon-> induce assimilation of ammonia and decrease deamination of nitrogenous compounds

Question 19

sodium benzoate

Answer 19

250-500 mg/kg/d

combines with endogenous glycine to form hippuric acid which is cleared by the kidneys

Question 20

sodium phenylacetate or phenylbutyrate

Answer 20

250-500 mg/kg/d

combines with glutamine to form phenylacetylglutamine which is excreted in the urine

Question 21

arginine

Answer 21

200-800 mg/kg/d

supplies the urea cycle with ornithine and NAG
supports NO synthesis

Question 22

citrulline

Answer 22

200-400 mg/kg/d

used for pts with OTC deficiency

Question 23

What is the overall stoichiometry of the urea cycle?

Answer 23

1 aspartate + 1 CO2 + 1 NH3 + 3 ATP => urea + fumarate + 2 ADP + AMP + Pi + PPi + H20