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

Nat Commun. 2014 Jul 24:5:4467. doi: 10.1038/ncomms5467.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Aldose-Ketose Isomerases / antagonists & inhibitors
  • Aldose-Ketose Isomerases / metabolism
  • Antimalarials / pharmacology
  • Catalytic Domain
  • Cytoplasm / metabolism
  • Drug Resistance
  • Erythritol / analogs & derivatives*
  • Erythritol / metabolism
  • Fosfomycin / analogs & derivatives
  • Fosfomycin / pharmacology
  • Genetic Complementation Test
  • Phosphoric Monoester Hydrolases / chemistry*
  • Phosphoric Monoester Hydrolases / genetics
  • Phosphoric Monoester Hydrolases / metabolism*
  • Plasmodium falciparum / drug effects
  • Plasmodium falciparum / genetics
  • Plasmodium falciparum / metabolism*
  • Protein Conformation
  • Protozoan Proteins / chemistry
  • Protozoan Proteins / genetics
  • Protozoan Proteins / metabolism
  • Sugar Phosphates / metabolism*
  • Xylose / analogs & derivatives
  • Xylose / metabolism

Substances

  • 2-C-methylerythritol 4-phosphate
  • Antimalarials
  • Protozoan Proteins
  • Sugar Phosphates
  • deoxyxylulose phosphate
  • Fosfomycin
  • fosmidomycin
  • Xylose
  • 1-deoxy-D-xylulose 5-phosphate reductoisomerase
  • Phosphoric Monoester Hydrolases
  • sugar-phosphatase
  • Aldose-Ketose Isomerases
  • Erythritol

Associated data

  • BioProject/PRJNA222697
  • PDB/4QJB
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