Identification of Lomaiviticin Biosynthetic Gene Clusters Unveils New Tailoring Mechanism

The lomaiviticins are a group of diazo-containing polyketides produced by a marine actinomycete Salinispora pacifica. They exhibit potent antitumor activity against human cancer cell lines. The anticancer activity and the unique structural features of the lomaiviticins have intrigued both biological and synthetic chemists. To elucidate the biosynthesis of these natural products, we have identified the lomaiviticin (lom) biosynthetic gene cluster in Salinispora pacifica strain DPJ-0019 using genome sequencing and bacterial genetics approaches. Dedicated enzymes for unusual enzymatic transformations, including diazo formation, oxidative dimerization, and L-deoxysugar installations, have been identified using comparative genomic analysis. In order to elucidate functions of these new tailoring enzymes, we have cloned the intact lom gene cluster into an E. coli-Streptomyces shuttle vector. The combination of heterologous expression and genetic manipulation of the lom gene cluster will pave the way for understanding the chemistry of lomaiviticin biosynthesis and the discovery of new enzymatic mechanism involved in complex natural product construction.