title: The role of tetrahydrobiopterin in superoxide generation from eNOS: enzymology and physiological implications.
abstract: 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 BH4 metabolites in the control of eNOS biochemistry are discussed in the light of clinical data indicating that BH4 levels are important in the regulation of superoxide levels and of endothelial reactivity.
authors.affiliation: Biophysics Research Institute and Free Radical Research Center, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA. jvvivar@mcw.edu
authors.forename: Jeannette
authors.initials: J
authors.lastname: Vásquez-Vivar
authors.forename: B
authors.initials: B
authors.lastname: Kalyanaraman
authors.forename: Pavel
authors.initials: P
authors.lastname: Martásek
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000737:chemistry; D001708:Biopterins / Q000031:analogs & derivatives* / Q000502:physiology*; D002384:Catalysis; D004578:Electron Spin Resonance Spectroscopy; D006801:Humans; D008954:Models, Biological; D008956:Models, Chemical; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D019097:Spin Trapping; D013481:Superoxides / Q000378:metabolism*
chemical_list: D000975:Antioxidants; D013481:Superoxides; D001708:Biopterins; C496314:NOS3 protein, human; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; C003402:sapropterin