Why Tetrahydrobiopterin?

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The effect of Tetrahydrobiopterin (H 4 biopterin) on nitric oxide (NO) synthesis is well specific and occurs at nanomolar concentrations; copurification of H 4 biopterin with NO synthase (NOS) suggests that the pteridine shows properties of a prosthetic group in addition to being a freely associating and dissociating cofactor of the enzyme. Intriguingly, autoxidation of free H4biopterin results in a rapid superoxide-mediated inactivation of NO. Thus, NOS has evolved as unique H 4 biopterin-containing cytochrome P-450, albeit free H 4 biopterin apparently destroys the biologically active reaction product. Obviously, there is something about H 4 biopterin that needs elucidation. This chapter provides a summary of the current knowledge of the functional, allosteric, and chemical effects of H 4 biopterin first and then discusses possible reasons for the evolution of H 4 biopterin as an NOS cofactor. NOS isozymes are the sole pteridine-dependent members of the cytochrome P-450 superfamily. Conceivably, the unique pteridine requirement of NOS could have its roots in the complex and unusual odd-electron chemistry of NO synthesis. This two-step redox reaction involves hydroxylation of L-arginine to N G -hydroxy-L-arginine first and subsequent oxidative cleavage of the intermediate to L-citrulline and NO. Both parts of the reaction exhibit a similar dependence on H 4 biopterin, indicating that the pteridine may not have a specific function in a distinct step of NO synthesis. The lack of experimental evidence for NADPH-dependent recycling of H 4 biopterin during NO synthesis seems to suggest that the pteridine is not redox active. However, the methods currently available would not reveal NADPH-dependent recycling of small amounts of enzyme-bound cofactor, and a lack of activity of enzyme-bound H 2 biopterin clearly hints at a requirement of NOS for pteridine-derived reducing equivalents.