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Structure and activity of Yersinia pestis 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase as a novel target for the development of antiplague therapeutics

  1. Author:
    Blaszczyk, J.
    Li, Y.
    Cherry, S.
    Alexandratos, J.
    Wu, Y.
    Shaw, G.
    Tropea, J. E.
    Waugh, D. S.
    Yan, H. G.
    Ji, X. H.

  2. Author Address

    Michigan State Univ, Dept Biochem & Mol Biol, E Lansing, MI 48824 USA. NCI, Macromol Crystallog Lab, Frederick, MD 21702 USA.;Yan, HG, Michigan State Univ, Dept Biochem & Mol Biol, E Lansing, MI 48824 USA.;yanh@msu.edu jix@ncifcrf.gov
    1. Year: 2007
    2. Date: Nov
  2. Journal: Acta Crystallographica Section D-Biological Crystallography
    1. 63
    2. Pages: 1169-1177
  4. Type of Article: Article
  5. ISSN: 0907-4449
  1. Abstract:

    6-Hydroxymethyl-7,8-dihydropterin pyrophosphokinase (HPPK) is a key enzyme in the folate-biosynthetic pathway and is essential for microorganisms but absent from mammals. HPPK catalyzes Mg2+-dependent pyrophosphoryl transfer from ATP to 6-hydroxymethyl-7,8-dihydropterin (HP). Previously, three-dimensional structures of Escherichia coli HPPK (EcHPPK) have been determined at almost every stage of its catalytic cycle and the reaction mechanism has been established. Here, the crystal structure of Yersinia pestis HPPK (YpHPPK) in complex with HP and an ATP analog is presented together with thermodynamic and kinetic characterizations. The two HPPK molecules differ significantly in a helix-loop area (alpha 2-Lp3). YpHPPK has lower affinities than EcHPPK for both nucleotides and HP, but its rate constants for the mechanistic steps of both chemical transformation and product release are comparable with those of EcHPPK. Y. pestis, which causes plague, is a category A select agent according to the Centers for Disease Control and Prevention (CDC). Therefore, these structural and biochemical data are valuable for the design of novel medical countermeasures against plague.

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External Sources

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  2. DOI: 10.1107/s0907444907047452
  3. View record in Web of Science®
  4. WOS: 000251029800006

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