{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T09:28:40Z","timestamp":1785403720553,"version":"3.56.0"},"posted":{"date-parts":[[2026,7,7]]},"group-title":"Biochemistry","reference-count":73,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T00:00:00Z","timestamp":1783382400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"award":["R35GM150910"],"award-info":[{"award-number":["R35GM150910"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"award":["Emerging Pathogens Initiative"],"award-info":[{"award-number":["Emerging Pathogens Initiative"]}],"id":[{"id":"https:\/\/ror.org\/006w34k90","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,7,7]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  The Lyme disease pathogen\n                  <jats:italic>Borrelia burgdorferi<\/jats:italic>\n                  contains a highly reduced genome lacking many primary metabolic pathways. 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-limiting step (3-hydroxy-3-methyl 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 the HMGR as a highly unusual cofactor-promiscuous 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":"10.64898\/2026.07.06.735745","type":"posted-content","created":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T13:10:41Z","timestamp":1783429841000},"source":"Crossref","is-referenced-by-count":0,"title":["A cofactor-promiscuous HMGR from the Lyme disease pathogen illuminates diversity in bacterial isoprenoid biosynthesis"],"prefix":"10.64898","author":[{"given":"Isaac A.","family":"Paddy","sequence":"first","affiliation":[{"name":"Department of Chemical and Systems Biology, Stanford School of Medicine"},{"name":"Sarafan ChEM-H Institute, Stanford University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua","family":"McCausland","sequence":"additional","affiliation":[{"name":"Sarafan ChEM-H Institute, Stanford University"},{"name":"Department of Biology, Stanford University"},{"name":"Howard Hughes Medical Institute, Stanford University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Madelyn","family":"Frazier","sequence":"additional","affiliation":[{"name":"Sarafan ChEM-H Institute, Stanford University"},{"name":"Department of Biology, Stanford University"},{"name":"Howard Hughes Medical Institute, Stanford University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Poulami","family":"Chatterjee","sequence":"additional","affiliation":[{"name":"Sarafan ChEM-H Institute, Stanford University"},{"name":"Department of Chemistry, Stanford University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mekedlawit","family":"Setegne","sequence":"additional","affiliation":[{"name":"Sarafan ChEM-H Institute, Stanford University"},{"name":"Department of Chemistry, Stanford University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oliv","family":"Eidam","sequence":"additional","affiliation":[{"name":"Innovative Medicines Accelerator, Stanford University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine","family":"Jacobs-Wagner","sequence":"additional","affiliation":[{"name":"Sarafan ChEM-H Institute, Stanford University"},{"name":"Department of Biology, Stanford University"},{"name":"Howard Hughes Medical Institute, Stanford University"},{"name":"Department Microbiology & Immunology, Stanford School of Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura M. 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