ArticleNature chemical biology2026
Biosynthesis of the α-D-mannosidase inhibitor (-)-Swainsonine.
Article in Nature chemical biology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.
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Who cites it
2 citing papers in PubMed.
- Targeting Selectivity: Improving Golgi α-Mannosidase II (GMII) Inhibitors Through In Silico Studies.Biomolecules · 2026Review
- From Respiration to Secondary Metabolism: A Heme A Synthase-Mediated Regulatory Network Expands Indolizidine Chemical Space in Fungi.Research (Washington, D.C.) · 2026Article
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3 authors.
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Abstract
(-)-Swainsonine is a polyhydroxylated indolizidine alkaloid with potent inhibitory activity against α-D-mannosidases. Although the genetic basis of its biosynthesis has been established, the biosynthetic mechanism underlying its formation remains poorly understood. Here we report the complete elucidation of the biosynthetic pathway through a combination of in vivo and in vitro reconstitution studies. Our findings reveal an unexpected epimerization mechanism mediated by two bifunctional α-ketoglutarate-dependent nonheme iron dioxygenases, SwnH2 and SwnH1, along with an unusual imine reductase, SwnN, which exhibits substrate-dependent stereospecificity. We further discovered that an O-acetyl group can serve as a detachable directing group that modulates the site selectivity of SwnH2-catalyzed hydroxylation without altering its stereoselectivity. These mechanistic insights into Swainsonine biosynthetic enzymes enable biocatalytic synthesis of an unnatural polyhydroxylated indolizidine alkaloid, opening doors to the biosynthesis of structurally diverse natural product-derived glycosidase inhibitors.
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