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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| Veröffentlicht in: | PLoS pathogens 2022-09, Vol.18 (9), p.e1010803-e1010803 |
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| creator | Jezewski, Andrew J Guggisberg, Ann M Hodge, Dana M Ghebremichael, Naomi John, Gavin Nicholas McLellan, Lisa K Odom John, Audrey Ragan |
| 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. |
| doi_str_mv | 10.1371/journal.ppat.1010803 |
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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.</description><identifier>ISSN: 1553-7374</identifier><identifier>ISSN: 1553-7366</identifier><identifier>EISSN: 1553-7374</identifier><identifier>DOI: 10.1371/journal.ppat.1010803</identifier><identifier>PMID: 36103572</identifier><language>eng</language><publisher>San Francisco: Public Library of Science</publisher><subject>Antiparasitic agents ; Biology and Life Sciences ; Biomarkers ; Biosynthesis ; Carbon ; Cloning ; Dehydrogenases ; Dosage and administration ; Drug metabolism ; Drug resistance ; Drug therapy ; Enzymes ; Erythrocytes ; Fosmidomycin ; Genetic aspects ; Genetic screening ; Genomes ; Glyceraldehyde ; Glyceraldehyde 3-phosphate ; Glyceraldehyde-3-phosphate dehydrogenase ; Glycolysis ; Heme ; Malaria ; Mammals ; Medicine and Health Sciences ; Metabolism ; Metabolites ; Mutation ; Oligomerization ; Parasite resistance ; Parasites ; Physical fitness ; Plasmodium falciparum ; Prevention ; Proteins ; Respiration ; Risk factors ; Therapeutic targets ; Vector-borne diseases</subject><ispartof>PLoS pathogens, 2022-09, Vol.18 (9), p.e1010803-e1010803</ispartof><rights>COPYRIGHT 2022 Public Library of Science</rights><rights>2022 Jezewski et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. 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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.</description><subject>Antiparasitic agents</subject><subject>Biology and Life Sciences</subject><subject>Biomarkers</subject><subject>Biosynthesis</subject><subject>Carbon</subject><subject>Cloning</subject><subject>Dehydrogenases</subject><subject>Dosage and administration</subject><subject>Drug metabolism</subject><subject>Drug resistance</subject><subject>Drug therapy</subject><subject>Enzymes</subject><subject>Erythrocytes</subject><subject>Fosmidomycin</subject><subject>Genetic aspects</subject><subject>Genetic screening</subject><subject>Genomes</subject><subject>Glyceraldehyde</subject><subject>Glyceraldehyde 3-phosphate</subject><subject>Glyceraldehyde-3-phosphate dehydrogenase</subject><subject>Glycolysis</subject><subject>Heme</subject><subject>Malaria</subject><subject>Mammals</subject><subject>Medicine and Health 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malaria parasites</atitle><jtitle>PLoS pathogens</jtitle><date>2022-09-14</date><risdate>2022</risdate><volume>18</volume><issue>9</issue><spage>e1010803</spage><epage>e1010803</epage><pages>e1010803-e1010803</pages><issn>1553-7374</issn><issn>1553-7366</issn><eissn>1553-7374</eissn><abstract>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.</abstract><cop>San Francisco</cop><pub>Public Library of Science</pub><pmid>36103572</pmid><doi>10.1371/journal.ppat.1010803</doi><tpages>e1010803</tpages><orcidid>https://orcid.org/0000-0001-8395-8537</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Antiparasitic agents Biology and Life Sciences Biomarkers Biosynthesis Carbon Cloning Dehydrogenases Dosage and administration Drug metabolism Drug resistance Drug therapy Enzymes Erythrocytes Fosmidomycin Genetic aspects Genetic screening Genomes Glyceraldehyde Glyceraldehyde 3-phosphate Glyceraldehyde-3-phosphate dehydrogenase Glycolysis Heme Malaria Mammals Medicine and Health Sciences Metabolism Metabolites Mutation Oligomerization Parasite resistance Parasites Physical fitness Plasmodium falciparum Prevention Proteins Respiration Risk factors Therapeutic targets Vector-borne diseases |
| title | GAPDH mediates drug resistance and metabolism in Plasmodium falciparum malaria parasites |
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