Figure 1.

Mitochondrial OTC in its metabolic context in liver and intestine. Selected metabolic pathways with key enzymes and metabolites. (A) Periportal hepatocytes, with urea cycle (red arrows), running the complete urea cycle for NH₄⁺ detoxification with all citrulline channeled into the cycle. (B) Intestine mucosa enterocytes, with citrulline and arginine synthesis (magenta arrows), generating mainly citrulline for export. Also shown are further reactions (grey arrows), entry points of nitrogenous compounds not detailed here (dashed grey arrows), and allosteric activations (dotted black arrows with +). Enzymes (circles) and transporters (squares) of the urea cycle (mitochondria: blue/red; cytosol: dark blue) and others (grey). The urea cycle comprises the mitochondrial enzymes carbamoyl phosphate synthase 1 (CPS1) and ornithine carbamoyltransferase (OTC), the inner membrane transporters ornithine carrier 1 (ORC, or ornithine transporter 1, ORNT1, SLC25A15) and citrin (CTR, or Ca-binding mitochondrial carrier protein Aralar2, SLC25A13), the cytosolic proteins argininosuccinate synthase (ASS), argininosuccinate lyase (ASL), and arginase 1 (ARG1), as well as generation of an allosteric activator by acetylglutamate synthase (NAGS). Glutaminolysis comprises mitochondrial glutaminase (GLN) and glutamate dehydrogenase (GDH). Ornithine and glutamate are linked by mitochondrial ornithine aminotransferase.