Mechanism of "Uncoupled" Tetrahydropterin Oxidation by Phenylalanine Hydroxylase†

Thomas A. Dix, Stephen Benkovic

Research output: Contribution to journalArticle

49 Scopus citations

Abstract

Phenylalanine hydroxylase can catalyze the oxidation of its tetrahydropterin cofactor without concomitant substrate hydroxylation. We now report that this "uncoupled" tetrahydropterin oxidation is mechanistically distinct from normal enzyme turnover. Tetrahydropterins are oxygenated to 4a-carbinolamines only during catalytic events involving substrate hydroxylation. In the absence of hydroxylation tetrahydropterins are oxidized directly to quinonoid dihydropterins. Stoichiometry studies define a ratio of two tetrahydropterins oxidized per O2 consumed in uncoupled enzyme turnover, thus indicating the complete reduction of O2 to H2O. Complementary results establish the lack of H2O2 production by the enzyme when uncoupled and define a tetrahydropterin oxidase activity for the enzyme. Thus, the hydroxylating intermediate of phenylalanine hydroxylase may be discharged in two ways, by substrate hydroxylation or by electron abstraction. A mechanism is proposed for the uncoupled oxidation of tetrahydropterins by phenylalanine hydroxylase, and the significance of these findings is discussed.

Original languageEnglish (US)
Pages (from-to)5839-5846
Number of pages8
JournalBiochemistry
Volume24
Issue number21
DOIs
StatePublished - Oct 1 1985

All Science Journal Classification (ASJC) codes

  • Biochemistry

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