Cross-talk of global nutritional regulators in the control of primary and secondary metabolism in Streptomyces

Limitation of different nutrients in Streptomyces coelicolor A3(2) triggers nutrient-stress responses, mediated by PhoP, GlnR, AfsR and other regulators, that are integrated at the molecular level and control secondary metabolite biosynthesis and differentiation. In addition, utilization of chitin or N-acetylglucosamine regulates secondary metabolite biosynthesis by a mechanism mediated by DasR. Phosphate control of primary and secondary metabolism in Streptomyces species is mediated by the two-component PhoR-PhoP system. In S. coelicolor, PhoP controls secondary metabolism by binding to a PHO box in the afsS promoter overlapping with the AfsR binding site. Therefore, the afsS promoter serves to integrate the PhoP-mediated response to phosphate limitation and AfsR-mediated responses to other unknown environmental stimuli. Interestingly, phosphate control oversees nitrogen regulation but not vice versa. In ΔphoP mutants, expression of some nitrogen metabolism genes including glnA, glnII and glnK is increased. Phosphate control of these genes is exerted through binding of PhoP to the promoters of glnR (the global nitrogen regulator), glnA, glnII and the amtB-glnK-glnD operon. This regulation allows a 'metabolic homeostasis' of phosphate and nitrogen utilization pathways, preventing nutritional unbalances. Similar mechanisms of interaction between phosphate control and carbon catabolite regulation or between phosphate and DasR-mediated N-acetylglucosamine regulation appear to exist. Transport of N-acetylglucosamine by the NagE2 permease and, therefore, regulation of secondary metabolism, is dependent upon the balance of phosphorylated/dephosphorylated proteins of the N-acetylglucosamine phosphotransferase system. These findings provide the bases for understanding the mechanisms underlying systems biology of Streptomyces species.