TAILIEUCHUNG - Báo cáo khoa học: Oxidase activity of a flavin-dependent thymidylate synthase

Flavin-dependent thymidylate synthases (FDTS) catalyze the production of dTMP from dUMP and N 5 ,N 10 -methylene-5,6,7,8-tetrahydrofolate (CH2H4 folate). In contrast to human and other classical thymidylate synth-ases, the activity of FDTS depends on a FAD coenzyme, and its catalytic mechanism is very different. | ỊFEBS Journal Oxidase activity of a flavin-dependent thymidylate synthase Zhen Wang1 Anatoly Chernyshev1 Eric M. Koehn1 Tony D. Manuel1 Scott A. Lesley2 and Amnon Kohen1 1 Department of Chemistry University of Iowa Iowa City IA USA 2 The Joint Center for StructuralGenomics at The Genomics Institute of Novartis Research Foundation San Diego CA USA Keywords competitive substrates enzyme kinetics flavin oxidase thymidylate synthase Correspondence A. Kohen Department of Chemistry University of Iowa Iowa City IA 52242 USA Fax 1 319 335 1270 Tel 1 319 335 0234 E-mail amnon-kohen@ Website http kohen Received 3 February 2009 revised 10 March 2009 accepted 12 March 2009 doi Flavin-dependent thymidylate synthases FDTS catalyze the production of dTMP from dUMP and N5 N10-methylene-5 6 7 8-tetrahydrofolate CH2H4folate . In contrast to human and other classical thymidylate synthases the activity of FDTS depends on a FAD coenzyme and its catalytic mechanism is very different. Several human pathogens rely on this recently discovered enzyme making it an attractive target for novel antibiotics. Like many other flavoenzymes FDTS can function as an oxidase which catalyzes the reduction of O2 to H2O2 using reduced NADPH or other reducing agents. In this study we exploit the oxidase activity of FDTS from Thermatoga maritima to probe the binding and release features of the substrates and products during its synthase activity. Results from steady-state and single-turnover experiments suggest a sequential kinetic mechanism of substrate binding during FDTS oxidase activity. CH2H4folate competitively inhibits the oxidase activity which indicates that CH2H4folate and O2 compete for the same reduced and dUMP-activated enzymatic complex FDTS-FADH2-NADP -dUMP . These studies imply that the binding of CH2H4folate precedes NADP release during FDTS activity. The inhibition constant of CH2H4folate towards the oxidase activity was .

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• Flavin dependent thymidylate synthases (FDTS) catalyze the production of dTMP from dUMP and N 5
• N 10 methylene 5
• 8 tetrahydrofolate (CH2H4 folate)
• In contrast to human and other classical thymidylate synth ases
• the activity of FDTS depends on a FAD coenzyme
• and its catalytic mechanism is very different
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