Distribution of the 3-hydroxyl-3-methylglutaryl coenzyme A reductase gene and isoprenoid production in marine-derived Actinobacteria

During the course of our screening program to isolate isoprenoids from marine Actinobacteria, 523 actinobacterial strains were isolated from 18 marine sponges, a tunicate, and two marine sediments. These strains belonged to 21 different genera, but most were members of Streptomyces, Nocardia, Rhodococcus, and Micromonospora. Some Actinobacteria have been reported to use the mevalonate pathway for the production of isoprenoids as secondary metabolites. Therefore, we investigated whether these strains possessed the 3-hydroxyl-3-methylglutaryl coenzyme A reductase (hmgr) gene, which indicates the presence of the mevalonate pathway. As a result, six strains belonging to the genera Streptomyces (SpC080624SC-11, SpA080624GE-02, and Sp080513GE-23), Nocardia (Sp080513SC-18), and Micromonospora (Se080624GE-07 and SpC080624GE-05) were found to possess the hmgr gene, and these genes were highly similar to hmgr genes in isoprenoid biosynthetic gene clusters. Among the six strains, the two strains SpC080624SC-11 and SpA080624GE-02 produced the novel isoprenoids, JBIR-46, -47, and -48, which consisted of phenazine chromophores, and Sp080513GE-23 produced a known isoprenoid, fumaquinone. Furthermore, these compounds showed cytotoxic activity against human acute myelogenous leukemia HL-60 cells.