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

Bartosz Bednarz,Krzysztof J Pawlik,Magdalena Kotowska

doi:10.1007/s00253-019-09975-w

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.

Highlights

Streptomyces are Gram-positive, filamentous bacteria that are potent producers of secondary metabolites—specialized compounds with adaptive functions (Traxler and Kolter 2015)— many of which have antibiotic, immunosuppressant, antitumor, and other biological activities (Hopwood 2007)
It was found that cellular levels of actII-orf4 and redD transcripts correlate with the production levels of respective secondary metabolites (Takano et al 1992; Gramajo et al 2014)
They have been believed to exert their functions on biosynthetic genes via cluster-situated regulators (McKenzie and Nodwell 2007) but later findings have demonstrated their ability to bind to promoters of biosynthetic genes (Ryding et al 2002) or even within the coding sequences, implying their direct role in the regulation of secondary metabolism

Summary

Introduction

Streptomyces are Gram-positive, filamentous bacteria that are potent producers of secondary metabolites—specialized compounds with adaptive functions (Traxler and Kolter 2015)— many of which have antibiotic, immunosuppressant, antitumor, and other biological activities (Hopwood 2007). Each biosynthetic gene cluster encodes its own pathway-specific Streptomyces antibiotic regulatory proteins (SARPs): CpkO (formerly KasO) and CpkN (cpk cluster), CdaR (cda cluster), RedZ and RedD (red cluster), and ActII-orf4 (act cluster) (Liu et al 2013).

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