Work

Structural Basis of Sequential Enantioselective Epoxidation by a Flavin‐Dependent Monooxygenase in Lasalocid A Biosynthesis

Year: 2025

Type: article

Abstract: Polyether polyketides are a structurally diverse group of natural products known for their antimicrobial and antiproliferative activities. Lasalocid A is a canonical natural polyether produced by the soil bacterium Streptomyces lasalocidi . In lasalocid A biosynthesis, a polyene polyketide intermediate is converted into a bisepoxide by the flavin‐dependent monooxygenase enzyme Lsd18. Remarkably, Lsd18 acts on two distinct C═C groups in the substrate molecule, forming two ( R , R ) epoxides. We have determined the X‐ray crystal structures of Lsd18 in the substrate‐free, substrate‐bound, and product‐bound forms. Our work has revealed that Lsd18 has an extra‐large substrate‐binding pocket that allows the polyene to adopt different conformations within the enzyme pocket. This feature enables Lsd18 to epoxidate both of the C═C groups. Additionally, a subpocket located near the Lsd18 active site controls stereoselectivity by dictating which face of the C═C group is placed next to the flavin. Molecular understanding of how Lsd18 transforms a polyene into a bisepoxide during lasalocid A biosynthesis lays the foundation for the production of designer polyethers for drug development.

Source: Angewandte Chemie

DOI: 10.1002/ange.202504982