{"doi":"10.1038/s41589-025-01970-9","title":"Enzymatic epimerization of monoterpene indole alkaloids in kratom","abstract":"Monoterpene indole alkaloids (MIAs) are a large, structurally diverse class of bioactive natural products. These compounds are biosynthetically derived from a stereoselective Pictet-Spengler condensation that generates a tetrahydro-β-carboline scaffold characterized by a 3S stereocenter. However, a subset of MIAs contains a noncanonical 3R stereocenter. Here we report the basis for 3R-MIA biosynthesis in Mitragyna speciosa (kratom). We discover the presence of the iminium species (20S)-3-dehydrocorynantheidine, which supports isomerization of 3S to 3R via oxidation and stereoselective reduction downstream of the initial Pictet-Spengler condensation. Isotopologue feeding experiments identify the sites for downstream MIA pathway biosynthesis as well as the oxidase/reductase pair that catalyzes this epimerization. This oxidase/reductase pair has broad substrate specificity, suggesting that this pathway may be responsible for the formation of many 3R-MIAs and downstream spirooxindole alkaloids in kratom. The elucidation of this epimerization mechanism allows biocatalytic access to a range of pharmacologically active spirooxindole alkaloid compounds.","journal":"Nature Chemical Biology","year":2025,"id":516277,"datarank":0.4662798391689559,"base_score":2.3978952727983707,"endowment":2.3978952727983707,"self_citation_contribution":0.3596842909197557,"citation_network_contribution":0.10659554824920021,"self_endowment_contribution":0.3596842909197557,"citer_contribution":0.10659554824920021,"corpus_percentile":null,"corpus_rank":null,"citation_count":10,"citer_count":8,"citers_with_citation_signal":4,"citers_with_endowment":4,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.945,"is_data_producer":true,"deposit_databanks":{"BioProject":["PRJNA1244102","PRJNA1167310","PV711318","PV711319","PV711320","PV711321","PV711322"]},"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1381636,"name":"Yoko Nakamura","orcid":"0000-0002-9622-1005","position":1,"is_corresponding":false},{"id":988400,"name":"Carsten Schotte","orcid":"0000-0001-5737-5178","position":2,"is_corresponding":false},{"id":1381637,"name":"Gabriel R. Titchiner","orcid":"0000-0002-6378-9884","position":3,"is_corresponding":false},{"id":880838,"name":"Kin H. Lau","orcid":"0000-0002-7405-1551","position":4,"is_corresponding":false},{"id":1381638,"name":"Ryan M. Alam","orcid":"0000-0002-0227-0771","position":5,"is_corresponding":false},{"id":1381639,"name":"Adriana A. Lopes","orcid":"0000-0003-1107-2547","position":6,"is_corresponding":false},{"id":907362,"name":"C. Robin Buell","orcid":"0000-0002-6727-4677","position":7,"is_corresponding":false},{"id":685231,"name":"Sarah E. O’Connor","orcid":"0000-0003-0356-6213","position":8,"is_corresponding":false},{"id":429668,"name":"Allwin D. McDonald","orcid":"0000-0001-9559-0856","position":0,"is_corresponding":true}],"reference_count":52,"raw_metadata":null,"created_at":"2026-07-19T02:48:49.486328Z","pmid":"40670688","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}