Tetrahydrobiopterin in nitric oxide synthesis: a novel biological role for pteridines

Ever since the discovery that (6R)-5,6,7,8-tetrahydro-L-biopterin (BH4) is a cofactor of NOS, its function has been the object of intense research and occasional controversy. Only in the last couple of years a consensus has been reached on what constitutes the main role of BH4 in NO synthesis. In this review we aim to provide an outline of the various ways in which BH4 affects NOS catalysis. First we give a brief general description of the structure and catalytic mechanism of NOS, with special emphasis on those aspects of catalysis that are actively debated, and that directly or indirectly involve BH4. Foremost among those issues is uncoupled catalysis, i.e. the NOS-catalyzed oxidation of NADPH in the absence of substrate or pterin that does not result in NO production. We also shortly discuss the ongoing debate on whether NO is the actual reaction product of NOS catalysis, as well as the phenomenon of NO-mediated autoinhibition. We describe the function of BH4 in aromatic amino acid hydroxylation, and discuss the allosteric and structural effects that BH4 exerts on NOS. Next we turn our attention to what is now becoming accepted as the central function of BH4: its capacity to act as a 1-electron donor during reductive activation of the oxyferrous complex of the heme. Finally, we illustrate how BH4 might transform the NOS dimer into an efficient S-nitrosoglutathione synthase,and briefly touch on some more speculative aspects of the role of BH4 in NO synthesis.