{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T10:08:57Z","timestamp":1790676537214,"version":"4.1.0"},"update-to":[{"DOI":"10.1371\/journal.ppat.1010803","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2022,9,26]],"date-time":"2022-09-26T00:00:00Z","timestamp":1664150400000}}],"reference-count":53,"publisher":"Public Library of Science (PLoS)","issue":"9","license":[{"start":{"date-parts":[[2022,9,14]],"date-time":"2022-09-14T00:00:00Z","timestamp":1663113600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["T32GM007067, 2T32AI007511"],"award-info":[{"award-number":["T32GM007067, 2T32AI007511"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100001247","name":"Monsanto Fund","doi-asserted-by":"publisher","award":["Monstanto Excellence Fund Graduate Fellowship"],"award-info":[{"award-number":["Monstanto Excellence Fund Graduate Fellowship"]}],"id":[{"id":"10.13039\/100001247","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007268","name":"Washington University in St. Louis","doi-asserted-by":"crossref","award":["Spencer Olin Fellowship for Women"],"award-info":[{"award-number":["Spencer Olin Fellowship for Women"]}],"id":[{"id":"10.13039\/100007268","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01-AI103280, R21-AI123808, and R21-AI130584,"],"award-info":[{"award-number":["R01-AI103280, R21-AI123808, and R21-AI130584,"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000861","name":"Burroughs Wellcome Fund","doi-asserted-by":"publisher","award":["PATH"],"award-info":[{"award-number":["PATH"]}],"id":[{"id":"10.13039\/100000861","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000097","name":"National Center for Research Resources","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100000097","id-type":"DOI","asserted-by":"crossref"}]},{"name":"NIH Roadmap for Medical Research"}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>Efforts to control the global malaria health crisis are undermined by antimalarial resistance. Identifying mechanisms of resistance will uncover the underlying biology of the <jats:italic>Plasmodium falciparum<\/jats:italic> 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 <jats:italic>gapdh<\/jats:italic> 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.<\/jats:p>","DOI":"10.1371\/journal.ppat.1010803","type":"journal-article","created":{"date-parts":[[2022,9,14]],"date-time":"2022-09-14T17:59:26Z","timestamp":1663178366000},"page":"e1010803","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":13,"title":["GAPDH mediates drug resistance and metabolism in Plasmodium falciparum malaria parasites"],"prefix":"10.1371","volume":"18","author":[{"given":"Andrew J.","family":"Jezewski","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ann M.","family":"Guggisberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dana M.","family":"Hodge","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naomi","family":"Ghebremichael","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gavin Nicholas","family":"John","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa K.","family":"McLellan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8395-8537","authenticated-orcid":true,"given":"Audrey Ragan","family":"Odom John","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2022,9,14]]},"reference":[{"key":"ppat.1010803.ref001","unstructured":"World Malaria Report. 2020."},{"key":"ppat.1010803.ref002","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1017\/S0031182013000826","article-title":"Antimalarial drug discovery\u2013the path towards eradication","volume":"141","author":"JN Burrows","year":"2014","journal-title":"Parasitology"},{"key":"ppat.1010803.ref003","doi-asserted-by":"crossref","first-page":"9217","DOI":"10.1021\/acs.jmedchem.9b01099","article-title":"Development of Chemical Entities Endowed with Potent Fast-Killing Properties against Plasmodium falciparum Malaria Parasites","volume":"62","author":"AN Matralis","year":"2019","journal-title":"J Med Chem"},{"key":"ppat.1010803.ref004","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1016\/j.ijantimicag.2012.12.007","article-title":"Antimalarial drug resistance: A review of the biology and strategies to delay emergence and spread","volume":"41","author":"EY Klein","year":"2013","journal-title":"Int J Antimicrob Agents"},{"key":"ppat.1010803.ref005","doi-asserted-by":"crossref","first-page":"272","DOI":"10.1038\/nrmicro2331","article-title":"Artemisinin resistance: current status and scenarios for containment","volume":"8","author":"AM Dondorp","year":"2010","journal-title":"Nat Rev Microbiol"},{"key":"ppat.1010803.ref006","doi-asserted-by":"crossref","first-page":"428","DOI":"10.1126\/science.1260867","article-title":"K13-propeller mutations confer artemisinin resistance in Plasmodium falciparum clinical isolates","volume":"347","author":"J Straimer","year":"2015","journal-title":"Science (80-)."},{"key":"ppat.1010803.ref007","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1016\/S1473-3099(15)00487-9","article-title":"Dihydroartemisinin-piperaquine resistance in Plasmodium falciparum malaria in Cambodia: A multisite prospective cohort study","volume":"16","author":"C Amaratunga","year":"2016","journal-title":"Lancet Infect Dis"},{"key":"ppat.1010803.ref008","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1056\/NEJMoa1314981","article-title":"Spread of artemisinin resistance in Plasmodium falciparum malaria","volume":"371","author":"EA Ashley","year":"2014","journal-title":"N Engl J Med"},{"key":"ppat.1010803.ref009","doi-asserted-by":"crossref","first-page":"917","DOI":"10.1038\/nm.4381","article-title":"Antimalarial drug resistance: linking Plasmodium falciparum parasite biology to the clinic","volume":"23","author":"B Blasco","year":"2017","journal-title":"Nat Med"},{"key":"ppat.1010803.ref010","doi-asserted-by":"crossref","first-page":"3735","DOI":"10.1242\/jeb.00589","article-title":"Antimalarial drug discovery: old and new approaches","volume":"206","author":"PJ Rosenthal","year":"2003","journal-title":"J Exp Biol"},{"key":"ppat.1010803.ref011","doi-asserted-by":"crossref","first-page":"1285","DOI":"10.1007\/s00018-011-0646-1","article-title":"The apicomplexan plastid and its evolution","volume":"68","author":"S. 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