{"doi":"10.1101/2024.09.26.615303","title":"Biosynthesis of the alpha-D-Mannosidase Inhibitor (-)-Swainsonine","abstract":"(-)-Swainsonine is a polyhydroxylated indolizidine alkaloid with potent inhibitory activity against α-D-mannosidases. In this work, we successfully reconstituted swainsonine biosynthetic pathway both in vivo and in vitro. Our study unveiled an unexpected epimerization mechanism involving two α-ketoglutarate-dependent non-heme iron dioxygenases (SwnH2 and SwnH1), and an unusual imine reductase (SwnN), which displays substrate-dependent stereospecificity. The stereochemical outcome of SwnN-catalyzed iminium reduction is ultimately dictated by SwnH1-catalyzed C8-hydroxylation. We also serendipitously discovered that an O-acetyl group can serve as a detachable protecting/directing group, altering the site-selectivity of SwnH2-catalyzed hydroxylation while maintaining the stereoselectivity. Insights gained from the biochemical characterization of these tailoring enzymes enabled biocatalytic synthesis of a new polyhydroxylated indolizidine alkaloid, opening doors to the biosynthesis of diverse natural product-based glycosidase inhibitors.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2024,"id":503892,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9521,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1354502,"name":"Zainab Batool","orcid":null,"position":1,"is_corresponding":false},{"id":476923,"name":"Yang Hai","orcid":"0000-0002-2039-5367","position":2,"is_corresponding":false},{"id":1222750,"name":"Shaonan Liu","orcid":"0009-0001-7864-9534","position":0,"is_corresponding":true}],"reference_count":41,"raw_metadata":null,"created_at":"2026-07-19T02:10:35.597333Z","pmid":"39386469","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":[]}