@article{1e5d8b2d0c2b4b70a898286d7c940176,
title = "A sugar phosphatase regulates the methylerythritol phosphate (MEP) pathway in malaria parasites",
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.",
author = "Guggisberg, {Ann M.} and Jooyoung Park and Edwards, {Rachel L.} and Kelly, {Megan L.} and Hodge, {Dana M.} and Tolia, {Niraj H.} and Odom, {Audrey R.}",
note = "Funding Information: We thank Andreas Mitchell for excellent technical assistance in the generation of FSMR strains. We also thank J. Nix and ALS Beamline 4.2.2 (contract DE-AC02-05CH11231) for assistance with X-ray data collection. We are grateful to Daniel Goldberg (Washington University) for critical reading of the manuscript. This work was supported by the Children{\textquoteright}s Discovery Institute of Washington University and St Louis Children{\textquoteright}s Hospital (MD-LI-2011-171, to AO and NT), NIH/NIAID R01AI103280 (to AO), a March of Dimes Basil O{\textquoteright}Connor Starter Scholar Research Award (to AO) and a Doris Duke Charitable Foundation Clinical Scientist Development award (to AO). A.M.G. is supported by an NIGMS Training grant (5T32GM007067) and a Monsanto Excellence Fund Graduate Fellowship. J.P. is supported by a Sondra Schlesinger Graduate Student Fellowship from Washington University. M.L.K. was supported by an HHMI Summer Scholars in Biology and Biomedical Research grant and a Washington University Summer Undergraduate Research Fellowship. M.L.K. was also supported by an ASM Undergraduate Research Fellowship and the Amgen Scholars Program at Washington University. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.",
year = "2014",
month = jul,
day = "24",
doi = "10.1038/ncomms5467",
language = "English",
volume = "5",
journal = "Nature communications",
issn = "2041-1723",
}