Molecular basis for enhanced biosynthesis of clavulanic acid by a redox-cycling agent, phenazine methosulfate, in Streptomyces clavuligerus.
Phenazine methosulfate (PMS), a generator of superoxide, evoked the transcription of cas2 and cefF, ultimately resulting in the enhanced biosyntheses of clavulanic acid (CA) and cephamycin C (CMC) in Streptomyces clavuligerus. The transcriptional activation of cas2 and cefF was accompanied with that of ccaR, a regulatory gene for biosyntheses of CA and CMC. PMS or H2O2 in cell-free extract exerted a positive regulation on in vitro protein phosphorylation. The PMS-mediated activation of protein phosphorylation was significantly offset by butylated hydroxyanisole, a radical scavenger. Staurosporine, a protein kinase inhibitor, was shown to have a negative effect on PMS-promoted CA accumulation. Therefore, it is suggestive that PMS-activated transcription of cas2 and cefF is mediated by protein phosphorylation and the expression of a pathway-specific transcriptional activator as found in other streptomycetes. These experimental results present an example of the functional relationship between oxidative stimuli and secondary metabolite production in streptomycetes.
Kwon
H J
HJ
Department of Agricultural Chemistry, School of Applied Biology and Chemistry, College of Agriculture and Life Sciences, Seoul National University, Suwon, Korea.
Kim
S U
SU
D000900:Anti-Bacterial Agents / Q000096:biosynthesis*; D019818:Clavulanic Acid / Q000096:biosynthesis*; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008773:Methylphenazonium Methosulfate / Q000494:pharmacology*; D010084:Oxidation-Reduction; D010766:Phosphorylation; D019311:Staurosporine / Q000494:pharmacology; D013302:Streptomyces / Q000378:metabolism*; D014158:Transcription, Genetic
D000900:Anti-Bacterial Agents; D019818:Clavulanic Acid; D008773:Methylphenazonium Methosulfate; D006861:Hydrogen Peroxide; D019311:Staurosporine