Enantioselective epoxidation followed by regioselective epoxide opening reaction are the key processes in construction of the polyether skeleton. Recent genetic analysis of ionophore polyether biosynthetic gene clusters suggested that flavin-containing monooxygenases (FMOs) could be involved in the oxidation steps. In vivo and in vitro analyses of Lsd18, an FMO involved in the biosynthesis of polyether lasalocid, using simple olefin or truncated diene of a putative substrate as substrate mimics demonstrated that enantioselective epoxidation affords natural type mono- or bis-epoxide in a stepwise manner. These findings allow us to figure out enzymatic polyether construction in lasalocid biosynthesis.

Enzymatic epoxidation represents a key biosynthetic transformation in the construction of polyether skeletons. A single flavin-containing monooxygenase, Lsd18, is involved in ionophore polyether lasalocid biosynthesis and participates in the enantioselective epoxidations of the diene precursor. Biotransformation studies utilizing structurally simplified monoolefin analogs with different substitution patterns revealed important structural requirements for the enantiofacial selectivity of Lsd18-catalyzed epoxidations. These results enabled us to propose a substrate binding model of Lsd18, which was applied to the biosynthesis of other polyethers.