Urea Cycle Flashcards
Where does the urea cycle occur (organ)?
liver
Where does the ammonium ions come from?
- catabolism of amino acid
- gut bacteria makes a lot as well
What amino acids can undergo deamination without aminotransferases?
Ser, Cys, His, and Thr
What is the rate-limiting step of the urea cycle?
formation of carbamoyl phosphate catalyzed by carbamoyl phosphate synthetase (step 1)
What are the substrates for carbamoyl phosphate synthetase?
HCO3- + 2ATP + NH4+
Where is carbamoyl phosphate synthetase located in the cell?
mitochondria
What is the allosteric acitvator of carbamoyl phosphate synthetase?
N-acetylglutamate (synthesized from N-acetylglutamate synthetase, which is activated by arginine, from a later step)
What is step 2 of the urea cycle?
Ornithine + Carbamoyl Phosphate»Citrulline
Enzyme: Ornithine Transcarbamoylase
Where is citrulline located?
Once synthesized, it is transported out of the mitochondria in exchange for ornithine
What is step 3 of the urea cycle?
Citrulline + Aspartate + ATP»Argininosuccinate
Enzyme: Argininosuccinate Synthetase
Where is step 3 occuring?
cytoplasm (remember that citrulline was exported out)
What is step 4 of the urea cycle?
Argininosuccinate»Arginine + Fumarate
Enzyme: Argininosuccinate Lyase
What is the final step of the urea cycle?
Arginine + H2O»Ornithine + Urea
Enzyme: Arginase
Where do the ammonium ions come from in the molecule of urea?
2 ammonium ions: 1 free NH4+ and 1 from aspartate
High levels of arginine are indicative of what?
elevated peripheral blood ammonia levels, thus urea cycle is active
When enterocytes take up glutamine from the diet, what do they do with it? And then what happens?
spits out ornithine and citrulline
- ornithine goes to the liver
- citrulline is taken up by the kidneys and goes through the same process as the liver to make arginine, then excretes it to circulation
This is the intestinal-renal axis
What organ can complete the entire urea cycle?
only the liver
Where is arginine made?
kidneys via the intestinal-renal axis
Why is arginine considered an essential amino acid if we can make it?
- the intestinal-renal axis is not well developed until a certain age therefore infants cannot synthesize arginine
- also as we age, it becomes essential because certain conditions impact the function of small intestines or kidneys, leading to pressure ulcers
Defects in which enzymes cause severe hyperammonemia and are often lethal?
Carbamoyl phosphate synthetase I and Ornithine transcarbamoylase
Why are defects in other urea cycle enzymes less harmful? Which enzymes are these?
- the intermediates are less toxic to the body and can be excreted by urine
- argininosuccinate synthetase, argininosuccinate lyase, and arginase
What condition is caused by defect in arginosuccinate synthetase?
Citrullinemia
- citrulline gets excreted, but that’s only one nitrogen, so supplement
What condition is caused by defect in argininosuccinate lyase?
Argininosuccinic Aciduria
What condition is caused by defect in arginase?
Hyperargininemia
What are some treatment option for conditions that deal with early cycle enzymes?
protein restriction (difficult for growth)
hemodialysis
treatment with phenylbutyrate and benzoate
How does the treatment with phenylbutyrate and benzoate work?
phenylbutyrate and benzoate both form water-soluble conjugates with glutamate and glycine, respectively, that the kidneys can eliminate easily
What is the treatment for argininosuccinic aciduria?
- defective enzyme is argininosuccinate lyase
- arginine supplement provides the body a way to eliminate urea. the substrate arginosuccinate gets excreted in urine
What is the treatment for citrullinemia?
- defective enzyme is argininosuccinate synthetase
- arginine supplement supports citrulline synthesis, which will get eliminated, but it only carrier one ammonium ion so either phenylbutyrate or benzoate should also be prescribed
What other conditions besides urea cycle defects can lead to toxic levels of ammonia accumulation?
liver disease because urea cycle occurs there
- early sign is swelling of brain due to glutamate taken up by astrocytes and converted to glutamine.
- lethargy, stupor, vomiting, and convulsions
hyperammonemia
ammonia is a potent neurotoxin
