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

Author

Listed:
  • 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)

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.

Suggested Citation

  • Eric M. Koehn & Todd Fleischmann & John A. Conrad & Bruce A. Palfey & Scott A. Lesley & Irimpan I. Mathews & Amnon Kohen, 2009. "An unusual mechanism of thymidylate biosynthesis in organisms containing the thyX gene," Nature, Nature, vol. 458(7240), pages 919-923, April.
    • Handle: RePEc:nat:nature:v:458:y:2009:i:7240:d:10.1038_nature07973
    DOI: 10.1038/nature07973
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    Cited by:

    1. Jonathan Filée & Hubert F. Becker & Lucille Mellottee & Rima Zein Eddine & Zhihui Li & Wenlu Yin & Jean-Christophe Lambry & Ursula Liebl & Hannu Myllykallio, 2023. "Bacterial origins of thymidylate metabolism in Asgard archaea and Eukarya," Nature Communications, Nature, vol. 14(1), pages 1-15, December.

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