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Whereas ITC biosynthesis via glucosinolates in plants has been studied in detail, there is a gap in understanding the bacterial route to specialized metabolites with such reactive heterocumulene groups, as in the antifungal sinapigladioside from <jats:italic>Burkholderia gladioli<\/jats:italic>. Here we propose an alternative ITC pathway by enzymatic sulfur transfer onto isonitriles catalyzed by rhodanese\u2010like enzymes (thiosulfate:cyanide sulfurtransferases). Mining the <jats:italic>B. gladioli<\/jats:italic> genome revealed six candidate genes (<jats:italic>rhdA\u2013F<\/jats:italic>), which were individually expressed in <jats:italic>E. coli<\/jats:italic>. By means of a synthetic probe, the gene products were evaluated for their ability to produce the key ITC intermediate in the sinapigladioside pathway. <jats:italic>In vitro<\/jats:italic> biotransformation assays identified RhdE, a prototype single\u2010domain rhodanese, as the most potent ITC synthase. Interestingly, while RhdE also efficiently transforms cyanide into thiocyanate, it shows high specificity for the natural pathway intermediate, indicating that the sinapigladioside pathway has recruited a ubiquitous detoxification enzyme for the formation of a bioactive specialized metabolite. These findings not only elucidate an elusive step in bacterial ITC biosynthesis but also reveal a new function of rhodanese\u2010like enzymes in specialized metabolism.<\/jats:p>","DOI":"10.1002\/cbic.202300732","type":"journal-article","created":{"date-parts":[[2023,11,2]],"date-time":"2023-11-02T11:44:51Z","timestamp":1698925491000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Bacterial Isothiocyanate Biosynthesis by Rhodanese\u2010Catalyzed Sulfur Transfer onto Isonitriles"],"prefix":"10.1002","volume":"25","author":[{"given":"Mandy D.","family":"Mlotek","sequence":"first","affiliation":[{"name":"Department of Biomolecular Chemistry Leibniz Institute for Natural Product Research and Infection Biology  Beutenbergstr. 11a 07745 Jena Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin","family":"Dose","sequence":"additional","affiliation":[{"name":"Department of Biomolecular Chemistry Leibniz Institute for Natural Product Research and Infection Biology  Beutenbergstr. 11a 07745 Jena Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0367-337X","authenticated-orcid":false,"given":"Christian","family":"Hertweck","sequence":"additional","affiliation":[{"name":"Department of Biomolecular Chemistry Leibniz Institute for Natural Product Research and Infection Biology  Beutenbergstr. 11a 07745 Jena Germany"},{"name":"Faculty of Biological Sciences Friedrich Schiller University Jena  07743 Jena Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,12,8]]},"reference":[{"key":"e_1_2_8_1_1","unstructured":"\u00a0"},{"key":"e_1_2_8_2_2","doi-asserted-by":"publisher","DOI":"10.1002\/1521-3765(20021115)8:22<5072::AID-CHEM5072>3.0.CO;2-M"},{"key":"e_1_2_8_3_2","doi-asserted-by":"publisher","DOI":"10.1021\/cr00001a001"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1023\/A:1024265420375"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.phyto.40.032602.130045"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2672.2009.04181.x"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.phytochem.2019.112100"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.89.6.2399"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.fitote.2016.02.007"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0040-4020(00)00226-X"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1095-6433(02)00265-9"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tet.2017.07.027"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1021\/jo00382a012"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1021\/ja00101a015"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.7164\/antibiotics.35.285"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms15172"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1111\/1462-2920.13868"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-04955-6"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1002\/cbic.202100330"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1469-8137.1994.tb02968.x"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0300-9629(97)00051-0"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12866-014-0213-7"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1002\/cbic.202100089"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1002\/cbic.201300794"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12934-016-0452-4"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.chemrestox.9b00504"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1080\/15216540701206859"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1574-6976.2006.00036.x"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0969-2126(01)00666-9"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0014-5793(02)02695-9"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M114.571935"},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2003.10.072"},{"key":"e_1_2_8_33_1","doi-asserted-by":"publisher","DOI":"10.1002\/pro.260"},{"key":"e_1_2_8_34_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.275.12.8283"},{"key":"e_1_2_8_35_1","unstructured":"P. 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