Polyether natural products such as monensin, salinomycin, and brevetoxin are one of the biosynthetic pathway of the polyether skeletons, which is a structural feature of these natural products, was proposed as follows; epoxidation of linear polyene, produced by polyketide synthase (PKS), followed by the cyclization of the generated polyepoxide to afford polyether skeleton (known as Cane-Celmer-Westley model). After this proposal, several groups attempted to prove this hypothesis, however, a detailed mechanism to the enzymatic polyether ring formation is still unconfirmed. Recently, we identified the whole biosynthetic gene cluster of lasalocid A, which is one of the most important ionophore antibiotics produced by Streptomyces lasaliensis. Among this cluster, lsd19, which showed significant homology to the putative epoxide hydrolase genes such as monBI and monBII involved in monensin biosynthesis, was assumed to be responsible for the construction of the polyether skeleton. Actually, in vitro analysis of Lsd19 clearly showed that Lsd19 catalyzes polyether ring formation from bisepoxyprelasalocid to lasalocid A. This is the first direxct experimental evidence of Cane-Celmer-Westley model. In thid presentation, details of the functional analysis of Lsd19 will be discussed.
