Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Guggisberg, Ann M., Park, Jooyoung, Edwards, Rachel L., Kelly, Megan L., Hodge, Dana M., Tolia, Niraj H., Odom, Audrey R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2014
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
_version_ 1782328184957566976
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
work_keys_str_mv AT guggisbergannm asugarphosphataseregulatesthemethylerythritolphosphatemeppathwayinmalariaparasites
AT parkjooyoung asugarphosphataseregulatesthemethylerythritolphosphatemeppathwayinmalariaparasites
AT edwardsrachell asugarphosphataseregulatesthemethylerythritolphosphatemeppathwayinmalariaparasites
AT kellymeganl asugarphosphataseregulatesthemethylerythritolphosphatemeppathwayinmalariaparasites
AT hodgedanam asugarphosphataseregulatesthemethylerythritolphosphatemeppathwayinmalariaparasites
AT tolianirajh asugarphosphataseregulatesthemethylerythritolphosphatemeppathwayinmalariaparasites
AT odomaudreyr asugarphosphataseregulatesthemethylerythritolphosphatemeppathwayinmalariaparasites
AT guggisbergannm sugarphosphataseregulatesthemethylerythritolphosphatemeppathwayinmalariaparasites
AT parkjooyoung sugarphosphataseregulatesthemethylerythritolphosphatemeppathwayinmalariaparasites
AT edwardsrachell sugarphosphataseregulatesthemethylerythritolphosphatemeppathwayinmalariaparasites
AT kellymeganl sugarphosphataseregulatesthemethylerythritolphosphatemeppathwayinmalariaparasites
AT hodgedanam sugarphosphataseregulatesthemethylerythritolphosphatemeppathwayinmalariaparasites
AT tolianirajh sugarphosphataseregulatesthemethylerythritolphosphatemeppathwayinmalariaparasites
AT odomaudreyr sugarphosphataseregulatesthemethylerythritolphosphatemeppathwayinmalariaparasites