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However,\n                    <jats:italic>B. burgdorferi<\/jats:italic>\n                    retains the mevalonate pathway that synthesizes isopentenyl pyrophosphate (IPP), the precursor to the peptidoglycan carrier lipid. While the mevalonate pathway and the enzyme that catalyzes its rate\u2010limiting step (3\u2010hydroxy\u20103\u2010methyl glutaryl coenzyme A reductase, HMGR) are well studied in vertebrates, little is known about the pathway in\n                    <jats:italic>B. burgdorferi<\/jats:italic>\n                    and many pathogenic bacteria. In this work, we reveal that HMGR is a critical metabolic enzyme in\n                    <jats:italic>B. burgdorferi<\/jats:italic>\n                    . We demonstrate that loss of HMGR causes morphological defects and muted de novo synthesis of peptidoglycan; these defects are ameliorated by exogenous mevalonate and IPP. Biochemical characterization unveiled HMGR as a highly unusual cofactor\u2010promiscuous oxidoreductase that functions with both nicotinamide cofactors. Bioinformatics and biochemical characterization uncovered examples of similarly promiscuous HMGRs and revealed a previously unrecognized evolutionary link to cofactor choice. Moreover, structures of the enzyme reveal a highly divergent active site architecture. Together, these findings firmly establish HMGR as an opportunity target for the development of antibacterials for a diderm pathogen while highlighting cofactor promiscuity as an evolutionary acquired feature in HMGRs.\n                  <\/jats:p>","DOI":"10.1002\/pro.70766","type":"journal-article","created":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T13:25:22Z","timestamp":1787145922000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A cofactor\u2010promiscuous\n                    <scp>HMGR<\/scp>\n                    from the Lyme disease pathogen illuminates diversity in bacterial isoprenoid biosynthesis"],"prefix":"10.1002","volume":"35","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6090-2191","authenticated-orcid":false,"given":"Isaac A.","family":"Paddy","sequence":"first","affiliation":[{"name":"Department of Chemical and Systems Biology Stanford School of Medicine  Stanford USA"},{"name":"Sarafan ChEM\u2010H Institute, Stanford University  Stanford USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua","family":"McCausland","sequence":"additional","affiliation":[{"name":"Sarafan ChEM\u2010H Institute, Stanford University  Stanford USA"},{"name":"Department of Biology Stanford University  Stanford USA"},{"name":"Howard Hughes Medical Institute, Stanford University  Stanford USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-5694-024X","authenticated-orcid":false,"given":"Madelyn","family":"Frazier","sequence":"additional","affiliation":[{"name":"Sarafan ChEM\u2010H Institute, Stanford University  Stanford USA"},{"name":"Department of Biology Stanford University  Stanford USA"},{"name":"Howard Hughes Medical Institute, Stanford University  Stanford USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Poulami","family":"Chatterjee","sequence":"additional","affiliation":[{"name":"Sarafan ChEM\u2010H Institute, Stanford University  Stanford USA"},{"name":"Department of Chemistry Stanford University  Stanford USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mekedlawit","family":"Setegne","sequence":"additional","affiliation":[{"name":"Sarafan ChEM\u2010H Institute, Stanford University  Stanford USA"},{"name":"Department of Chemistry Stanford University  Stanford USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oliv","family":"Eidam","sequence":"additional","affiliation":[{"name":"Innovative Medicines Accelerator Stanford University  Stanford USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine","family":"Jacobs\u2010Wagner","sequence":"additional","affiliation":[{"name":"Sarafan ChEM\u2010H Institute, Stanford University  Stanford USA"},{"name":"Department of Biology Stanford University  Stanford USA"},{"name":"Howard Hughes Medical Institute, Stanford University  Stanford USA"},{"name":"Department Microbiology &amp; Immunology Stanford School of Medicine  Stanford USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0851-6373","authenticated-orcid":false,"given":"Laura M. K.","family":"Dassama","sequence":"additional","affiliation":[{"name":"Sarafan ChEM\u2010H Institute, Stanford University  Stanford USA"},{"name":"Department of Chemistry Stanford University  Stanford USA"},{"name":"Department Microbiology &amp; Immunology Stanford School of Medicine  Stanford USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,8,19]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.3389\/fmed.2023.1183344"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.3389\/fbioe.2014.00030"},{"issue":"4","key":"e_1_2_8_4_1","first-page":"521","article-title":"Isolation and cultivation of Lyme disease spirochetes","volume":"57","author":"Barbour AG","year":"1984","journal-title":"Yale J Biol 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