Manipulation of pathway regulation in Streptomyces globisporus for overproduction of the enediyne antitumor antibiotic C-1027.

Manipulation of pathway regulation is an efficient strategy to increase specific secondary metabolite production. In this study, we successfully improved the production of both the enediyne antitumor antibiotic C-1027 and a heptaene, an early metabolite of the C-1027 pathway, by manipulating the three regulatory genes, sgcR1, sgcR2 and sgcR3, within the C-1027 biosynthetic gene cluster. SgcR3 has previously been established as an activator, and we now propose that SgcR1 and SgcR2 are also positive regulators based on their upregulation effects on titer and/or timing of heptaene and C-1027 production in Streptomyces globisporus. Specifically, overexpression of sgcR1 significantly improved the production of heptaene (about fivefold) and C-1027 (two- to threefold) compared with the wild-type strain. However, the titers of heptaene and C-1027 were not increased by overexpressing all the three activators together, underscoring the complexity of C-1027 biosynthetic pathway regulation. The possibility of exploiting the heptaene as a readily identifiable and unique indicator for rapidly detecting enediyne production was also assessed.