Nitric oxide biosynthesis, nitric oxide synthase inhibitors and arginase competition for L-arginine utilization

Abstract.

Nitric oxide (NO) is a recently discovered mediator produced by mammalian cells. It plays a key role in neurotransmission, control of blood pressure, and cellular defense mechanisms. Nitric oxide synthases (NOSs) catalyze the oxidation of L-arginine to NO and L-citrulline. NOSs are unique enzymes in that they possess on the same polypeptidic chain a reductase domain and an oxygenase domain closely related to cytochrome P450s. NO and superoxide formation as well as NOS stability are finely regulated by Ca²⁺/calmodulin interactions, by the cofactor tetrahydrobiopterin, and by substrate availability. Strong interactions between the L-arginine-metabolizing enzymes are clearly demonstrated by competition between NOSs and arginases for L-arginine utilization, and by potent inhibition of arginase activity by N^ω-hydroxy-L-arginine, an intermediate in the L-arginine to NO pathway.