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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...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2022
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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. |
format | Online Article Text |
id | pubmed-9512246 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
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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