An unusual mechanism of thymidylate biosynthesis in organisms containing the thyX gene

Eric M. Koehn, Todd Fleischmann, John A. Conrad, Bruce A. Palfey, Scott A. Lesley, Irimpan I. Mathews and Amnon Kohen ()
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Eric M. Koehn: University of Iowa, Iowa City, Iowa 52242, USA
Todd Fleischmann: University of Iowa, Iowa City, Iowa 52242, USA
John A. Conrad: University of Michigan Medical School, Ann Arbor, Michigan 48109, USA
Bruce A. Palfey: University of Michigan Medical School, Ann Arbor, Michigan 48109, USA
Scott A. Lesley: The Joint Center for Structural Genomics at the Genomics Institute of Novartis Research Foundation, San Diego, California 92121, USA
Irimpan I. Mathews: Stanford Synchrotron Radiation Laboratory, Stanford University, Menlo Park, California 94025, USA
Amnon Kohen: University of Iowa, Iowa City, Iowa 52242, USA

Nature, 2009, vol. 458, issue 7240, 919-923

Abstract: Byways to thymidine Thymine, one of the four ubiquitous DNA bases, is synthesized by the enzyme thymidylate synthase, which catalyses the methylation of the uracil moiety of 2′-deoxyuridine-5′-monophosphate. Conventional thymidylate synthases, including the human enzyme, use an active site amino acid side-chain to activate the substrate at this stage of the reaction. A few years ago an alternative mode of thymidylate biosynthesis was recognized in a number of organisms — including several human pathogens — this one involving a flavin-dependent thymidylate synthase, the product of the thyX gene. Koehn et al. have now characterized this alternative route to thymine, and find that in does not require an enzymatic nucleophile. Instead, a hydride ion appears to be transferred from the reduced flavin cofactor directly to the uracil ring. Since several human pathogens depend on this biosynthetic pathway for DNA biosynthesis, it may be possible to develop new, highly selective antibiotics that target this enzyme.

Date: 2009
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DOI: 10.1038/nature07973

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