Fate of Ammonia
The amino acids glycine and glutamate are important neurotransmitters in the CNS. A number of other neurotransmitters and hormones are derived from amino acids by simple reactions such as decarboxylation.
Hyperammonemia in hepatic encephalopathy results in depletion of alpha-ketoglutarate, causing inhibition of the Krebs cycle. Excess ammonia also depletes glutamate, an excitatory neurotransmitter, and causes accumulation of glutamine, resulting in astrocyte swelling and dysfunction.
Tx
limit protein diet
Rx - Lactulose - to acidify the GI tract and trap NH4+ for excretion;
Rifaximin to reduce colonic ammoniagenic bacteria
Benzoate, phenylacetate, or phenylbutyrate to bind to NH4+ and lead to excretion.
Carbamoyl phosphate synthase (the rate-limiting enzyme in the urea cycle), forms carbamoyl phosphate as the first step of the urea cycle. Carbamoyl phosphate then combines with ornithine to form citrulline in a reaction catalyzed by ornithine transcarbamoylase in the mitochondrial matrix. Citrulline then enters the cytosol and is converted to argininosuccinate, which is then converted to arginine. The conversion of arginine to ornithine by the cytosolic enzyme arginase completes the urea cycle by releasing a urea molecule.
Remember that urea synthesis is a cyclic process and that while ammonium ion, CO2, ATP, and aspartate are consumed in this process, there is no net loss or gain of ornithine, citrulline, argininosuccinate, or arginine. The molecule N-acetylglutamate serves as a regulator of the urea cycle through allosteric activation of carbamoyl phosphate synthetase I.
Disorders of the urea cycle can result from defects in any of the following six enzymes: