{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T20:07:03Z","timestamp":1792181223008,"version":"4.4.0"},"reference-count":97,"publisher":"eLife Sciences Publications, Ltd","license":[{"start":{"date-parts":[[2022,3,8]],"date-time":"2022-03-08T00:00:00Z","timestamp":1646697600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2022,3,8]],"date-time":"2022-03-08T00:00:00Z","timestamp":1646697600000},"content-version":"am","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2022,3,8]],"date-time":"2022-03-08T00:00:00Z","timestamp":1646697600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["R35GM133764"],"award-info":[{"award-number":["R35GM133764"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000090","name":"Congressionally Directed Medical Research Programs","doi-asserted-by":"publisher","award":["W81XWH1810060"],"award-info":[{"award-number":["W81XWH1810060"]}],"id":[{"id":"10.13039\/100000090","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["R01AI125534"],"award-info":[{"award-number":["R01AI125534"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000861","name":"Burroughs Wellcome Fund","doi-asserted-by":"publisher","award":["1011969"],"award-info":[{"award-number":["1011969"]}],"id":[{"id":"10.13039\/100000861","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000875","name":"Pew Charitable Trusts","doi-asserted-by":"publisher","award":["32099"],"award-info":[{"award-number":["32099"]}],"id":[{"id":"10.13039\/100000875","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","award":["T32DK007115"],"award-info":[{"award-number":["T32DK007115"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["T32AI007417"],"award-info":[{"award-number":["T32AI007417"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","award":["U54DK110858"],"award-info":[{"award-number":["U54DK110858"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["1S10OD016232"],"award-info":[{"award-number":["1S10OD016232"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["1S10OD018210"],"award-info":[{"award-number":["1S10OD018210"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["1S10OD021505"],"award-info":[{"award-number":["1S10OD021505"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100015283","name":"Bloomberg Philanthropies","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100015283","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Johns Hopkins Malaria Research Institute"}],"content-domain":{"domain":["elifesciences.org"],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2022,3,4]]},"abstract":"<jats:p>\n                    Isopentenyl pyrophosphate (IPP) is an essential metabolic output of the apicoplast organelle in\n                    <jats:italic>Plasmodium falciparum<\/jats:italic>\n                    malaria parasites and is required for prenylation-dependent vesicular trafficking and other cellular processes. We have elucidated a critical and previously uncharacterized role for IPP in apicoplast biogenesis. Inhibiting IPP synthesis blocks apicoplast elongation and inheritance by daughter merozoites, and apicoplast biogenesis is rescued by exogenous IPP and polyprenols. Knockout of the only known isoprenoid-dependent apicoplast pathway, tRNA prenylation by MiaA, has no effect on blood-stage parasites and thus cannot explain apicoplast reliance on IPP. However, we have localized an annotated polyprenyl synthase (PPS) to the apicoplast. PPS knockdown is lethal to parasites, rescued by IPP and long- (C\n                    <jats:sub>50<\/jats:sub>\n                    ) but not short-chain (\u2264C\n                    <jats:sub>20<\/jats:sub>\n                    ) prenyl alcohols, and blocks apicoplast biogenesis, thus explaining apicoplast dependence on isoprenoid synthesis. We hypothesize that PPS synthesizes long-chain polyprenols critical for apicoplast membrane fluidity and biogenesis. This work critically expands the paradigm for isoprenoid utilization in malaria parasites and identifies a novel essential branch of apicoplast metabolism suitable for therapeutic targeting.\n                  <\/jats:p>","DOI":"10.7554\/elife.73208","type":"journal-article","created":{"date-parts":[[2022,3,8]],"date-time":"2022-03-08T07:15:40Z","timestamp":1646723740000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.73208","source":"Crossref","is-referenced-by-count":58,"title":["Critical role for isoprenoids in apicoplast biogenesis by malaria parasites"],"prefix":"10.7554","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4398-9819","authenticated-orcid":true,"given":"Megan","family":"Okada","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/055j5q029","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Biochemistry, University of Utah School of Medicine","place":["Salt Lake City, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4830-5471","authenticated-orcid":true,"given":"Krithika","family":"Rajaram","sequence":"additional","affiliation":[{"name":"Department of Molecular Microbiology and Immunology, Johns Hopkins School of Public Health","place":["Baltimore, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Russell P","family":"Swift","sequence":"additional","affiliation":[{"name":"Department of Molecular Microbiology and Immunology, Johns Hopkins School of Public Health","place":["Baltimore, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amanda","family":"Mixon","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/055j5q029","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Biochemistry, University of Utah School of Medicine","place":["Salt Lake City, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John Alan","family":"Maschek","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03r0ha626","id-type":"ROR","asserted-by":"publisher"}],"name":"Metabolomics Core, University of Utah Health Sciences Center","place":["Salt Lake City, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9684-1733","authenticated-orcid":true,"given":"Sean T","family":"Prigge","sequence":"additional","affiliation":[{"name":"Department of Molecular Microbiology and Immunology, Johns Hopkins School of Public Health","place":["Baltimore, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3464-3042","authenticated-orcid":true,"given":"Paul A","family":"Sigala","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/055j5q029","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Biochemistry, University of Utah School of Medicine","place":["Salt Lake City, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"4374","published-online":{"date-parts":[[2022,3,8]]},"reference":[{"key":"bib1","doi-asserted-by":"publisher","first-page":"1709","DOI":"10.1105\/tpc.16.00796","article-title":"Polyprenols Are Synthesized by a Plastidial cis-Prenyltransferase and Influence Photosynthetic Performance","volume":"29","author":"Akhtar","year":"2017","journal-title":"The Plant Cell"},{"key":"bib2","doi-asserted-by":"publisher","first-page":"420","DOI":"10.1038\/s41587-019-0036-z","article-title":"SignalP 5.0 improves signal peptide predictions using deep neural networks","volume":"37","author":"Almagro Armenteros","year":"2019","journal-title":"Nature Biotechnology"},{"key":"bib3","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.29865","article-title":"Small molecule inhibition of apicomplexan FtsH1 disrupts plastid biogenesis in human pathogens","volume":"6","author":"Amberg-Johnson","year":"2017","journal-title":"eLife"},{"key":"bib4","doi-asserted-by":"publisher","first-page":"3315","DOI":"10.1074\/jbc.M109.027235","article-title":"Molecular characterization of a novel geranylgeranyl pyrophosphate synthase from Plasmodium parasites","volume":"286","author":"Artz","year":"2011","journal-title":"The Journal of Biological Chemistry"},{"key":"bib5","doi-asserted-by":"publisher","first-page":"16391","DOI":"10.1073\/pnas.0504679102","article-title":"High-efficiency transformation of Plasmodium falciparum by the lepidopteran transposable element piggyBac","volume":"102","author":"Balu","year":"2005","journal-title":"PNAS"},{"key":"bib6","doi-asserted-by":"publisher","first-page":"752","DOI":"10.1016\/j.chom.2020.09.011","article-title":"A Comprehensive Subcellular Atlas of the Toxoplasma Proteome via hyperLOPIT Provides Spatial Context for Protein Functions","volume":"28","author":"Barylyuk","year":"2020","journal-title":"Cell Host & Microbe"},{"key":"bib7","doi-asserted-by":"publisher","first-page":"592","DOI":"10.1038\/nature13574","article-title":"PTEX component HSP101 mediates export of diverse malaria effectors into host erythrocytes","volume":"511","author":"Beck","year":"2014","journal-title":"Nature"},{"key":"bib8","doi-asserted-by":"publisher","first-page":"W29","DOI":"10.1093\/nar\/gkt282","article-title":"BLAST: a more efficient report with usability improvements","volume":"41","author":"Boratyn","year":"2013","journal-title":"Nucleic Acids Research"},{"key":"bib9","doi-asserted-by":"publisher","first-page":"7506","DOI":"10.1073\/pnas.1301251110","article-title":"Atypical lipid composition in the purified relict plastid (apicoplast) of malaria parasites","volume":"110","author":"Bott\u00e9","year":"2013","journal-title":"PNAS"},{"key":"bib10","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.2005895","article-title":"Integrative proteomics and bioinformatic prediction enable a high-confidence apicoplast proteome in malaria parasites","volume":"16","author":"Boucher","year":"2018","journal-title":"PLOS Biology"},{"key":"bib11","doi-asserted-by":"publisher","DOI":"10.1128\/mSphere.00710-18","article-title":"Disruption of Apicoplast Biogenesis by Chemical Stabilization of an Imported Protein Evades the Delayed-Death Phenotype in Malaria Parasites","volume":"4","author":"Boucher","year":"2019","journal-title":"MSphere"},{"key":"bib12","doi-asserted-by":"publisher","first-page":"357","DOI":"10.1016\/j.plipres.2005.09.003","article-title":"Biogenesis, molecular regulation and function of plant isoprenoids","volume":"44","author":"Bouvier","year":"2005","journal-title":"Progress in Lipid Research"},{"key":"bib13","doi-asserted-by":"publisher","first-page":"811","DOI":"10.1128\/AAC.01500-13","article-title":"Antiapicoplast and gametocytocidal screening to identify the mechanisms of action of compounds within the malaria box","volume":"58","author":"Bowman","year":"2014","journal-title":"Antimicrobial Agents and Chemotherapy"},{"key":"bib14","doi-asserted-by":"publisher","first-page":"260","DOI":"10.1016\/j.cell.2017.06.030","article-title":"Functional Profiling of a Plasmodium Genome Reveals an Abundance of Essential Genes","volume":"170","author":"Bushell","year":"2017","journal-title":"Cell"},{"key":"bib15","doi-asserted-by":"publisher","first-page":"51749","DOI":"10.1074\/jbc.M408360200","article-title":"The methylerythritol phosphate pathway is functionally active in all intraerythrocytic stages of Plasmodium falciparum","volume":"279","author":"Cassera","year":"2004","journal-title":"The Journal of Biological Chemistry"},{"key":"bib16","doi-asserted-by":"publisher","first-page":"779","DOI":"10.1111\/j.1432-1033.1996.00779.x","article-title":"Computational method to predict mitochondrially imported proteins and their targeting sequences","volume":"241","author":"Claros","year":"1996","journal-title":"European Journal of Biochemistry"},{"key":"bib17","doi-asserted-by":"publisher","first-page":"629","DOI":"10.1042\/bj3410629","article-title":"Active isoprenoid pathway in the intra-erythrocytic stages of Plasmodium falciparum: presence of dolichols of 11 and 12 isoprene units","volume":"341 (Pt 3)","author":"Couto","year":"1999","journal-title":"The Biochemical Journal"},{"key":"bib18","doi-asserted-by":"publisher","first-page":"478","DOI":"10.1111\/j.1365-313X.2004.02309.x","article-title":"A study in scarlet: enzymes of ketocarotenoid biosynthesis in the flowers of Adonis aestivalis","volume":"41","author":"Cunningham","year":"2005","journal-title":"The Plant Journal"},{"key":"bib19","doi-asserted-by":"publisher","first-page":"3124","DOI":"10.1128\/AAC.00394-06","article-title":"Tetracyclines specifically target the apicoplast of the malaria parasite Plasmodium falciparum","volume":"50","author":"Dahl","year":"2006","journal-title":"Antimicrobial Agents and Chemotherapy"},{"key":"bib20","doi-asserted-by":"publisher","first-page":"3485","DOI":"10.1128\/AAC.00527-07","article-title":"Multiple antibiotics exert delayed effects against the Plasmodium falciparum apicoplast","volume":"51","author":"Dahl","year":"2007","journal-title":"Antimicrobial Agents and Chemotherapy"},{"key":"bib21","doi-asserted-by":"publisher","first-page":"1076","DOI":"10.1126\/science.aah4563","article-title":"A key malaria metabolite modulates vector blood seeking, feeding, and susceptibility to infection","volume":"355","author":"Emami","year":"2017","journal-title":"Science (New York, N.Y.)"},{"key":"bib22","doi-asserted-by":"publisher","first-page":"7256","DOI":"10.1128\/JB.181.23.7256-7265.1999","article-title":"Identification of the miaB gene, involved in methylthiolation of isopentenylated A37 derivatives in the tRNA of Salmonella typhimurium and Escherichia coli","volume":"181","author":"Esberg","year":"1999","journal-title":"Journal of Bacteriology"},{"key":"bib23","doi-asserted-by":"publisher","first-page":"10931","DOI":"10.1073\/pnas.94.20.10931","article-title":"Transformation with human dihydrofolate reductase renders malaria parasites insensitive to WR99210 but does not affect the intrinsic activity of proguanil","volume":"94","author":"Fidock","year":"1997","journal-title":"PNAS"},{"key":"bib24","doi-asserted-by":"publisher","first-page":"705","DOI":"10.1126\/science.1078599","article-title":"Dissecting apicoplast targeting in the malaria parasite Plasmodium falciparum","volume":"299","author":"Foth","year":"2003","journal-title":"Science (New York, N.Y.)"},{"key":"bib25","doi-asserted-by":"publisher","first-page":"1545","DOI":"10.1016\/0006-2952(92)90213-3","article-title":"Site of action of the antimalarial hydroxynaphthoquinone, 2-[trans-4-(4'-chlorophenyl) cyclohexyl]-3-hydroxy-1,4-naphthoquinone (566C80)","volume":"43","author":"Fry","year":"1992","journal-title":"Biochemical Pharmacology"},{"key":"bib26","doi-asserted-by":"publisher","DOI":"10.1038\/srep18429","article-title":"Single-target high-throughput transcription analyses reveal high levels of alternative splicing present in the FPPS\/GGPPS from Plasmodium falciparum","volume":"5","author":"Gabriel","year":"2015","journal-title":"Scientific Reports"},{"key":"bib27","doi-asserted-by":"publisher","first-page":"3180","DOI":"10.1128\/AAC.04500-14","article-title":"Squalestatin is an inhibitor of carotenoid biosynthesis in Plasmodium falciparum","volume":"59","author":"Gabriel","year":"2015","journal-title":"Antimicrobial Agents and Chemotherapy"},{"key":"bib28","doi-asserted-by":"publisher","first-page":"575","DOI":"10.1002\/prot.22582","article-title":"Plasmodium falciparum acyl carrier protein crystal structures in disulfide-linked and reduced states and their prevalence during blood stage growth","volume":"78","author":"Gallagher","year":"2010","journal-title":"Proteins"},{"key":"bib29","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1016\/j.molbiopara.2011.01.004","article-title":"Yeast dihydroorotate dehydrogenase as a new selectable marker for Plasmodium falciparum transfection","volume":"177","author":"Ganesan","year":"2011","journal-title":"Molecular and Biochemical Parasitology"},{"key":"bib30","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms10727","article-title":"Synthetic RNA-protein modules integrated with native translation mechanisms to control gene expression in malaria parasites","volume":"7","author":"Ganesan","year":"2016","journal-title":"Nature Communications"},{"key":"bib31","doi-asserted-by":"publisher","first-page":"819","DOI":"10.1038\/nbt.2925","article-title":"Genome editing in the human malaria parasite Plasmodium falciparum using the CRISPR-Cas9 system","volume":"32","author":"Ghorbal","year":"2014","journal-title":"Nature Biotechnology"},{"key":"bib32","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1003655","article-title":"The suf iron-sulfur cluster synthesis pathway is required for apicoplast maintenance in malaria parasites","volume":"9","author":"Gisselberg","year":"2013","journal-title":"PLOS Pathogens"},{"key":"bib33","doi-asserted-by":"publisher","first-page":"185","DOI":"10.1016\/j.chembiol.2017.11.010","article-title":"Specific Inhibition of the Bifunctional Farnesyl\/Geranylgeranyl Diphosphate Synthase in Malaria Parasites via a New Small-Molecule Binding Site","volume":"25","author":"Gisselberg","year":"2018","journal-title":"Cell Chemical Biology"},{"key":"bib34","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1006511","article-title":"Plasmodium heme biosynthesis: To be or not to be essential","volume":"13","author":"Goldberg","year":"2017","journal-title":"PLOS Pathogens"},{"key":"bib35","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0091178","article-title":"Ycf93 (Orf105), a small apicoplast-encoded membrane protein in the relict plastid of the malaria parasite Plasmodium falciparum that is conserved in Apicomplexa","volume":"9","author":"Goodman","year":"2014","journal-title":"PLOS ONE"},{"key":"bib36","doi-asserted-by":"publisher","first-page":"1348","DOI":"10.1128\/EC.00160-14","article-title":"Isoprenoid biosynthesis in Plasmodium falciparum","volume":"13","author":"Guggisberg","year":"2014","journal-title":"Eukaryotic Cell"},{"key":"bib37","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1016\/j.abb.2011.10.018","article-title":"At the membrane frontier: a prospectus on the remarkable evolutionary conservation of polyprenols and polyprenyl-phosphates","volume":"517","author":"Hartley","year":"2012","journal-title":"Archives of Biochemistry and Biophysics"},{"key":"bib38","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbc.2021.101468","article-title":"Toxoplasma gondii apicoplast-resident ferredoxin is an essential electron transfer protein for the MEP isoprenoid biosynthetic pathway","volume":"298","author":"Henkel","year":"2022","journal-title":"The Journal of Biological Chemistry"},{"key":"bib39","doi-asserted-by":"publisher","first-page":"215","DOI":"10.1128\/EC.00073-12","article-title":"Isoprenoid biosynthesis inhibition disrupts Rab5 localization and food vacuolar integrity in Plasmodium falciparum","volume":"12","author":"Howe","year":"2013","journal-title":"Eukaryotic Cell"},{"key":"bib40","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1007\/s40588-014-0006-7","article-title":"Isoprenoid metabolism in apicomplexan parasites","volume":"1","author":"Imlay","year":"2014","journal-title":"Current Clinical Microbiology Reports"},{"key":"bib41","doi-asserted-by":"publisher","first-page":"3359","DOI":"10.1021\/bi0206614","article-title":"Bacterial phytoene synthase: molecular cloning, expression, and characterization of Erwinia herbicola phytoene synthase","volume":"42","author":"Iwata-Reuyl","year":"2003","journal-title":"Biochemistry"},{"key":"bib42","doi-asserted-by":"publisher","first-page":"1573","DOI":"10.1126\/science.285.5433.1573","article-title":"Inhibitors of the nonmevalonate pathway of isoprenoid biosynthesis as antimalarial drugs","volume":"285","author":"Jomaa","year":"1999","journal-title":"Science (New York, N.Y.)"},{"key":"bib43","doi-asserted-by":"publisher","DOI":"10.1186\/1475-2875-12-184","article-title":"Cloning and characterization of bifunctional enzyme farnesyl diphosphate\/geranylgeranyl diphosphate synthase from Plasmodium falciparum","volume":"12","author":"Jord\u00e3o","year":"2013","journal-title":"Malaria Journal"},{"key":"bib44","doi-asserted-by":"publisher","first-page":"1154","DOI":"10.1093\/mp\/ssp088","article-title":"Chloroplast proteomics and the compartmentation of plastidial isoprenoid biosynthetic pathways","volume":"2","author":"Joyard","year":"2009","journal-title":"Molecular Plant"},{"key":"bib45","doi-asserted-by":"publisher","first-page":"34827","DOI":"10.1074\/jbc.M114.615831","article-title":"The heme biosynthesis pathway is essential for Plasmodium falciparum development in mosquito stage but not in blood stages","volume":"289","author":"Ke","year":"2014","journal-title":"The Journal of Biological Chemistry"},{"key":"bib46","doi-asserted-by":"publisher","first-page":"570","DOI":"10.1016\/s1367-5931(97)80054-3","article-title":"Chain elongation in the isoprenoid biosynthetic pathway","volume":"1","author":"Kellogg","year":"1997","journal-title":"Current Opinion in Chemical Biology"},{"key":"bib47","doi-asserted-by":"publisher","DOI":"10.1128\/mBio.00235-15","article-title":"Malaria parasites produce volatile mosquito attractants","volume":"6","author":"Kelly","year":"2015","journal-title":"MBio"},{"key":"bib48","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.3000376","article-title":"Delayed death in the malaria parasite Plasmodium falciparum is caused by disruption of prenylation-dependent intracellular trafficking","volume":"17","author":"Kennedy","year":"2019","journal-title":"PLOS Biology"},{"key":"bib49","doi-asserted-by":"publisher","first-page":"747","DOI":"10.1016\/j.pt.2019.07.010","article-title":"Delayed Death by Plastid Inhibition in Apicomplexan Parasites","volume":"35","author":"Kennedy","year":"2019","journal-title":"Trends in Parasitology"},{"key":"bib50","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1083\/jcb200307147","article-title":"Trafficking of plasmepsin II to the food vacuole of the malaria parasite Plasmodium falciparum","volume":"164","author":"Klemba","year":"2004","journal-title":"The Journal of Cell Biology"},{"key":"bib51","doi-asserted-by":"publisher","first-page":"290","DOI":"10.1016\/j.chom.2020.01.002","article-title":"Functional and Computational Genomics Reveal Unprecedented Flexibility in Stage-Specific Toxoplasma Metabolism","volume":"27","author":"Krishnan","year":"2020","journal-title":"Cell Host & Microbe"},{"key":"bib52","doi-asserted-by":"publisher","first-page":"8716","DOI":"10.1073\/pnas.96.15.8716","article-title":"A set of independent selectable markers for transfection of the human malaria parasite Plasmodium falciparum","volume":"96","author":"Mamoun","year":"1999","journal-title":"PNAS"},{"key":"bib53","doi-asserted-by":"publisher","first-page":"973","DOI":"10.1046\/j.1365-2958.2001.02289.x","article-title":"Plasmodium protein phosphatase 2C dephosphorylates translation elongation factor 1beta and inhibits its PKC-mediated nucleotide exchange activity in vitro","volume":"39","author":"Mamoun","year":"2001","journal-title":"Molecular Microbiology"},{"key":"bib54","doi-asserted-by":"publisher","DOI":"10.1128\/mSphere.00579-20","article-title":"Dispensable Role of Mitochondrial Fission Protein 1 (Fis1) in the Erythrocytic Development of Plasmodium falciparum","volume":"5","author":"Maruthi","year":"2020","journal-title":"MSphere"},{"key":"bib55","doi-asserted-by":"publisher","first-page":"13192","DOI":"10.1073\/pnas.0603391103","article-title":"Apicoplast fatty acid synthesis is essential for organelle biogenesis and parasite survival in Toxoplasma gondii","volume":"103","author":"Mazumdar","year":"2006","journal-title":"PNAS"},{"key":"bib56","doi-asserted-by":"publisher","first-page":"2567","DOI":"10.1021\/acsinfecdis.0c00548","article-title":"The Malaria Metabolite HMBPP Does Not Trigger Erythrocyte Terpene Release","volume":"6","author":"Miller","year":"2020","journal-title":"ACS Infectious Diseases"},{"key":"bib57","doi-asserted-by":"publisher","first-page":"9572","DOI":"10.1073\/pnas.0602293103","article-title":"Membrane transporters in the relict plastid of malaria parasites","volume":"103","author":"Mullin","year":"2006","journal-title":"PNAS"},{"key":"bib58","doi-asserted-by":"publisher","first-page":"3541","DOI":"10.1128\/JB.00511-12","article-title":"Complete genome sequence of phototrophic betaproteobacterium Rubrivivax gelatinosus IL144","volume":"194","author":"Nagashima","year":"2012","journal-title":"Journal of Bacteriology"},{"key":"bib59","doi-asserted-by":"publisher","first-page":"1547","DOI":"10.1084\/jem.20110039","article-title":"Apicoplast isoprenoid precursor synthesis and the molecular basis of fosmidomycin resistance in Toxoplasma gondii","volume":"208","author":"Nair","year":"2011","journal-title":"The Journal of Experimental Medicine"},{"key":"bib60","doi-asserted-by":"publisher","first-page":"4058","DOI":"10.1073\/pnas.1118215109","article-title":"Lipophilic analogs of zoledronate and risedronate inhibit Plasmodium geranylgeranyl diphosphate synthase (GGPPS) and exhibit potent antimalarial activity","volume":"109","author":"No","year":"2012","journal-title":"PNAS"},{"key":"bib61","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.60246","article-title":"Doxycycline has distinct apicoplast-specific mechanisms of antimalarial activity","volume":"9","author":"Okada","year":"2020","journal-title":"eLife"},{"key":"bib62","doi-asserted-by":"publisher","first-page":"1152","DOI":"10.1016\/0300-9084(94)90044-2","article-title":"Synthesis and function of isopentenyl adenosine derivatives in tRNA","volume":"76","author":"Persson","year":"1994","journal-title":"Biochimie"},{"key":"bib63","doi-asserted-by":"publisher","first-page":"3649","DOI":"10.1021\/jm8001026","article-title":"Triazolopyrimidine-based dihydroorotate dehydrogenase inhibitors with potent and selective activity against the malaria parasite Plasmodium falciparum","volume":"51","author":"Phillips","year":"2008","journal-title":"Journal of Medicinal Chemistry"},{"key":"bib64","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1007\/s11101-005-4887-1","article-title":"Farnesyl diphosphate synthase. A paradigm for understanding structure and functional relationships in E-polyprenyl diphosphate synthases","volume":"5","author":"Poulter","year":"2006","journal-title":"Phytochemistry Reviews"},{"key":"bib65","doi-asserted-by":"publisher","DOI":"10.1128\/mSphere.00457-20","article-title":"Redesigned TetR-Aptamer System To Control Gene Expression in Plasmodium falciparum","volume":"5","author":"Rajaram","year":"2020","journal-title":"MSphere"},{"key":"bib66","doi-asserted-by":"publisher","first-page":"203","DOI":"10.1038\/nrmicro843","article-title":"Metabolic maps and functions of the Plasmodium falciparum apicoplast","volume":"2","author":"Ralph","year":"2004","journal-title":"Nature Reviews. Microbiology"},{"key":"bib67","doi-asserted-by":"publisher","first-page":"307","DOI":"10.1128\/AAC.00808-06","article-title":"Inhibitors of nonhousekeeping functions of the apicoplast defy delayed death in Plasmodium falciparum","volume":"51","author":"Ramya","year":"2007","journal-title":"Antimicrobial Agents and Chemotherapy"},{"key":"bib68","doi-asserted-by":"publisher","first-page":"353","DOI":"10.1002\/mas.21390","article-title":"Identification of carotenoids using mass spectrometry","volume":"33","author":"Rivera","year":"2014","journal-title":"Mass Spectrometry Reviews"},{"key":"bib69","doi-asserted-by":"publisher","first-page":"1101","DOI":"10.1038\/nprot.2008.73","article-title":"Analyzing real-time PCR data by the comparative C(T) method","volume":"3","author":"Schmittgen","year":"2008","journal-title":"Nature Protocols"},{"key":"bib70","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1016\/j.molbiopara.2015.03.004","article-title":"Fatty acid metabolism in the Plasmodium apicoplast: Drugs, doubts and knockouts","volume":"199","author":"Shears","year":"2015","journal-title":"Molecular and Biochemical Parasitology"},{"key":"bib71","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.09143","article-title":"Deconvoluting heme biosynthesis to target blood-stage malaria parasites","volume":"4","author":"Sigala","year":"2015","journal-title":"eLife"},{"key":"bib72","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-019-55506-y","article-title":"Biosynthesis of heme O in intraerythrocytic stages of Plasmodium falciparum and potential inhibitors of this pathway","volume":"9","author":"Sim\u00e3o-Gurge","year":"2019","journal-title":"Scientific Reports"},{"key":"bib73","doi-asserted-by":"publisher","DOI":"10.1111\/cmi.12719","article-title":"The chaperonin TRiC forms an oligomeric complex in the malaria parasite cytosol","volume":"19","author":"Spillman","year":"2017","journal-title":"Cellular Microbiology"},{"key":"bib74","doi-asserted-by":"publisher","first-page":"235","DOI":"10.1016\/j.plipres.2005.05.002","article-title":"Polyisoprenoids: structure, biosynthesis and function","volume":"44","author":"Swiezewska","year":"2005","journal-title":"Progress in Lipid Research"},{"key":"bib75","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.50807","article-title":"The NTP generating activity of pyruvate kinase II is critical for apicoplast maintenance in Plasmodium falciparum","volume":"9","author":"Swift","year":"2020","journal-title":"eLife"},{"key":"bib76","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1008316","article-title":"A mevalonate bypass system facilitates elucidation of plastid biology in malaria parasites","volume":"16","author":"Swift","year":"2020","journal-title":"PLOS Pathogens"},{"key":"bib77","doi-asserted-by":"publisher","first-page":"15018","DOI":"10.1073\/pnas.93.26.15018","article-title":"Regulation of product chain length by isoprenyl diphosphate synthases","volume":"93","author":"Tarshis","year":"1996","journal-title":"PNAS"},{"key":"bib78","doi-asserted-by":"publisher","first-page":"15819","DOI":"10.1021\/ja065573b","article-title":"Farnesyl diphosphate synthase: The art of compromise between substrate selectivity and stereoselectivity","volume":"128","author":"Thulasiram","year":"2006","journal-title":"Journal of the American Chemical Society"},{"key":"bib79","doi-asserted-by":"publisher","first-page":"1540","DOI":"10.4161\/auto.25832","article-title":"Plasmodium falciparum ATG8 implicated in both autophagy and apicoplast formation","volume":"9","author":"Tomlins","year":"2013","journal-title":"Autophagy"},{"key":"bib80","doi-asserted-by":"publisher","first-page":"117","DOI":"10.1042\/BJ20050441","article-title":"Identification, molecular cloning and functional characterization of an octaprenyl pyrophosphate synthase in intra-erythrocytic stages of Plasmodium falciparum","volume":"392","author":"Tonhosolo","year":"2005","journal-title":"The Biochemical Journal"},{"key":"bib81","doi-asserted-by":"publisher","first-page":"9974","DOI":"10.1074\/jbc.M807464200","article-title":"Carotenoid biosynthesis in intraerythrocytic stages of Plasmodium falciparum","volume":"284","author":"Tonhosolo","year":"2009","journal-title":"The Journal of Biological Chemistry"},{"key":"bib82","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1016\/j.molbiopara.2004.05.009","article-title":"Localization of organellar proteins in Plasmodium falciparum using a novel set of transfection vectors and a new immunofluorescence fixation method","volume":"137","author":"Tonkin","year":"2004","journal-title":"Molecular and Biochemical Parasitology"},{"key":"bib83","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01161-17","article-title":"Validation of Putative Apicoplast-Targeting Drugs Using a Chemical Supplementation Assay in Cultured Human Malaria Parasites","volume":"62","author":"Uddin","year":"2018","journal-title":"Antimicrobial Agents and Chemotherapy"},{"key":"bib84","doi-asserted-by":"publisher","first-page":"23612","DOI":"10.1074\/jbc.M201748200","article-title":"Processing of an apicoplast leader sequence in Plasmodium falciparum and the identification of a putative leader cleavage enzyme","volume":"277","author":"van Dooren","year":"2002","journal-title":"The Journal of Biological Chemistry"},{"key":"bib85","doi-asserted-by":"publisher","first-page":"405","DOI":"10.1111\/j.1365-2958.2005.04699.x","article-title":"Development of the endoplasmic reticulum, mitochondrion and apicoplast during the asexual life cycle of Plasmodium falciparum","volume":"57","author":"van Dooren","year":"2005","journal-title":"Molecular Microbiology"},{"key":"bib86","doi-asserted-by":"publisher","first-page":"596","DOI":"10.1111\/j.1574-6976.2006.00027.x","article-title":"Metabolic maps and functions of the Plasmodium mitochondrion","volume":"30","author":"van Dooren","year":"2006","journal-title":"FEMS Microbiology Reviews"},{"key":"bib87","doi-asserted-by":"publisher","first-page":"2350","DOI":"10.1093\/pcp\/pcy157","article-title":"Medium-Chain Polyprenols Influence Chloroplast Membrane Dynamics in Solanum lycopersicum","volume":"59","author":"Van Gelder","year":"2018","journal-title":"Plant & Cell Physiology"},{"key":"bib88","doi-asserted-by":"publisher","first-page":"550","DOI":"10.1128\/EC.00264-13","article-title":"Type II fatty acid biosynthesis is essential for Plasmodium falciparum sporozoite development in the midgut of Anopheles mosquitoes","volume":"13","author":"van Schaijk","year":"2014","journal-title":"Eukaryotic Cell"},{"key":"bib89","doi-asserted-by":"publisher","first-page":"1794","DOI":"10.1093\/emboj\/19.8.1794","article-title":"Protein trafficking to the plastid of Plasmodium falciparum is via the secretory pathway","volume":"19","author":"Waller","year":"2000","journal-title":"The EMBO Journal"},{"key":"bib90","doi-asserted-by":"publisher","first-page":"253","DOI":"10.1038\/345253a0","article-title":"Chloroquine resistance not linked to mdr-like genes in a Plasmodium falciparum cross","volume":"345","author":"Wellems","year":"1990","journal-title":"Nature"},{"key":"bib91","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.1001138","article-title":"Chemical rescue of malaria parasites lacking an apicoplast defines organelle function in blood-stage Plasmodium falciparum","volume":"9","author":"Yeh","year":"2011","journal-title":"PLOS Biology"},{"key":"bib92","doi-asserted-by":"publisher","first-page":"567","DOI":"10.1016\/j.chom.2008.11.001","article-title":"The Fatty Acid Biosynthesis Enzyme Fabl Plays a Key Role in the Development of Liver-Stage Malarial Parasites","volume":"4","author":"Yu","year":"2008","journal-title":"Cell Host & Microbe"},{"key":"bib93","doi-asserted-by":"publisher","first-page":"3570","DOI":"10.1021\/bi200113y","article-title":"A second target of the antimalarial and antibacterial agent fosmidomycin revealed by cellular metabolic profiling","volume":"50","author":"Zhang","year":"2011","journal-title":"Biochemistry"},{"key":"bib94","doi-asserted-by":"publisher","DOI":"10.1126\/science.aap7847","article-title":"Uncovering the essential genes of the human malaria parasite Plasmodium falciparum by saturation mutagenesis","volume":"360","author":"Zhang","year":"2018","journal-title":"Science (New York, N.Y.)"},{"key":"bib95","doi-asserted-by":"publisher","first-page":"3558","DOI":"10.1073\/pnas.1420831112","article-title":"Arabidopsis OR proteins are the major posttranscriptional regulators of phytoene synthase in controlling carotenoid biosynthesis","volume":"112","author":"Zhou","year":"2015","journal-title":"PNAS"},{"key":"bib96","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-020-70246-0","article-title":"Metabolomics profiling reveals new aspects of dolichol biosynthesis in Plasmodium falciparum","volume":"10","author":"Zimbres","year":"2020","journal-title":"Scientific Reports"},{"key":"bib97","doi-asserted-by":"publisher","first-page":"2237","DOI":"10.1016\/j.jmb.2017.12.007","article-title":"A Completely Reimplemented MPI Bioinformatics Toolkit with a New HHpred Server at its Core","volume":"430","author":"Zimmermann","year":"2018","journal-title":"Journal of Molecular Biology"}],"container-title":["eLife"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/cdn.elifesciences.org\/articles\/73208\/elife-73208-v2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/cdn.elifesciences.org\/articles\/73208\/elife-73208-v2.xml","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/elifesciences.org\/articles\/73208","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,11]],"date-time":"2023-10-11T21:08:03Z","timestamp":1697058483000},"score":1,"resource":{"primary":{"URL":"https:\/\/elifesciences.org\/articles\/73208"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,3,8]]},"references-count":97,"alternative-id":["10.7554\/eLife.73208"],"URL":"https:\/\/doi.org\/10.7554\/elife.73208","archive":["CLOCKSS"],"relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2021.08.19.456988","asserted-by":"subject"},{"id-type":"doi","id":"10.1101\/2021.08.19.456988","asserted-by":"object"}],"has-review":[{"id-type":"doi","id":"10.7554\/eLife.73208.sa2","asserted-by":"object"},{"id-type":"doi","id":"10.7554\/eLife.73208.sa1","asserted-by":"object"},{"id-type":"doi","id":"10.7554\/eLife.73208.sa0","asserted-by":"object"}]},"ISSN":["2050-084X"],"issn-type":[{"value":"2050-084X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,3,8]]},"assertion":[{"value":"single anonymised","name":"peer_review_transparency","label":"Peer review transparency","group":{"name":"peer_review_taxonomy"}},{"value":"other reviewer(s), editor","name":"peer_review_interaction","label":"Peer review interaction","group":{"name":"peer_review_taxonomy"}},{"value":"review summaries, review reports, author\/editor communication, reviewer identities reviewer opt in, editor identities","name":"peer_review_published","label":"Peer review published","group":{"name":"peer_review_taxonomy"}},{"value":"open (sign in with ORCID iD required)","name":"post_publication_commenting","label":"Post publication commenting","group":{"name":"post_publication_commenting"}}],"article-number":"e73208"}}