Defects in amino acid metabolism - the urea cycle and its disorders

The urea cycle is the major pathway responsible for the removal of excess ammonia from the blood and it provides a biosynthetic pathway for the amino acid arginine. It works primarily in the liver and to a lesser extent in the kidneys and converts ammonia (NH3) to the less toxic urea prior to renal excretion (PMID:24473688). In a first step, carbamoyl phosphate synthetase (CPS1), localized in mitochondria, catalyzes the condensation of NH3 with HCO3- to form carbamoyl phosphate (PMID:24508527). HCO3- is produced by the enzyme carbonic anhydrase VA (CA5A) (PMID:24530203) and CPS1 requires activation by N-acetyl glutamate synthesized by N-acetyl glutamate synthethase (NAGS) (PMID:21941437). The next step is the conversion of carbamoyl phosphate and ornithine to citrulline via the enzyme ornithine transcarbamylase (OTC) (PMID:24508627). All these steps take place in the matrix of the mitochondria. Citrulline produced in the mitochondria is transported to the cytoplasm by the ornithine/citrulline transporter (ORNT1, SLC25A15) (PMID:10369256). In the cytoplasm citrulline and aspartate is converted to argininosuccinate by the enzyme argininosuccinate synthase (ASS1). Citrin, the liver-specific isoform of the mitochondrial aspartate-glutamate carrier SLC25A13, supplies the aspartate for this reaction (PMID:24508627). Argininosuccinate lyase (ASL) cleaves argininosuccinate into fumarate and arginine (PMID:24508627) which is further cleaved into ornithine and urea by the enzyme arginase (ARG1) (PMID:12655043). The generated ornithine is transported into the mitochondrial matrix via the ornithine/citrulline transporter ORNT1 (PMID:10369256). Mutations leading to severe diseases are described for all of the seven enzymes and the two transporters.


Interactions40Proteins/Genes9Chemical compounds/drugs12
Biological Process(GO)0Phenotype0

Biological Process(GO)