Ornithine carbamoyltransferase and N-acetylornithine carbamoyltransferase (OTC/AOTC)

Ornithine carbamoyltransferase (OTC) and N-acetylornithine carbamoyltransferase (AOTC) are enzymes within the carbamoyltransferase family that play pivotal roles in nitrogen metabolism. OTC is a key enzyme in the mammalian urea cycle, responsible for converting carbamoyl phosphate and ornithine into citrulline; its deficiency is the most common urea cycle disorder, leading to toxic ammonia accumulation and neurological impairment (UniProt: P00480). AOTC is primarily found in bacteria and plants as part of the linear arginine biosynthetic pathway, where it catalyzes the carbamoylation of N-acetylornithine (PubMed: 25605328). In several pathogenic bacteria, such as Moraxella catarrhalis and Xanthomonas campestris, a single bifunctional enzyme possesses both AOTC and OTC activities, facilitating survival and virulence. These enzymes are significant therapeutic targets; while human OTC research focuses on gene therapy and enzyme replacement to treat metabolic disorders, bacterial AOTC/OTC is targeted by transition-state analogs like N-phosphonacetyl-L-ornithine (PALO) to develop novel antibiotics (PubChem: CID 123840). Mutations in the human OTC gene are monitored via biomarkers such as elevated plasma ammonia and urinary orotic acid (StatPearls: NBK482137). Safety concerns for drugs targeting the bacterial versions include potential off-target inhibition of the human mitochondrial enzyme, which could induce hyperammonemia.

Other names

Ornithine transcarbamylaseN-acetylornithine transcarbamylaseOTCaseAOTCaseArgFArgI

Competitive inhibition of the carbamoyltransferase active site by transition-state analogs