Salinomycin biosynthesis reversely regulates the beta-oxidation pathway in Streptomyces albus by carrying a 3-hydroxyacyl-CoA dehydrogenase gene in its biosynthetic gene cluster

Streptomyces is well known for synthesis of many biologically active secondary metabolites, such as polyketides and non-ribosomal peptides. Understanding the coupling mechanisms of primary and secondary metabolism can help develop strategies to improve secondary metabolite production in Streptomyces. In this work, Streptomyces albus ZD11, an oil-preferring industrial Streptomyces strain, was proved to have a remarkable capability to generate abundant acyl-CoA precursors for salinomycin biosynthesis with the aid of its enhanced beta -oxidation pathway. It was found that the salinomycin biosynthetic gene cluster contains a predicted 3-hydroxyacyl-CoA dehydrogenase (FadB3), which is the third enzyme of beta -oxidation cycle. Deletion of fadB3 significantly reduced the production of salinomycin. A variety of experimental evidences showed that FadB3 was mainly involved in the beta -oxidation pathway rather than ethylmalonyl-CoA biosynthesis and played a very important role in regulating the rate of beta -oxidation in S. albus ZD11. Our findings elucidate an interesting coupling mechanism by which a PKS biosynthetic gene cluster could regulate the beta -oxidation pathway by carrying beta -oxidation genes, enabling Streptomyces to efficiently synthesize target polyketides and economically utilize environmental nutrients.