Biosynthesis of the α-D-mannosidase inhibitor (-)-Swainsonine.

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-catalyze

SUBMITTER: Liu S 

PROVIDER: S-EPMC12466120 | biostudies-literature | 2026 Feb

REPOSITORIES: biostudies-literature