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Here, we uncover an unexpected enzymatic logic in which a consortium of distinct oxidoreductases cooperatively orchestrates indolethiophene skeleton formation and subsequent bioactivation, ultimately generating the authentic antibacterial metabolite thienoxidolin (\n                    <jats:bold>10<\/jats:bold>\n                    ). Following thiotryptophan formation by SDR enzyme TndE, the heme\u2010dependent DUF6875 enzyme TndD initiates C\u2013S bond formation via\n                    <jats:italic>N<\/jats:italic>\n                    \u2010hydroxylation to yield a dearomatized tricyclic species, which is efficiently driven forward and stabilized by aromatization catalyzed by the FAD\u2010dependent oxidoreductase TndG. Notably, TndD functions as a bidirectional redox enzyme, reverting the\n                    <jats:italic>N<\/jats:italic>\n                    \u2010hydroxyl group to the stable N\u2013H form to complete the indolethiophene scaffold construction. After amide formation, late\u2010stage\n                    <jats:italic>N<\/jats:italic>\n                    \u2010hydroxylation by the cytochrome P450 enzyme TndC, previously misassigned as the C\u2013S bond\u2010forming enzyme, produces the bioactive product\n                    <jats:bold>10<\/jats:bold>\n                    . Intriguingly, TndD may also mediate the deactivation of\n                    <jats:bold>10<\/jats:bold>\n                    back to\n                    <jats:bold>1<\/jats:bold>\n                    , representing an intrinsic self\u2010protection mechanism. Together, these results expand the catalytic repertoire of heme\u2010dependent enzymes and highlight reversible\n                    <jats:italic>N<\/jats:italic>\n                    \u2010hydroxylation as a pivotal strategy for heterocycle formation and bioactivity regulation in microbial secondary metabolism.\n                  <\/jats:p>","DOI":"10.1002\/anie.7072895","type":"journal-article","created":{"date-parts":[[2026,6,11]],"date-time":"2026-06-11T17:11:07Z","timestamp":1781197867000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Distinct Oxidoreductases Orchestrate Indolethiophene Skeleton Formation and\n                    <i>N<\/i>\n                    \u2010Hydroxylation\u2010Mediated Bioactivation in Thienoxidolin Biosynthesis"],"prefix":"10.1002","volume":"65","author":[{"given":"Yuanyuan","family":"Shi","sequence":"first","affiliation":[{"name":"CAMS Key Laboratory of Synthetic Biology For Drug 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