Multi-level regulation of coelimycin synthesis in Streptomyces coelicolor A3(2)

Abstract

Despite being a yellow pigment visible to the human eye, coelimycin (CPK) remained to be an undiscovered secondary metabolite for over 50 years of Streptomyces research. Although the function of this polyketide is still unclear, we now know that its "cryptic" nature is attributed to a very complex and precise mechanism of cpk gene cluster regulation in the model actinomycete S. coelicolor A3(2). It responds to the stringent culture density and timing of the transition phase by the quorum-sensing butanolide system and to the specific nutrient availability/uptake signals mediated by the global (pleiotropic) regulators; many of which are two-component signal transduction systems. The final effectors of this regulation cascade are predicted to be two cluster-situated Streptomyces antibiotic regulatory proteins (SARPs) putatively activating the expression of type I polyketide synthase (PKS I) genes. After its synthesis, unstable, colorless antibiotic coelimycin A reacts with specific compounds in the medium losing its antibacterial properties and giving rise to yellow coelimycins P1 and P2. Here we review the current knowledge on coelimycin synthesis regulation in Streptomyces coelicolor A3(2). We focus on the regulatory feedback loop which interconnects the butanolide system with other cpk cluster-situated regulators. We also present the effects exerted on cpk genes expression by the global, pleiotropic regulators, and the regulatory connections between cpk and other biosynthetic gene clusters.

Keywords: Actinomycetes; Antibiotics; Coelimycin; Secondary metabolism; Streptomyces coelicolor; Type I polyketide synthase.

Fig. 1

Coelimycin biosynthetic gene cluster regulation by the cluster-situated regulators. CPK biosynthetic genes are marked with a yellow background. The lines ending with arrows indicate transcription activation, with the exception of an arrow indicating γ-butyrolactone SCB1 production. The lines ending with bars indicate repression of transcription or inhibition of ScbR by SCB1. The solid lines indicate promoter binding while dashed lines imply an indirect or unknown regulatory mechanism. See the text for further information and references

Fig. 2

The regulatory pathways interconnected with cpk cluster regulation. The diagram links nutrient signals with pleiotropic and pathway-specific regulators affecting coelimycin synthesis and the feedback effect of cpk cluster genes. The blue lines ending with an arrow indicate activation. The red lines ending with a bar indicate repression. The green line with no ending indicates evidence of DNA binding, but the effect on transcription is unknown. The solid lines indicate the direct effect (DNA or ligand binding), dashed lines indicate indirect effect, and dotted lines indicate proposed but direct interactions. The thin black lines indicate transport or transformation of chemical compounds. Only the effects of butanolide system proteins ScbR and ScbR2 on other biosynthetic gene clusters were included in the diagram as they most accurately represent the impact of cpk cluster transcription on the production of other antibiotics. CCR–carbon catabolite repression. See the text for further information and references