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Folate binding site of flavin-dependent thymidylate synthase

Academic Article
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Overview

authors

  • Koehn, E. M.
  • Perissinotti, L. L.
  • Moghram, S.
  • Prabhakar, A.
  • Lesley, Scott
  • Mathews, I. I.
  • Kohen, A.

publication date

  • September 2012

journal

  • Proceedings of the National Academy of Sciences of the United States of America  Journal

abstract

  • The DNA nucleotide thymidylate is synthesized by the enzyme thymidylate synthase, which catalyzes the reductive methylation of deoxyuridylate using the cofactor methylene-tetrahydrofolate (CH(2)H(4)folate). Most organisms, including humans, rely on the thyA- or TYMS-encoded classic thymidylate synthase, whereas, certain microorganisms, including all Rickettsia and other pathogens, use an alternative thyX-encoded flavin-dependent thymidylate synthase (FDTS). Although several crystal structures of FDTSs have been reported, the absence of a structure with folates limits understanding of the molecular mechanism and the scope of drug design for these enzymes. Here we present X-ray crystal structures of FDTS with several folate derivatives, which together with mutagenesis, kinetic analysis, and computer modeling shed light on the cofactor binding and function. The unique structural data will likely facilitate further elucidation of FDTSs' mechanism and the design of structure-based inhibitors as potential leads to new antimicrobial drugs.

subject areas

  • Bacterial Proteins
  • Binding Sites
  • Crystallography, X-Ray
  • Folic Acid
  • Protein Structure, Tertiary
  • Rickettsia
  • Thymidylate Synthase
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Research

keywords

  • crystallography
  • methylene transfer
  • thymine biosynthesis
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Identity

PubMed Central ID

  • PMC3465422

International Standard Serial Number (ISSN)

  • 0027-8424

Digital Object Identifier (DOI)

  • 10.1073/pnas.1206077109

PubMed ID

  • 23019356
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Additional Document Info

start page

  • 15722

end page

  • 15727

volume

  • 109

issue

  • 39

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