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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2023,5,9]]},"abstract":"<jats:p>\n                    The mitochondrial electron transport chain (ETC) of\n                    <jats:italic>Plasmodium<\/jats:italic>\n                    malaria parasites is a major antimalarial drug target, but critical cytochrome\u00a0(cyt) functions remain unstudied and enigmatic. Parasites express two distinct cyt\n                    <jats:italic>c<\/jats:italic>\n                    homologs (\n                    <jats:italic>c<\/jats:italic>\n                    and\n                    <jats:italic>c<\/jats:italic>\n                    -2) with unusually sparse sequence identity and uncertain fitness contributions.\n                    <jats:italic>P. falciparum<\/jats:italic>\n                    cyt\n                    <jats:italic>c<\/jats:italic>\n                    -2 is the most divergent eukaryotic cyt\n                    <jats:italic>c<\/jats:italic>\n                    homolog currently known and has sequence features predicted to be incompatible with canonical ETC function. We tagged both cyt\n                    <jats:italic>c<\/jats:italic>\n                    homologs and the related cyt\n                    <jats:italic>c<\/jats:italic>\n                    <jats:sub>1<\/jats:sub>\n                    for inducible knockdown. Translational repression of cyt\n                    <jats:italic>c<\/jats:italic>\n                    and cyt\n                    <jats:italic>c<\/jats:italic>\n                    <jats:sub>1<\/jats:sub>\n                    was lethal to parasites, which died from ETC dysfunction and impaired ubiquinone recycling. In contrast, cyt\n                    <jats:italic>c<\/jats:italic>\n                    -2 knockdown or knockout had little impact on blood-stage growth, indicating that parasites rely fully on the more conserved cyt\n                    <jats:italic>c<\/jats:italic>\n                    for ETC function. Biochemical and structural studies revealed that both cyt\n                    <jats:italic>c<\/jats:italic>\n                    and\n                    <jats:italic>c<\/jats:italic>\n                    -2 are hemylated by holocytochrome\n                    <jats:italic>c<\/jats:italic>\n                    synthase, but UV-vis absorbance and EPR spectra strongly suggest that cyt\n                    <jats:italic>c<\/jats:italic>\n                    -2 has an unusually open active site in which heme is stably coordinated by only a single axial amino acid ligand and can bind exogenous small molecules. These studies provide a direct dissection of cytochrome functions in the ETC of malaria parasites and identify a highly divergent\n                    <jats:italic>Plasmodium<\/jats:italic>\n                    cytochrome\n                    <jats:italic>c<\/jats:italic>\n                    with molecular adaptations that defy a conserved role in eukaryotic evolution.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2301047120","type":"journal-article","created":{"date-parts":[[2023,5,1]],"date-time":"2023-05-01T15:11:27Z","timestamp":1682953887000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":24,"title":["Direct tests of cytochrome\n                    <i>c<\/i>\n                    and\n                    <i>c<\/i>\n                    <sub>1<\/sub>\n                    functions in the electron transport chain of malaria parasites"],"prefix":"10.1073","volume":"120","author":[{"given":"Tanya\u00a0J.","family":"Espino-Sanchez","sequence":"first","affiliation":[{"name":"Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT 84112"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7948-3241","authenticated-orcid":false,"given":"Henry","family":"Wienkers","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT 84112"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca\u00a0G.","family":"Marvin","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT 84112"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shai-anne","family":"Nalder","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, University of Utah School of 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