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A sugar phosphatase regulates the methylerythritol phosphate (MEP) pathway in malaria parasites
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. We employ a forward genetics approach to understand MEP pathway re...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4112465/ https://www.ncbi.nlm.nih.gov/pubmed/25058848 http://dx.doi.org/10.1038/ncomms5467 |
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author | Guggisberg, Ann M. Park, Jooyoung Edwards, Rachel L. Kelly, Megan L. Hodge, Dana M. Tolia, Niraj H. Odom, Audrey R. |
author_facet | Guggisberg, Ann M. Park, Jooyoung Edwards, Rachel L. Kelly, Megan L. Hodge, Dana M. Tolia, Niraj H. Odom, Audrey R. |
author_sort | Guggisberg, Ann M. |
collection | PubMed |
description | 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. 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 homologs in plants and bacteria, other HAD proteins may be MEP pathway regulators. |
format | Online Article Text |
id | pubmed-4112465 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
record_format | MEDLINE/PubMed |
spelling | pubmed-41124652015-01-24 A sugar phosphatase regulates the methylerythritol phosphate (MEP) pathway in malaria parasites Guggisberg, Ann M. Park, Jooyoung Edwards, Rachel L. Kelly, Megan L. Hodge, Dana M. Tolia, Niraj H. Odom, Audrey R. Nat Commun Article 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. 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 homologs in plants and bacteria, other HAD proteins may be MEP pathway regulators. 2014-07-24 /pmc/articles/PMC4112465/ /pubmed/25058848 http://dx.doi.org/10.1038/ncomms5467 Text en http://www.nature.com/authors/editorial_policies/license.html#terms Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms |
spellingShingle | Article Guggisberg, Ann M. Park, Jooyoung Edwards, Rachel L. Kelly, Megan L. Hodge, Dana M. Tolia, Niraj H. Odom, Audrey R. A sugar phosphatase regulates the methylerythritol phosphate (MEP) pathway in malaria parasites |
title | A sugar phosphatase regulates the methylerythritol phosphate (MEP) pathway in malaria parasites |
title_full | A sugar phosphatase regulates the methylerythritol phosphate (MEP) pathway in malaria parasites |
title_fullStr | A sugar phosphatase regulates the methylerythritol phosphate (MEP) pathway in malaria parasites |
title_full_unstemmed | A sugar phosphatase regulates the methylerythritol phosphate (MEP) pathway in malaria parasites |
title_short | A sugar phosphatase regulates the methylerythritol phosphate (MEP) pathway in malaria parasites |
title_sort | sugar phosphatase regulates the methylerythritol phosphate (mep) pathway in malaria parasites |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4112465/ https://www.ncbi.nlm.nih.gov/pubmed/25058848 http://dx.doi.org/10.1038/ncomms5467 |
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