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A sugar phosphatase regulates the methylerythritol phosphate (MEP) pathway in malaria parasites

Author

Listed:
  • Ann M. Guggisberg

    (Washington University School of Medicine)

  • Jooyoung Park

    (Washington University School of Medicine)

  • Rachel L. Edwards

    (Washington University School of Medicine)

  • Megan L. Kelly

    (Washington University School of Medicine)

  • Dana M. Hodge

    (Washington University School of Medicine)

  • Niraj H. Tolia

    (Washington University School of Medicine
    Washington University School of Medicine)

  • Audrey R. Odom

    (Washington University School of Medicine
    Washington University School of Medicine)

Abstract

Isoprenoid biosynthesis through the methylerythritol phosphate (MEP) pathway generates commercially important products and is a target for antimicrobial drug development. MEP pathway regulation is poorly understood in microorganisms. Here we employ a forward genetics approach to understand MEP pathway regulation in the malaria parasite, Plasmodium falciparum. The antimalarial fosmidomycin inhibits the MEP pathway enzyme deoxyxylulose 5-phosphate reductoisomerase (DXR). Fosmidomycin-resistant P. falciparum are enriched for changes in the PF3D7_1033400 locus (hereafter referred to as PfHAD1), encoding a homologue of haloacid dehalogenase (HAD)-like sugar phosphatases. We describe the structural basis for loss-of-function PfHAD1 alleles and find that PfHAD1 dephosphorylates a variety of sugar phosphates, including glycolytic intermediates. Loss of PfHAD1 is required for fosmidomycin resistance. Parasites lacking PfHAD1 have increased MEP pathway metabolites, particularly the DXR substrate, deoxyxylulose 5-phosphate. PfHAD1 therefore controls substrate availability to the MEP pathway. Because PfHAD1 has homologues in plants and bacteria, other HAD proteins may be MEP pathway regulators.

Suggested Citation

  • Ann M. Guggisberg & Jooyoung Park & Rachel L. Edwards & Megan L. Kelly & Dana M. Hodge & Niraj H. Tolia & Audrey R. Odom, 2014. "A sugar phosphatase regulates the methylerythritol phosphate (MEP) pathway in malaria parasites," Nature Communications, Nature, vol. 5(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms5467
    DOI: 10.1038/ncomms5467
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