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Here we show that the methoxy group in quinine and related alkaloids is introduced onto the starting substrate tryptamine. Feeding studies definitively show that 5\u2010methoxytryptamine is utilized as a quinine biosynthetic intermediate <jats:italic>in planta<\/jats:italic>. We discover the biosynthetic genes that encode the responsible oxidase and methyltransferase, and we use these genes to reconstitute the early steps of the alkaloid biosynthetic pathway in <jats:italic>Nicotiana benthamiana<\/jats:italic> to produce a mixture of methoxylated and non\u2010methoxylated alkaloid intermediates. Importantly, we show that the co\u2010occurrence of both tryptamine and 5\u2010methoxytryptamine substrates, along with the substrate promiscuity of downstream pathway enzymes, enable parallel formation of both methoxylated and non\u2010methoxylated alkaloids.<\/jats:p>","DOI":"10.1002\/anie.202418306","type":"journal-article","created":{"date-parts":[[2024,11,7]],"date-time":"2024-11-07T08:25:02Z","timestamp":1730967902000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Biosynthetic Origin of the Methoxy Group in Quinine and Related Alkaloids"],"prefix":"10.1002","volume":"64","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4298-3108","authenticated-orcid":false,"given":"Blaise Kimbadi","family":"Lombe","sequence":"first","affiliation":[{"name":"Department of Natural Product Biosynthesis Max Planck Institute for Chemical Ecology  Hans-Kn\u00f6ll-Stra\u00dfe 8 07745 Jena Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tingan","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Natural Product Biosynthesis Max Planck Institute for Chemical Ecology  Hans-Kn\u00f6ll-Stra\u00dfe 8 07745 Jena Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7783-6733","authenticated-orcid":false,"given":"Lorenzo","family":"Caputi","sequence":"additional","affiliation":[{"name":"Department of Natural Product Biosynthesis Max Planck Institute for Chemical Ecology  Hans-Kn\u00f6ll-Stra\u00dfe 8 07745 Jena Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kerstin","family":"Ploss","sequence":"additional","affiliation":[{"name":"Department of Natural Product Biosynthesis Max Planck Institute for Chemical Ecology  Hans-Kn\u00f6ll-Stra\u00dfe 8 07745 Jena Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah E.","family":"O'Connor","sequence":"additional","affiliation":[{"name":"Department of Natural Product Biosynthesis Max Planck Institute for Chemical Ecology  Hans-Kn\u00f6ll-Stra\u00dfe 8 07745 Jena Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,11,22]]},"reference":[{"key":"e_1_2_3_1_1","unstructured":"\u00a0"},{"key":"e_1_2_3_2_2","doi-asserted-by":"publisher","DOI":"10.1186\/1475-2875-10-144"},{"key":"e_1_2_3_3_2","doi-asserted-by":"publisher","DOI":"10.3390\/toxins10120491"},{"key":"e_1_2_3_4_2","doi-asserted-by":"publisher","DOI":"10.1002\/anie.200400663"},{"key":"e_1_2_3_5_2","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-642-22144-6_22"},{"key":"e_1_2_3_6_1","unstructured":"\u00a0"},{"key":"e_1_2_3_7_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199801013380107"},{"key":"e_1_2_3_8_2","doi-asserted-by":"publisher","DOI":"10.2174\/1389557517666170707110450"},{"key":"e_1_2_3_9_1","unstructured":"\u00a0"},{"key":"e_1_2_3_10_2","first-page":"331","volume-title":"The Alkaloids: Chemistry and Pharmacology, Vol. 34","author":"Verpoorte R.","year":"1989"},{"key":"e_1_2_3_11_2","doi-asserted-by":"publisher","DOI":"10.2174\/0115680266270796231109171808"},{"key":"e_1_2_3_12_1","unstructured":"\u00a0"},{"key":"e_1_2_3_13_2","doi-asserted-by":"publisher","DOI":"10.1002\/anie.200602318"},{"key":"e_1_2_3_14_2","doi-asserted-by":"publisher","DOI":"10.1021\/ar030048s"},{"key":"e_1_2_3_15_2","doi-asserted-by":"publisher","DOI":"10.1021\/cr020061a"},{"key":"e_1_2_3_16_2","doi-asserted-by":"publisher","DOI":"10.1002\/9781119802280.ch11"},{"key":"e_1_2_3_17_2","first-page":"0961","volume":"2001","author":"Kacprzak K.","year":"2001","journal-title":"Synthesis"},{"key":"e_1_2_3_18_1","unstructured":"\u00a0"},{"key":"e_1_2_3_19_2","doi-asserted-by":"publisher","DOI":"10.1021\/ja01233a516"},{"key":"e_1_2_3_20_2","doi-asserted-by":"publisher","DOI":"10.1021\/ja00704a037"},{"key":"e_1_2_3_21_2","doi-asserted-by":"publisher","DOI":"10.1021\/ja00470a036"},{"key":"e_1_2_3_22_2","doi-asserted-by":"publisher","DOI":"10.1021\/ja004325r"},{"key":"e_1_2_3_23_2","doi-asserted-by":"publisher","DOI":"10.1002\/anie.200705421"},{"key":"e_1_2_3_24_2","doi-asserted-by":"publisher","DOI":"10.1002\/anie.201804551"},{"key":"e_1_2_3_25_2","doi-asserted-by":"publisher","DOI":"10.1002\/anie.201811530"},{"key":"e_1_2_3_26_2","doi-asserted-by":"publisher","DOI":"10.1002\/anie.201804848"},{"key":"e_1_2_3_27_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.orglett.3c01659"},{"key":"e_1_2_3_28_1","unstructured":"\u00a0"},{"key":"e_1_2_3_29_2","doi-asserted-by":"publisher","DOI":"10.1021\/ja01038a049"},{"key":"e_1_2_3_30_2","doi-asserted-by":"publisher","DOI":"10.1021\/ja00883a058"},{"key":"e_1_2_3_31_2","doi-asserted-by":"publisher","DOI":"10.1007\/BF00040805"},{"key":"e_1_2_3_32_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0040-4039(01)87704-2"},{"key":"e_1_2_3_33_2","first-page":"810","author":"Battersby A. 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