Carbon catabolite regulation of secondary metabolite formation, an old but not well-established regulatory system

Abstract

Secondary microbial metabolites have various functions for the producer microorganisms, which allow them to interact and survive in adverse environments. In addition to these functions, other biological activities may have clinical relevance, as diverse as antimicrobial, anticancer and hypocholesterolaemic effects. These metabolites are usually formed during the idiophase of growth and have a wide diversity in their chemical structures. Their synthesis is under the impact of the type and concentration of the culture media nutrients. Some of the molecular mechanisms that affect the synthesis of secondary metabolites in bacteria (Gram-positive and negative) and fungi are partially known. Moreover, all microorganisms have their peculiarities in the control mechanisms of carbon sources, even those belonging to the same genus. This regulatory knowledge is necessary to establish culture conditions and manipulation methods for genetic improvement and product fermentation. As the carbon source is one of the essential nutritional factors for antibiotic production, its study has been imperative both at the industrial and research levels. This review aims to draw the utmost recent advances performed to clarify the molecular mechanisms of the negative effect exerted by the carbon source on the secondary metabolite formation, emphasizing those found in Streptomyces, one of the genera most profitable antibiotic producers.

Fig. 1

Involvement of the PTS, DasR and AtrA in the Streptomyces CCR. GlcNAc transport occurs via PTS which also phosphorylates it. When GlcNAc is at a high concentration, Nag A deacetylates GlcNAc‐6P obtaining GlcN‐6P, which negatively modulates DasR activity. Nag B converts GlcN‐6P into Fru‐6P, which can flow in the glycolysis pathway. At high glucose concentration DasR negatively affects NagA and NagB activities. DasR also represses the genes of morphological differentiation and secondary metabolites production (streptomycin, actinorhodin [ACT], undecylprodigiosin [RED], calcium‐dependent antibiotic [CDA] and coelimycin [CPK]). On the contrary, AtrA acts as an antagonist of DasR since it activates ACT, streptomycin production and GlcNAc transport.

Fig. 2

The roles of glucose, Glk and Rok7B7 in the Streptomyces CCR. Glucose transport occurs by the symporter GlcP, which has been proposed to interact with Glk, eliciting its modification. The modified Glk exert CCR on the uptake and metabolism of other carbon sources like glycerol (glpK) or agarose (dagA). Xylose is transported and phosphorylated by XylFGH to produce Xyl‐5P. This compound activates the regulatory protein Rok7B7 to repress the expression of glcP, xylFGH (xylose uptake) glkA and the production of the secondary metabolites RED, CDA and siderophores. On the contrary, it stimulates ACT production.

Fig. 3

Roles of the MalR, Reg1 and BldD regulators in the Streptomyces CCR. MalFG transports maltose and maltodextrin. Internal maltose concentrations inhibit the specific regulator MalR which represses the gene malE (maltose‐binding protein) for maltose utilization. Maltose is hydrolysed to glucose and converted to Glc‐6P. High concentrations of this metabolite activate MalR, which subsequently exerts CCR on malE. The orthologous protein of MalR in S. lividans is Reg1. This protein represses the expression of genes encoding for hydrolytic enzymes like amylase (aml), chitinase (chiA), cellulase (celB) and xylanase (xlnB). The morphological differentiation protein BldB is also involved in the production of ACT and RED. When glucose is present, BldB suppresses the use of other carbon sources such as galactose (galP), agarose (dagA) and glycerol (gyl).

Fig. 4

The negative effect of the carbon source in Saccharopolyspora erythraea. GlcNAc is transported by PTS converting it to GlcNAc‐6P. Deacetylation of this compound produces GlcN‐6P, an inhibitor of DasR activity. On the contrary, when other carbon sources different from GlcNAc are present, DasR binds to its dre boxes in genes such as acetate (acsA1) and citrate (citA‐A4) synthases which affect acetate and citrate assimilation.