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

Ann M. Guggisberg, Jooyoung Park, Rachel L. Edwards, Megan L. Kelly, Dana M. Hodge, Niraj H. Tolia, Audrey R. Odom

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39 Scopus citations

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.

Original languageEnglish
Article number4467
JournalNature communications
Volume5
DOIs
StatePublished - Jul 24 2014

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    Guggisberg, A. M., Park, J., Edwards, R. L., Kelly, M. L., Hodge, D. M., Tolia, N. H., & Odom, A. R. (2014). A sugar phosphatase regulates the methylerythritol phosphate (MEP) pathway in malaria parasites. Nature communications, 5, [4467]. https://doi.org/10.1038/ncomms5467