title: Oxidation of tetrahydrobiopterin by biological radicals and scavenging of the trihydrobiopterin radical by ascorbate.
abstract: One-electron oxidation of (6R)-5,6,7,8-tetrahydrobiopterin (H(4)B) by the azide radical generates the radical cation (H(4)B(*)(+)) which rapidly deprotonates at physiological pH to give the neutral trihydrobiopterin radical (H(3)B(*)); pK(a) (H(4)B(*)(+) <==> H(3)B(*) + H(+)) = (5.2 +/- 0.1). In the absence of ascorbate both the H(4)B(*)(+) and H(3)B(*) radicals undergo disproportionation to form quinonoid dihydrobiopterin (qH(2)B) and the parent H(4)B with rate constants k(H(4)B(*)(+) + H(4)B(*)(+)) = 6.5 x 10(3) M(-1) s(-1) and k(H(3)B(*) + H(3)B(*)) = 9.3 x 10(4) M(-1) s(-1), respectively. The H(3)B(*) radical is scavenged by ascorbate (AscH(-)) with an estimated rate constant of k(H(3)B(*) + AscH(-)) similar 1.7 x 10(5) M(-1) s(-1). At physiological pH the pterin rapidly scavenges a range of biological oxidants often associated with cellular oxidative stress and nitric oxide synthase (NOS) dysfunction including hydroxyl ((*)OH), nitrogen dioxide (NO(2)(*)), glutathione thiyl (GS(*)), and carbonate (CO(3)(*-)) radicals. Without exception these radicals react appreciably faster with H(4)B than with AscH(-) with k(*OH + H(4)B) = 8.8 x 10(9) M(-1) s(-1), k(NO(2)(*) + H(4)B) = 9.4 x 10(8) M(-1) s(-1), k(CO(3)(*-) + H(4)B) = 4.6 x 10(9) M(-1) s(-1), and k(GS(*) + H(4)B) = 1.1 x 10(9) M(-1) s(-1), respectively. The glutathione disulfide radical anion (GSSG(*-)) rapidly reduces the pterin to the tetrahydrobiopterin radical anion (H(4)B(*-)) with a rate constant of k(GSSG(*-) + H(4)B) similar 4.5 x 10(8) M(-1) s(-1). The results are discussed in the context of the general antioxidant properties of the pterin and the redox role played by H(4)B in NOS catalysis.
authors.affiliation: Gray Cancer Institute, Mount Vernon Hospital, Northwood, Middlesex, UK.
authors.forename: Kantilal B
authors.initials: KB
authors.lastname: Patel
authors.forename: Michael R L
authors.initials: MR
authors.lastname: Stratford
authors.forename: Peter
authors.initials: P
authors.lastname: Wardman
authors.forename: Steven A
authors.initials: SA
authors.lastname: Everett
mesh_terms: D001205:Ascorbic Acid / Q000378:metabolism*; D001708:Biopterins / Q000031:analogs & derivatives* / Q000378:metabolism*; D002254:Carbonates / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D016166:Free Radical Scavengers / Q000378:metabolism*; D005609:Free Radicals / Q000378:metabolism*; D019803:Glutathione Disulfide / Q000378:metabolism; D006863:Hydrogen-Ion Concentration; D017665:Hydroxyl Radical / Q000378:metabolism; D007700:Kinetics; D019001:Nitric Oxide Synthase / Q000378:metabolism; D009585:Nitrogen Dioxide / Q000378:metabolism; D010084:Oxidation-Reduction; D011675:Pulse Radiolysis; D013997:Time Factors
chemical_list: D002254:Carbonates; D016166:Free Radical Scavengers; D005609:Free Radicals; D001708:Biopterins; D017665:Hydroxyl Radical; D019001:Nitric Oxide Synthase; C003402:sapropterin; D001205:Ascorbic Acid; D009585:Nitrogen Dioxide; D019803:Glutathione Disulfide