{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T01:09:14Z","timestamp":1790644154646,"version":"4.1.0"},"update-to":[{"DOI":"10.1371\/journal.ppat.1014269","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T00:00:00Z","timestamp":1780444800000}}],"reference-count":84,"publisher":"Public Library of Science (PLoS)","issue":"5","license":[{"start":{"date-parts":[[2026,5,27]],"date-time":"2026-05-27T00:00:00Z","timestamp":1779840000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["R01 AI125534"],"award-info":[{"award-number":["R01 AI125534"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007880","name":"Johns Hopkins University","doi-asserted-by":"publisher","award":["Johns Hopkins Discovery Award"],"award-info":[{"award-number":["Johns Hopkins Discovery Award"]}],"id":[{"id":"10.13039\/100007880","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\/100011780","name":"Johns Hopkins Malaria Research Institute, Johns Hopkins Bloomberg School of Public Health","doi-asserted-by":"publisher","award":["JHMRI Postdoctoral Fellowship"],"award-info":[{"award-number":["JHMRI Postdoctoral Fellowship"]}],"id":[{"id":"10.13039\/100011780","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008309","name":"Johns Hopkins Bloomberg School of Public Health","doi-asserted-by":"publisher","award":["Samuel Jordan Graham Postdoctoral Fellowship"],"award-info":[{"award-number":["Samuel Jordan Graham Postdoctoral Fellowship"]}],"id":[{"id":"10.13039\/100008309","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>\n                    The malaria parasite\n                    <jats:italic>Plasmodium falciparum<\/jats:italic>\n                    depends entirely on\n                    <jats:italic>de novo<\/jats:italic>\n                    pyrimidine synthesis, as it is unable to salvage these essential nucleotides. This reliance makes the pyrimidine biosynthesis pathway a compelling target for antimalarial drugs, with several inhibitors targeting its rate-limiting enzyme, dihydroorotate dehydrogenase (\n                    <jats:italic>Pf<\/jats:italic>\n                    DHODH), already in clinical development. In this study, we investigated the roles of three other pathway enzymes: aspartate transcarbamoylase (\n                    <jats:italic>Pf<\/jats:italic>\n                    ATC), carbamoyl phosphate synthetase II (\n                    <jats:italic>Pf<\/jats:italic>\n                    CPSII), and dihydroorotase (\n                    <jats:italic>Pf<\/jats:italic>\n                    DHO).\n                    <jats:italic>Pf<\/jats:italic>\n                    ATC features a unique N-terminal extension predicted to serve as an apicoplast trafficking peptide. However, using antibodies against the native protein and epitope-tagged versions, we found no evidence of apicoplast localization. Knockdown of\n                    <jats:italic>Pf<\/jats:italic>\n                    ATC expression proved lethal and could not be rescued by an apicoplast metabolic bypass. Complementation assays further revealed that truncation of the N-terminal domain impaired parasite growth, suggesting that this region is important for\n                    <jats:italic>Pf<\/jats:italic>\n                    ATC function or stability\n                    <jats:italic>in vivo<\/jats:italic>\n                    .\n                    <jats:italic>Pf<\/jats:italic>\n                    CPSII, which harbors large\n                    <jats:italic>Plasmodium<\/jats:italic>\n                    -specific insertions between its catalytic domains, was likewise found to be essential for parasite proliferation. To assess the role of\n                    <jats:italic>Pf<\/jats:italic>\n                    DHO, we engineered parasites to salvage uracil via heterologous expression of a yeast enzyme. Deletion of\n                    <jats:italic>Pf<\/jats:italic>\n                    DHO in this parasite line resulted in uracil auxotrophy, confirming the enzyme\u2019s essential function in pyrimidine synthesis. Together, these findings reveal multiple vulnerable nodes within the pyrimidine biosynthesis pathway.\n                  <\/jats:p>","DOI":"10.1371\/journal.ppat.1014269","type":"journal-article","created":{"date-parts":[[2026,5,27]],"date-time":"2026-05-27T17:43:38Z","timestamp":1779903818000},"page":"e1014269","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":1,"title":["Genetic analysis of pyrimidine biosynthetic enzymes in Plasmodium falciparum"],"prefix":"10.1371","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4830-5471","authenticated-orcid":true,"given":"Krithika","family":"Rajaram","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Montana L.","family":"Sievert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rubayet","family":"Elahi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James","family":"Blauwkamp","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucas B.","family":"Dillard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabrina","family":"Absalon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9684-1733","authenticated-orcid":true,"given":"Sean T.","family":"Prigge","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2026,5,27]]},"reference":[{"issue":"1465","key":"ppat.1014269.ref001","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1098\/rstb.2005.1756","article-title":"Niche metabolism in parasitic protozoa","volume":"361","author":"ML Ginger","year":"2006","journal-title":"Philos Trans R Soc Lond B Biol Sci"},{"issue":"3","key":"ppat.1014269.ref002","doi-asserted-by":"crossref","first-page":"254","DOI":"10.1080\/10409238.2017.1290043","article-title":"Genomics of apicomplexan parasites","volume":"52","author":"LS Swapna","year":"2017","journal-title":"Crit Rev Biochem Mol Biol"},{"issue":"1","key":"ppat.1014269.ref003","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1146\/annurev-micro-041222-025305","article-title":"Inside the host: understanding the evolutionary trajectories of intracellular 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