In search of a function for tetrahydrobiopterin in the biosynthesis of nitric oxide

(6R)-5,6,7,8-Tetrahydro-L-biopterin(H4biopterin) is well known as a cofactor of enzymes that hydroxylate aromatic amino acids. More recent work has revealed an essential role of H4biopterin in the biosynthesis of nitric oxide (NO), an intercellular messenger molecule synthesized from L-arginine by different NO synthase isozymes in many species and tissues. While the function of H4biopterin in aromatic amino acid hydroxylation is well established, the role of this pteridine in NO synthesis is, as yet, elusive. Current experimental evidence hints at a dual mode of action of H4biopterin, involving both an allosteric effect on the NO synthase protein and participation as a reactant in L-arginine oxidation. As discussed in detail in the present article, the latter effect of this pteridine may be related to the protection of NO synthase from feedback inhibition by NO.