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Previous studies reported that, in\n                      <jats:italic>S. coelicolor<\/jats:italic>\n                      , disruption of the\n                      <jats:italic>sco2730\/2731<\/jats:italic>\n                      copper chaperone\u2013transporter system (Sc-M1 mutant) markedly enhances secondary metabolism. However, this activation is only partially reproduced by antisense knockdown constructs targeting\n                      <jats:italic>sco2730\/sco2731<\/jats:italic>\n                      in\n                      <jats:italic>S. coelicolor<\/jats:italic>\n                      (Sc-M2 mutant) and other species (\n                      <jats:italic>S. venezuelae<\/jats:italic>\n                      ,\n                      <jats:italic>S. albidoflavus<\/jats:italic>\n                      ). This study investigates the basis of the strong activation observed in Sc-M1, with the aim of exploiting this mechanism for activating silent BGCs in\n                      <jats:italic>Streptomyces<\/jats:italic>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Genomic analysis revealed that, in addition to\n                      <jats:italic>sco2730\/2731<\/jats:italic>\n                      inactivation, the Sc-M1 mutant possesses a spontaneous deletion of both chromosomal ends. Construction of a\n                      <jats:italic>sco2730<\/jats:italic>\n                      knockout mutant (\u0394\n                      <jats:italic>sco2730<\/jats:italic>\n                      , also affecting\n                      <jats:italic>sco2731<\/jats:italic>\n                      ; Sc-M3 mutant) showed an effect on secondary metabolism comparable to that of the Sc-M2 mutant, and demonstrated that\n                      <jats:italic>sco2730<\/jats:italic>\n                      disruption increases chromosomal-end instability. Metabolomic analyses showed that inactivation of\n                      <jats:italic>sco2730\/2731<\/jats:italic>\n                      (Sc-M3 mutant) or chromosomal-end deletion (Sc-M4 mutant) individually enhanced secondary metabolism. However, only the combination of \u0394\n                      <jats:italic>sco2730<\/jats:italic>\n                      and chromosomal-end deletion (Sc-M5 mutant) approached the extensive metabolic activation observed in Sc-M1, affecting up to 60 secondary-metabolite adducts from 17 biosynthetic pathways. Similar synergistic effects were observed in\n                      <jats:italic>S. venezuelae<\/jats:italic>\n                      , where combined knockdown of the\n                      <jats:italic>sco2730\/2731<\/jats:italic>\n                      orthologues and chromosomal-end deletion strongly modulated secondary metabolism, repressing chloramphenicol production while inducing pikromycin biosynthesis, a typically silent and difficult-to-activate\n                      <jats:italic>S. venezuelae<\/jats:italic>\n                      BGC.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      Simultaneous disruption of the\n                      <jats:italic>sco2730\/31<\/jats:italic>\n                      copper chaperone\u2013transporter system and chromosomal-end deletion synergistically enhance secondary metabolism production in\n                      <jats:italic>S. coelicolor<\/jats:italic>\n                      and\n                      <jats:italic>S. venezuelae<\/jats:italic>\n                      . This combined genetic manipulation provides a novel strategy for the challenging task of activating silent biosynthetic pathways and for potentially discovering new bioactive compounds across\n                      <jats:italic>Streptomyces<\/jats:italic>\n                      species.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12934-026-03000-2","type":"journal-article","created":{"date-parts":[[2026,4,6]],"date-time":"2026-04-06T07:24:20Z","timestamp":1775460260000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Inactivation of the sco2730\/2731 copper chaperone\u2013transporter system in Streptomyces coelicolor and its orthologs in Streptomyces venezuelae, together with chromosomal end deletion, greatly enhances secondary metabolism"],"prefix":"10.1186","volume":"25","author":[{"given":"Gemma","family":"Fern\u00e1ndez-Garc\u00eda","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paula","family":"Vald\u00e9s-Chiara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paula","family":"Garc\u00eda-Cancela","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathaly","family":"Gonz\u00e1lez-Qui\u00f1\u00f3nez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan","family":"Serna-Diestro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Felipe","family":"Lomb\u00f3","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda","family":"Montes-Bay\u00f3n","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u00c1ngel","family":"Manteca","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,4,6]]},"reference":[{"key":"3000_CR1","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/ja.2005.1","volume":"58","author":"J Berdy","year":"2005","unstructured":"Berdy J. 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