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It has been demonstrated that cannabigerolic acid is successfully formed by the reaction catalysed by NphB using geranyl diphosphate and olivetolic acid as substrates. In this study, the substrate specificity of NphB was further determined by using olivetolic acid derivatives as potential substrates for the formation of new synthetic cannabinoids. The derivatives differ in the hydrocarbon chain attached to C6 of the core structure. We performed in silico experiments, including docking of olivetolic acid derivatives, to identify differences in their binding modes. Substrate acceptance was predicted. Based on these results, a library of olivetolic acid derivatives was constructed and synthesized by using different organic synthetic routes. Conversion was monitored in in\u2005vitro assays with purified NphB versions. For the substrates leading to a high conversion olivetolic acid\u2010C8, olivetolic acid\u2010C2 and 2\u2010benzyl\u20104,6\u2010dihydroxybenzoic acid, the products were further elucidated and identified as cannbigerolic acid derivatives. Therefore, these substrates show potential to be adapted in cannabinoid biosynthesis.<\/jats:p>","DOI":"10.1002\/cbic.202300441","type":"journal-article","created":{"date-parts":[[2023,9,10]],"date-time":"2023-09-10T22:30:21Z","timestamp":1694385021000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Generation of Cannabigerolic Acid Derivatives and Their Precursors by Using the Promiscuity of the Aromatic Prenyltransferase NphB"],"prefix":"10.1002","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0361-4249","authenticated-orcid":false,"given":"Saskia","family":"Spitzer","sequence":"first","affiliation":[{"name":"Technical Biochemistry Laboratory Technical University Dortmund  44227 Dortmund Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1380-3692","authenticated-orcid":false,"given":"Jasmin","family":"Wloka","sequence":"additional","affiliation":[{"name":"Institute of Bioorganic Chemistry Heinrich-Heine University D\u00fcsseldorf  52426 J\u00fclich Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9819-889X","authenticated-orcid":false,"given":"J\u00f6rg","family":"Pietruszka","sequence":"additional","affiliation":[{"name":"Institute of Bioorganic Chemistry Heinrich-Heine University D\u00fcsseldorf  52426 J\u00fclich Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6131-2495","authenticated-orcid":false,"given":"Oliver","family":"Kayser","sequence":"additional","affiliation":[{"name":"Technical Biochemistry Laboratory Technical University Dortmund  44227 Dortmund Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,9,29]]},"reference":[{"key":"e_1_2_9_1_1","doi-asserted-by":"publisher","DOI":"10.1021\/ja01062a046"},{"key":"e_1_2_9_2_1","doi-asserted-by":"crossref","first-page":"605","DOI":"10.1016\/S0026-895X(25)09876-1","volume":"34","author":"Devane W. 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