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.
authors: Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors: Ann M
authors: AM
authors: Guggisberg
authors: Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors: Jooyoung
authors: J
authors: Park
authors: Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors: Rachel L
authors: RL
authors: Edwards
authors: Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors: Megan L
authors: ML
authors: Kelly
authors: Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors: Dana M
authors: DM
authors: Hodge
authors: Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110, USA.|Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors: Niraj H
authors: NH
authors: Tolia
authors: Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA.|Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors: Audrey R
authors: AR
authors: Odom
mesh_terms: D019747:Aldose-Ketose Isomerases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000962:Antimalarials / Q000494:pharmacology; D020134:Catalytic Domain; D003593:Cytoplasm / Q000378:metabolism; D004351:Drug Resistance; D004896:Erythritol / Q000031:analogs & derivatives* / Q000378:metabolism; D005578:Fosfomycin / Q000031:analogs & derivatives / Q000494:pharmacology; D005816:Genetic Complementation Test; D010744:Phosphoric Monoester Hydrolases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D010963:Plasmodium falciparum / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D011487:Protein Conformation; D015800:Protozoan Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D013403:Sugar Phosphates / Q000378:metabolism*; D014994:Xylose / Q000031:analogs & derivatives / Q000378:metabolism
chemical_list: C114232:2-C-methylerythritol 4-phosphate; D000962:Antimalarials; D015800:Protozoan Proteins; D013403:Sugar Phosphates; C492551:deoxyxylulose phosphate; D005578:Fosfomycin; C024640:fosmidomycin; D014994:Xylose; C114231:1-deoxy-D-xylulose 5-phosphate reductoisomerase; D010744:Phosphoric Monoester Hydrolases; C022700:sugar-phosphatase; D019747:Aldose-Ketose Isomerases; D004896:Erythritol