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Sterol methyltransferase (SMT) is directly involved in the synthesis of parasite\u2010specific C24\u2010methylated sterols, including ergosterol and 5\u2010dehydroepisterol. While pharmacological studies hint at its potential as a drug target against trypanosomatids, direct evidence for the cellular function and essentiality of SMT is lacking. Here, we characterized the SMT knockout mutants and their complemented strains in\n                    <jats:italic>Leishmania major<\/jats:italic>\n                    , the causative agent for cutaneous leishmaniasis. Deletion of\n                    <jats:italic>SMT<\/jats:italic>\n                    alleles led to a complete loss of C24\u2010methylated sterols, which were replaced by cholestane\u2010based sterols. SMT\u2010null mutants were fully viable and replicative in culture but showed increased sensitivity to sphingolipid synthesis inhibition. They were not particularly vulnerable to heat, acidic pH, nitrosative or oxidative stress, yet exhibited high mitochondrial membrane potential and increased superoxide generation indicating altered physiology of the mitochondria. Despite possessing high levels of GPI\u2010anchored glycoconjugates, SMT\u2010null mutants showed significantly attenuated virulence in mice. In total, our study reveals that the biosynthesis of ergostane\u2010based sterols is crucial for the proper function of mitochondria and the proliferation of\n                    <jats:italic>Leishmania<\/jats:italic>\n                    parasites in mammals.\n                  <\/jats:p>","DOI":"10.1111\/mmi.14139","type":"journal-article","created":{"date-parts":[[2018,9,27]],"date-time":"2018-09-27T06:45:12Z","timestamp":1538030712000},"page":"65-81","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":62,"title":["Sterol methyltransferase is required for optimal mitochondrial function and virulence in\n                    <i>Leishmania major<\/i>"],"prefix":"10.1111","volume":"111","author":[{"given":"Sumit","family":"Mukherjee","sequence":"first","affiliation":[{"name":"Department of Biological Sciences Texas Tech University Lubbock TX 79409 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