4QJB

Crystal structure of the sugar phosphatase PfHAD1 from Plasmodium falciparum

Summary for 4QJB

• Entry DOI: 10.2210/pdb4qjb/pdb
• Descriptor: Haloacid dehalogenase-like hydrolase, MAGNESIUM ION, CHLORIDE ION, ... (4 entities in total)
• Functional Keywords: had-like hydrolase, had rossmanoid fold, three-layered alpha-beta-alpha sandwich, sugar phosphatase, hydrolase
• Biological source: Plasmodium falciparum
• Total number of polymer chains: 2
• Total formula weight: 67948.82

Authors

Tolia, N.H.,Park, J. (deposition date: 2014-06-03, release date: 2014-07-02, Last modification date: 2024-02-28)

Primary citation

Guggisberg, A.M.,Park, J.,Edwards, R.L.,Kelly, M.L.,Hodge, D.M.,Tolia, N.H.,Odom, A.R.
A sugar phosphatase regulates the methylerythritol phosphate (MEP) pathway in malaria parasites.
Nat Commun, 5:4467-4467, 2014

PubMed 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.

PubMed: 25058848
DOI: 10.1038/ncomms5467

Experimental method

X-RAY DIFFRACTION (2.05 Å)