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• W2437715850 endingPage "6068" @default.
• W2437715850 startingPage "6061" @default.
• W2437715850 abstract "Thymidylate synthase (TSase) catalyzes the de novo biosynthesis of thymidylate, a precursor for DNA, and is thus an important target for chemotherapeutics and antibiotics. Two sequential C–H bond cleavages catalyzed by TSase are of particular interest: a reversible proton abstraction from the 2′-deoxyuridylate substrate, followed by an irreversible hydride transfer forming the thymidylate product. QM/MM calculations of the former predicted a mechanism in which the abstraction of the proton leads to formation of a novel nucleotide-folate intermediate that is not covalently bound to the enzyme (Wang, Z.; Ferrer, S.; Moliner, V.; Kohen, A. Biochemistry 2013, 52, 2348–2358). Existence of such an intermediate would hold promise as a target for a new class of drugs. Calculations of the subsequent hydride transfer predicted a concerted H transfer and elimination of the enzymatic cysteine (Kanaan, N.; Ferrer, S.; Marti, S.; Garcia-Viloca, M.; Kohen, A.; Moliner, V. J. Am. Chem. Soc. 2011, 133, 6692–6702). A key to both C–H activations is a highly conserved arginine (R166) that stabilizes the transition state of both H transfers. Here, we test these predictions by studying the R166-to-lysine mutant of Escherichia coli TSase (R166 K) using intrinsic kinetic isotope effects and their temperature dependence to assess effects of the mutation on both chemical steps. The findings confirmed the predictions made by the QM/MM calculations, implicate R166 as an integral component of both reaction coordinates, and thus provide critical support to the nucleotide-folate intermediate as a new target for rational drug design." @default.
• W2437715850 created "2016-06-24" @default.
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• W2437715850 date "2015-09-16" @default.
• W2437715850 modified "2023-10-15" @default.
• W2437715850 title "Activation of Two Sequential H Transfers in the Thymidylate Synthase Catalyzed Reaction" @default.
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• W2437715850 doi "https://doi.org/10.1021/acscatal.5b01332" @default.
• W2437715850 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/4643671" @default.
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