The Role of Tetrahydrobiopterin in Superoxide Generation from eNOS: Enzymology and Physiological Implications

Tetrahydrobiopterin (BH₄) is a ubiquitous pteridine metabolite that serves as a NOS cofactor. Recently, we showed that BH₄ efficiently inhibits superoxide generation from the heme group at the oxygenase domain of eNOS. This role indicates that BH₄ acts as a redox switch in the catalytic mechanism of the enzyme, which may have important consequences in the physiology of the endothelium. Here the mechanism by which BH₄ inhibits superoxide release from eNOS and the "uncoupling" effects of oxidized BH₄ metabolites are presented. The implications of the disparate actions of fully reduced and oxidized BH 4 metabolites in the control of eNOS biochemistry are discussed in the light of clinical data indicating that BH 4 levels are important in the regulation of superoxide levels and of endothelial reactivity.