Disruption of a methyltransferase gene in actinomycin G gene cluster in S treptomyces iakyrus increases the production of phenazinomycin

Phenazinomycin is a hybrid natural product consisting of two chemical entities, a phenazine and a cyclic terpenoid. Phenazinomycin exhibits potent activity against murine tumors and adriamycin‐resistant P 388 leukemia cells. S treptomyces iakyrus DSM 41873 is known to produce five actinomycin G 2 – G 6 . In the previous study, we identified the gene cluster directing the biosynthesis of actinomycin G 2 –G 4 . Inactivation of acm G 5 ′ gene in the actinomycin G gene cluster in S . iakyrus completely abolished the production of actinomycin G . Metabolic profiling, chemical isolation, and structural elucidation of the resulting mutant SIA Δ acm G 5′ showed a previously unnoticed metabolite phenazinomycin in S . iakyrus . In silico analysis identified a hybrid biosynthetic gene cluster in the genome of S . iakyrus that could be responsible for the biosynthesis of phenazinomycin. It is proposed that the perturbation of actinomycin G to enhance the phenazinomycin production in the mutant may result from the lifted competition of chorismate, the common precursor of the biosynthetic pathways of these two structurally unrelated natural products.