A sugar phosphatase regulates the methylerythritol phosphate (MEP) pathway in malaria parasites.
Nat Commun
; 5: 4467, 2014 Jul 24.
Article
em En
| MEDLINE
| ID: mdl-25058848
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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Plasmodium falciparum
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Fosfatos Açúcares
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Monoéster Fosfórico Hidrolases
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Eritritol
Idioma:
En
Ano de publicação:
2014
Tipo de documento:
Article