{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T04:55:45Z","timestamp":1791176145704,"version":"4.1.0"},"reference-count":56,"publisher":"Public Library of Science (PLoS)","issue":"1","license":[{"start":{"date-parts":[[2014,1,2]],"date-time":"2014-01-02T00:00:00Z","timestamp":1388620800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plosgenetics.org"],"crossmark-restriction":false},"short-container-title":["PLoS Genet"],"DOI":"10.1371\/journal.pgen.1004085","type":"journal-article","created":{"date-parts":[[2014,1,2]],"date-time":"2014-01-02T21:25:15Z","timestamp":1388697915000},"page":"e1004085","update-policy":"https:\/\/doi.org\/10.1371\/journal.pgen.corrections_policy","source":"Crossref","is-referenced-by-count":87,"title":["Metabolic QTL Analysis Links Chloroquine Resistance in Plasmodium falciparum to Impaired Hemoglobin Catabolism"],"prefix":"10.1371","volume":"10","author":[{"given":"Ian A.","family":"Lewis","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Wacker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kellen L.","family":"Olszewski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simon A.","family":"Cobbold","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katelynn S.","family":"Baska","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Asako","family":"Tan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael T.","family":"Ferdig","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manuel","family":"Llin\u00e1s","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2014,1,2]]},"reference":[{"key":"ref1","doi-asserted-by":"crossref","first-page":"153","DOI":"10.4269\/ajtmh.2007.77.153","article-title":"Responding to the challenge of antimalarial drug resistance by routine monitoring to update national malaria treatment policies","volume":"77","author":"LS Vestergaard","year":"2007","journal-title":"Am J Trop Med Hyg"},{"key":"ref2","doi-asserted-by":"crossref","first-page":"1870","DOI":"10.1086\/375419","article-title":"Reemergence of chloroquine-sensitive plasmodium falciparum malaria after cessation of chloroquine use in malawi","volume":"187","author":"JG Kublin","year":"2003","journal-title":"J Infect Dis"},{"key":"ref3","first-page":"483","article-title":"Changes in the resistance of plasmodium falciparum to chloroquine in hainan, china","volume":"73","author":"DQ Liu","year":"1995","journal-title":"Bull World Health Organ"},{"key":"ref4","first-page":"37","article-title":"The development of pyrimethamine resistance by plasmodium falciparum","volume":"20","author":"RW BURGESS","year":"1959","journal-title":"Bull World Health Organ"},{"key":"ref5","doi-asserted-by":"crossref","first-page":"861","DOI":"10.1016\/S1097-2765(05)00077-8","article-title":"Mutations in the P. falciparum digestive vacuole transmembrane protein PfCRT and evidence for their role in chloroquine resistance","volume":"6","author":"DA Fidock","year":"2000","journal-title":"Mol Cell"},{"key":"ref6","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1124\/mol.61.1.35","article-title":"Alternative mutations at position 76 of the vacuolar transmembrane protein PfCRT are associated with chloroquine resistance and unique stereospecific quinine and quinidine responses in plasmodium falciparum","volume":"61","author":"RA Cooper","year":"2002","journal-title":"Mol Pharmacol"},{"key":"ref7","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1038\/nature00813","article-title":"Genetic diversity and chloroquine selective sweeps in plasmodium falciparum","volume":"418","author":"JC Wootton","year":"2002","journal-title":"Nature"},{"key":"ref8","doi-asserted-by":"crossref","first-page":"3500","DOI":"10.1128\/AAC.47.11.3500-3505.2003","article-title":"Pfcrt allelic types with two novel amino acid mutations in chloroquine-resistant plasmodium falciparum isolates from the philippines","volume":"47","author":"N Chen","year":"2003","journal-title":"Antimicrob Agents Chemother"},{"key":"ref9","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1590\/S0074-02762004000400008","article-title":"Pfcrt and pfmdr1 alleles associated with chloroquine resistance in plasmodium falciparum from guyana, south america","volume":"99","author":"W Best Plummer","year":"2004","journal-title":"Mem Inst Oswaldo Cruz"},{"key":"ref10","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1016\/j.molbiopara.2004.03.016","article-title":"Variations in the sequence and expression of the plasmodium falciparum chloroquine resistance transporter (pfcrt) and their relationship to chloroquine resistance in vitro","volume":"136","author":"V Durrand","year":"2004","journal-title":"Mol Biochem Parasitol"},{"key":"ref11","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1126\/science.1074045","article-title":"Chloroquine resistance in plasmodium falciparum malaria parasites conferred by pfcrt mutations","volume":"298","author":"AB Sidhu","year":"2002","journal-title":"Science"},{"key":"ref12","doi-asserted-by":"crossref","first-page":"1938","DOI":"10.1093\/molbev\/msh205","article-title":"The malaria parasite's chloroquine resistance transporter is a member of the drug\/metabolite transporter superfamily","volume":"21","author":"RE Martin","year":"2004","journal-title":"Mol Biol Evol"},{"key":"ref13","doi-asserted-by":"crossref","first-page":"1285","DOI":"10.1111\/j.1365-2958.2004.04470.x","article-title":"pfmdr1 mutations associated with chloroquine resistance incur a fitness cost in plasmodium falciparum","volume":"55","author":"R Hayward","year":"2005","journal-title":"Mol Microbiol"},{"key":"ref14","doi-asserted-by":"crossref","first-page":"906","DOI":"10.1038\/35002615","article-title":"Pgh1 modulates sensitivity and resistance to multiple antimalarials in plasmodium falciparum","volume":"403","author":"MB Reed","year":"2000","journal-title":"Nature"},{"key":"ref15","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1111\/j.1365-2958.2005.04556.x","article-title":"Defining the role of PfCRT in plasmodium falciparum chloroquine resistance","volume":"56","author":"PG Bray","year":"2005","journal-title":"Mol Microbiol"},{"key":"ref16","doi-asserted-by":"crossref","first-page":"7687","DOI":"10.1074\/jbc.M806944200","article-title":"Disruption of a plasmodium falciparum multidrug resistance-associated protein (PfMRP) alters its fitness and transport of antimalarial drugs and glutathione","volume":"284","author":"DK Raj","year":"2009","journal-title":"J Biol Chem"},{"key":"ref17","doi-asserted-by":"crossref","first-page":"842","DOI":"10.1038\/ng1815","article-title":"The genetics of plant metabolism","volume":"38","author":"JJ Keurentjes","year":"2006","journal-title":"Nat Genet"},{"key":"ref18","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1016\/j.pbi.2008.12.003","article-title":"Genetical metabolomics: Closing in on phenotypes","volume":"12","author":"JJ Keurentjes","year":"2009","journal-title":"Curr Opin Plant Biol"},{"key":"ref19","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1016\/j.ijpara.2012.03.004","article-title":"Analysis of malaria parasite phenotypes using experimental genetic crosses of plasmodium falciparum","volume":"42","author":"LC Ranford-Cartwright","year":"2012","journal-title":"Int J Parasitol"},{"key":"ref20","doi-asserted-by":"crossref","first-page":"1351","DOI":"10.1126\/science.286.5443.1351","article-title":"A genetic map and recombination parameters of the human malaria parasite plasmodium falciparum","volume":"286","author":"X Su","year":"1999","journal-title":"Science"},{"key":"ref21","doi-asserted-by":"crossref","first-page":"e238","DOI":"10.1371\/journal.pbio.0060238","article-title":"Regulatory hotspots in the malaria parasite genome dictate transcriptional variation","volume":"6","author":"JM Gonzales","year":"2008","journal-title":"PLoS Biol"},{"key":"ref22","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1186\/1471-2164-11-577","article-title":"Quantitative trait loci mapping reveals candidate pathways regulating cell cycle duration in plasmodium falciparum","volume":"11","author":"HB Reilly Ayala","year":"2010","journal-title":"BMC Genomics"},{"key":"ref23","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1016\/j.chom.2008.06.001","article-title":"Erythrocyte binding protein PfRH5 polymorphisms determine species-specific pathways of plasmodium falciparum invasion","volume":"4","author":"K Hayton","year":"2008","journal-title":"Cell Host Microbe"},{"key":"ref24","doi-asserted-by":"crossref","first-page":"770","DOI":"10.1111\/j.1365-2958.2010.07366.x","article-title":"Chloroquine susceptibility and reversibility in a plasmodium falciparum genetic cross","volume":"78","author":"JJ Patel","year":"2010","journal-title":"Mol Microbiol"},{"key":"ref25","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1038\/nrg2126","article-title":"Genetic linkage and association analyses for trait mapping in plasmodium falciparum","volume":"8","author":"X Su","year":"2007","journal-title":"Nat Rev Genet"},{"key":"ref26","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1126\/science.781840","article-title":"Human malaria parasites in continuous culture","volume":"193","author":"W Trager","year":"1976","journal-title":"Science"},{"key":"ref27","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1038\/nbt0208-162","article-title":"Metabolite identification via the madison metabolomics consortium database","volume":"26","author":"Q Cui","year":"2008","journal-title":"Nat Biotechnol"},{"key":"ref28","doi-asserted-by":"crossref","first-page":"D521","DOI":"10.1093\/nar\/gkl923","article-title":"HMDB: The human metabolome database","volume":"35","author":"DS Wishart","year":"2007","journal-title":"Nucleic Acids Res"},{"key":"ref29","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1016\/j.chroma.2006.05.019","article-title":"Separation and quantitation of water soluble cellular metabolites by hydrophilic interaction chromatography-tandem mass spectrometry","volume":"1125","author":"SU Bajad","year":"2006","journal-title":"J Chromatogr A"},{"key":"ref30","doi-asserted-by":"crossref","first-page":"504","DOI":"10.1016\/j.pt.2012.08.002","article-title":"PfCRT and its role in antimalarial drug resistance","volume":"28","author":"A Ecker","year":"2012","journal-title":"Trends Parasitol"},{"key":"ref31","doi-asserted-by":"crossref","first-page":"8840","DOI":"10.1073\/pnas.0601876103","article-title":"Plasmodium falciparum ensures its amino acid supply with multiple acquisition pathways and redundant proteolytic enzyme systems","volume":"103","author":"J Liu","year":"2006","journal-title":"Proc Natl Acad Sci U S A"},{"key":"ref32","first-page":"275","article-title":"Hemoglobin degradation","volume":"295","author":"DE Goldberg","year":"2005","journal-title":"Curr Top Microbiol Immunol"},{"key":"ref33","doi-asserted-by":"crossref","first-page":"1602","DOI":"10.1172\/JCI117140","article-title":"Order and specificity of the plasmodium falciparum hemoglobin degradation pathway","volume":"93","author":"IY Gluzman","year":"1994","journal-title":"J Clin Invest"},{"key":"ref34","doi-asserted-by":"crossref","first-page":"E3278","DOI":"10.1073\/pnas.1209823109","article-title":"Plasmodium falciparum responds to amino acid starvation by entering into a hibernatory state","volume":"109","author":"SE Babbitt","year":"2012","journal-title":"Proc Natl Acad Sci U S A"},{"key":"ref35","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1016\/S0166-6851(01)00427-3","article-title":"Intraerythrocytic plasmodium falciparum utilizes only a fraction of the amino acids derived from the digestion of host cell cytosol for the biosynthesis of its proteins","volume":"119","author":"M Krugliak","year":"2002","journal-title":"Mol Biochem Parasitol"},{"issue":"Pt 2","key":"ref36","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1042\/bj3390363","article-title":"Inhibition of the peroxidative degradation of haem as the basis of action of chloroquine and other quinoline antimalarials","volume":"339","author":"P Loria","year":"1999","journal-title":"Biochem J"},{"key":"ref37","doi-asserted-by":"crossref","first-page":"4189","DOI":"10.1182\/blood-2002-08-2654","article-title":"Excess hemoglobin digestion and the osmotic stability of plasmodium falciparum-infected red blood cells","volume":"101","author":"VL Lew","year":"2003","journal-title":"Blood"},{"key":"ref38","doi-asserted-by":"crossref","first-page":"2435","DOI":"10.1128\/AAC.46.8.2435-2441.2002","article-title":"Mutations in cytochrome b resulting in atovaquone resistance are associated with loss of fitness in plasmodium falciparum","volume":"46","author":"JM Peters","year":"2002","journal-title":"Antimicrob Agents Chemother"},{"key":"ref39","doi-asserted-by":"crossref","first-page":"1959","DOI":"10.1056\/NEJMoa062032","article-title":"Return of chloroquine antimalarial efficacy in malawi","volume":"355","author":"MK Laufer","year":"2006","journal-title":"N Engl J Med"},{"key":"ref40","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1128\/AAC.00711-07","article-title":"No genetic bottleneck in plasmodium falciparum wild-type pfcrt alleles reemerging in hainan island, china, following high-level chloroquine resistance","volume":"52","author":"N Chen","year":"2008","journal-title":"Antimicrob Agents Chemother"},{"key":"ref41","doi-asserted-by":"crossref","first-page":"1967","DOI":"10.1007\/s00018-011-0906-0","article-title":"Know your enemy: Understanding the role of PfCRT in drug resistance could lead to new antimalarial tactics","volume":"69","author":"RL Summers","year":"2012","journal-title":"Cell Mol Life Sci"},{"issue":"7","key":"ref42","doi-asserted-by":"crossref","first-page":"683","DOI":"10.1089\/ars.2012.4625","article-title":"Glutathione transport: A new role for PfCRT in chloroquine resistance","volume":"19","author":"EM Patzewitz","year":"2012","journal-title":"Antioxid Redox Signal"},{"key":"ref43","doi-asserted-by":"crossref","first-page":"2331","DOI":"10.1073\/pnas.0913689107","article-title":"Plant homologs of the plasmodium falciparum chloroquine-resistance transporter, PfCRT, are required for glutathione homeostasis and stress responses","volume":"107","author":"SC Maughan","year":"2010","journal-title":"Proc Natl Acad Sci U S A"},{"key":"ref44","doi-asserted-by":"crossref","first-page":"30150","DOI":"10.1074\/jbc.M405192200","article-title":"Mechanisms and functional properties of two peptide transporters, AtPTR2 and fPTR2","volume":"279","author":"CS Chiang","year":"2004","journal-title":"J Biol Chem"},{"key":"ref45","doi-asserted-by":"crossref","first-page":"1624","DOI":"10.1242\/jcs.016758","article-title":"A verapamil-sensitive chloroquine-associated H+ leak from the digestive vacuole in chloroquine-resistant malaria parasites","volume":"121","author":"AM Lehane","year":"2008","journal-title":"J Cell Sci"},{"key":"ref46","doi-asserted-by":"crossref","first-page":"25719","DOI":"10.1074\/jbc.272.41.25719","article-title":"Biochemical characteristics of caspases-3, -6, -7, and -8","volume":"272","author":"HR Stennicke","year":"1997","journal-title":"J Biol Chem"},{"key":"ref47","doi-asserted-by":"crossref","first-page":"5392","DOI":"10.1073\/pnas.1218412110","article-title":"Protein complex directs hemoglobin-to-hemozoin formation in plasmodium falciparum","volume":"110","author":"M Chugh","year":"2013","journal-title":"Proc Natl Acad Sci U S A"},{"key":"ref48","doi-asserted-by":"crossref","first-page":"382-2875-11-382","DOI":"10.1186\/1475-2875-11-382","article-title":"Compounds from sorindeia juglandifolia (anacardiaceae) exhibit potent anti-plasmodial activities in vitro and in vivo","volume":"11","author":"RG Kamkumo","year":"2012","journal-title":"Malar J"},{"key":"ref49","doi-asserted-by":"crossref","first-page":"622","DOI":"10.1016\/0035-9203(84)90221-9","article-title":"A simple method for isolating viable mature parasites of plasmodium falciparum from cultures","volume":"78","author":"AR Dluzewski","year":"1984","journal-title":"Trans R Soc Trop Med Hyg"},{"key":"ref50","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1016\/j.chom.2009.01.004","article-title":"Host-parasite interactions revealed by plasmodium falciparum metabolomics","volume":"5","author":"KL Olszewski","year":"2009","journal-title":"Cell Host Microbe"},{"key":"ref51","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1093\/genetics\/159.1.371","article-title":"A statistical framework for quantitative trait mapping","volume":"159","author":"S Sen","year":"2001","journal-title":"Genetics"},{"key":"ref52","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1023\/B:BEGE.0000013726.65708.c2","article-title":"Adjusting for covariates in variance components QTL linkage analysis","volume":"34","author":"M Zeegers","year":"2004","journal-title":"Behav Genet"},{"key":"ref53","doi-asserted-by":"crossref","first-page":"963","DOI":"10.1093\/genetics\/138.3.963","article-title":"Empirical threshold values for quantitative trait mapping","volume":"138","author":"GA Churchill","year":"1994","journal-title":"Genetics"},{"key":"ref54","doi-asserted-by":"crossref","first-page":"9440","DOI":"10.1073\/pnas.1530509100","article-title":"Statistical significance for genomewide studies","volume":"100","author":"JD Storey","year":"2003","journal-title":"Proc Natl Acad Sci U S A"},{"key":"ref55","doi-asserted-by":"crossref","first-page":"889","DOI":"10.1093\/bioinformatics\/btg112","article-title":"R\/qtl: QTL mapping in experimental crosses","volume":"19","author":"KW Broman","year":"2003","journal-title":"Bioinformatics"},{"key":"ref56","first-page":"Unit14.11","article-title":"LC-MS data processing with MAVEN: A metabolomic analysis and visualization engine","volume":"Chapter 14","author":"MF Clasquin","year":"2012","journal-title":"Curr Protoc Bioinformatics"}],"container-title":["PLoS Genetics"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/dx.plos.org\/10.1371\/journal.pgen.1004085","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,3,21]],"date-time":"2022-03-21T05:40:28Z","timestamp":1647841228000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pgen.1004085"}},"subtitle":[],"editor":[{"given":"Daniel E.","family":"Neafsey","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2014,1,2]]},"references-count":56,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2014,1,2]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pgen.1004085","relation":{},"ISSN":["1553-7404"],"issn-type":[{"value":"1553-7404","type":"electronic"}],"subject":[],"published":{"date-parts":[[2014,1,2]]}}}