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GAPDH mediates drug resistance and metabolism in Plasmodium falciparum malaria parasites

Efforts to control the global malaria health crisis are undermined by antimalarial resistance. Identifying mechanisms of resistance will uncover the underlying biology of the Plasmodium falciparum malaria parasites that allow evasion of our most promising therapeutics and may reveal new drug targets...

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Autores principales: Jezewski, Andrew J., Guggisberg, Ann M., Hodge, Dana M., Ghebremichael, Naomi, John, Gavin Nicholas, McLellan, Lisa K., Odom John, Audrey Ragan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9512246/
https://www.ncbi.nlm.nih.gov/pubmed/36103572
http://dx.doi.org/10.1371/journal.ppat.1010803
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author Jezewski, Andrew J.
Guggisberg, Ann M.
Hodge, Dana M.
Ghebremichael, Naomi
John, Gavin Nicholas
McLellan, Lisa K.
Odom John, Audrey Ragan
author_facet Jezewski, Andrew J.
Guggisberg, Ann M.
Hodge, Dana M.
Ghebremichael, Naomi
John, Gavin Nicholas
McLellan, Lisa K.
Odom John, Audrey Ragan
author_sort Jezewski, Andrew J.
collection PubMed
description Efforts to control the global malaria health crisis are undermined by antimalarial resistance. Identifying mechanisms of resistance will uncover the underlying biology of the Plasmodium falciparum malaria parasites that allow evasion of our most promising therapeutics and may reveal new drug targets. We utilized fosmidomycin (FSM) as a chemical inhibitor of plastidial isoprenoid biosynthesis through the methylerythritol phosphate (MEP) pathway. We have thus identified an unusual metabolic regulation scheme in the malaria parasite through the essential glycolytic enzyme, glyceraldehyde 3-phosphate dehydrogenase (GAPDH). Two parallel genetic screens converged on independent but functionally analogous resistance alleles in GAPDH. Metabolic profiling of FSM-resistant gapdh mutant parasites indicates that neither of these mutations disrupt overall glycolytic output. While FSM-resistant GAPDH variant proteins are catalytically active, they have reduced assembly into the homotetrameric state favored by wild-type GAPDH. Disrupted oligomerization of FSM-resistant GAPDH variant proteins is accompanied by altered enzymatic cooperativity and reduced susceptibility to inhibition by free heme. Together, our data identifies a new genetic biomarker of FSM-resistance and reveals the central role of GAPDH in MEP pathway control and antimalarial sensitivity.
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spelling pubmed-95122462022-09-27 GAPDH mediates drug resistance and metabolism in Plasmodium falciparum malaria parasites Jezewski, Andrew J. Guggisberg, Ann M. Hodge, Dana M. Ghebremichael, Naomi John, Gavin Nicholas McLellan, Lisa K. Odom John, Audrey Ragan PLoS Pathog Research Article Efforts to control the global malaria health crisis are undermined by antimalarial resistance. Identifying mechanisms of resistance will uncover the underlying biology of the Plasmodium falciparum malaria parasites that allow evasion of our most promising therapeutics and may reveal new drug targets. We utilized fosmidomycin (FSM) as a chemical inhibitor of plastidial isoprenoid biosynthesis through the methylerythritol phosphate (MEP) pathway. We have thus identified an unusual metabolic regulation scheme in the malaria parasite through the essential glycolytic enzyme, glyceraldehyde 3-phosphate dehydrogenase (GAPDH). Two parallel genetic screens converged on independent but functionally analogous resistance alleles in GAPDH. Metabolic profiling of FSM-resistant gapdh mutant parasites indicates that neither of these mutations disrupt overall glycolytic output. While FSM-resistant GAPDH variant proteins are catalytically active, they have reduced assembly into the homotetrameric state favored by wild-type GAPDH. Disrupted oligomerization of FSM-resistant GAPDH variant proteins is accompanied by altered enzymatic cooperativity and reduced susceptibility to inhibition by free heme. Together, our data identifies a new genetic biomarker of FSM-resistance and reveals the central role of GAPDH in MEP pathway control and antimalarial sensitivity. Public Library of Science 2022-09-14 /pmc/articles/PMC9512246/ /pubmed/36103572 http://dx.doi.org/10.1371/journal.ppat.1010803 Text en © 2022 Jezewski et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Jezewski, Andrew J.
Guggisberg, Ann M.
Hodge, Dana M.
Ghebremichael, Naomi
John, Gavin Nicholas
McLellan, Lisa K.
Odom John, Audrey Ragan
GAPDH mediates drug resistance and metabolism in Plasmodium falciparum malaria parasites
title GAPDH mediates drug resistance and metabolism in Plasmodium falciparum malaria parasites
title_full GAPDH mediates drug resistance and metabolism in Plasmodium falciparum malaria parasites
title_fullStr GAPDH mediates drug resistance and metabolism in Plasmodium falciparum malaria parasites
title_full_unstemmed GAPDH mediates drug resistance and metabolism in Plasmodium falciparum malaria parasites
title_short GAPDH mediates drug resistance and metabolism in Plasmodium falciparum malaria parasites
title_sort gapdh mediates drug resistance and metabolism in plasmodium falciparum malaria parasites
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9512246/
https://www.ncbi.nlm.nih.gov/pubmed/36103572
http://dx.doi.org/10.1371/journal.ppat.1010803
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