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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2026,7,28]]},"abstract":"<jats:p>\n                    The presence of self-resistance genes in antibiotic-producing organisms poses a paradox: How can resistance evolve before the antibiotic exists, and how can an antibiotic producer arise without first evolving resistance? Here, we examine the evolutionary origins of self-resistance to mycophenolic acid (MPA), an inhibitor of inosine monophosphate dehydrogenase (IMPDH). The MPA biosynthetic gene cluster (BGC) includes a resistant IMPDH-B. Homologs of IMPDH-B occur not only in MPA producers but also in many nonproducing fungi, where remnants of the MPA BGC remain detectable. The phylogeny of IMPDH-B is incongruent with the fungal species tree, consistent with multiple horizontal gene transfer events between\n                    <jats:italic toggle=\"yes\">Aspergillus<\/jats:italic>\n                    and Sordariomycetes. We characterized eleven extant IMPDH-Bs, five from MPA producers and six from nonproducers, along with seven resurrected ancestral enzymes (Anc1\u2013Anc7). MPA resistance appeared between Anc2 and Anc3 and coincided with a loss of catalytic efficiency. Across both ancestral and extant enzymes, MPA resistance correlated strongly with reduced activity, revealing a robust activity\u2013resistance trade-off that has persisted for millions of years. Unexpectedly, both the IMPDH-Bs and ancestral enzymes Anc3\u2013Anc7 were also resistant to ribavirin-5\u2032-monophosphate (RVP), an IMP-competitive inhibitor. Because MPA and RVP bind to similar enzyme conformations, the activity\u2013resistance trade-off may reflect a design constraint imposed by the need to maintain resistance to multiple inhibitors. Intriguingly, although Anc1 and Anc2 are equally sensitive to MPA, Anc2 shows reduced susceptibility to RVP. This pattern suggests that preexisting resistance to another IMPDH inhibitor may have created a permissive background for the later evolution of MPA biosynthesis.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2602068123","type":"journal-article","created":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T17:34:43Z","timestamp":1784828083000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":0,"title":["An activity\u2013resistance trade-off constrains enzyme evolution"],"prefix":"10.1073","volume":"123","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-0554-0667","authenticated-orcid":false,"given":"Alexander W.","family":"Sarkis","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/05abbep66","id-type":"ROR","asserted-by":"publisher"}],"name":"Graduate Program in Biochemistry and Biophysics, Department of Biochemistry, Brandeis University","place":["Waltham"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2392-5343","authenticated-orcid":false,"given":"Jens Laurids","family":"S\u00f8rensen","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04m5j1k67","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Chemistry and Bioscience, Aalborg University","place":["Esbjerg, Denmark"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4455-7498","authenticated-orcid":false,"given":"Teis Esben","family":"Sondergaard","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04m5j1k67","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Chemistry and Bioscience, Aalborg University","place":["Esbjerg, Denmark"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5598-4401","authenticated-orcid":false,"given":"K\u00e5re Lehmann","family":"Nielsen","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04m5j1k67","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Chemistry and Bioscience, Aalborg University","place":["Aalborg, Denmark"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0573-4340","authenticated-orcid":false,"given":"Jens C.","family":"Frisvad","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04qtj9h94","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Biotechnology and Biomedicine (DTU Bioengineering), Technical University of Denmark","place":["Kongens Lygnby, Denmark"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2695-8343","authenticated-orcid":false,"given":"Douglas L.","family":"Theobald","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/05abbep66","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Biochemistry, Brandeis University","place":["Waltham"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8432-3322","authenticated-orcid":false,"given":"Lizbeth","family":"Hedstrom","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/05abbep66","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Biology, Brandeis University","place":["Waltham"]},{"id":[{"id":"https:\/\/ror.org\/05abbep66","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Chemistry, Brandeis University","place":["Waltham"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2026,7,23]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1021\/acschembio.8b00173"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1039\/C9NP00050J"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.3390\/antibiotics12010035"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.3390\/biom13060986"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.2165\/00003088-200746010-00002"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1007\/s12016-023-08963-3"},{"key":"e_1_3_4_7_2","first-page":"95","article-title":"Production of mycophenolic acid by fungi of the genus Penicillium link","volume":"41","author":"Vinokurova N. 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