## 1 Actinobacteria and Their Primary Metabolism as Basis for Secondary Metabolism Precursor Supply
### Carbon Metabolism as a Source of Precursors  
Actinobacteria live in soil under varied nutrient conditions and therefore are able to utilize different C-sources, including monosaccharides, polyols, disaccharides, amino acids, sugar alcohols, deoxy sugars, glycosyl, dicarboxylic acids, ketooids [6; 7], polyamines and monoamines including ethanolamine [8]. From these substrates, hexoses are preferred because they can be directly introduced into glycolysis. Many other substrates require multiple catalytic reactions in order to allow the incorporation of such compounds into cellular metabolism. This requires additional energy, and therefore, processes are necessary to prioritize energy usage. The cells should be constantly protected against wasting the protein-synthesizing machinery. A mechanism to ensure this is carbon catabolic repression (CCR), which is an important part of the global control system in bacteria. It has been extensively studied in _E. coli_, but also investigated as a conserved mechanism in high GC Gram-positive bacteria including _Streptomyces_ spp. and _Mycobacterium_ spp. [9; 10]. The selection of preferred carbon sources is especially important and is considered to be a main determining factor in the microbial growth rate, supporting successful competition against other microorganisms in the environment [11]. The most optimal carbon source is glucose. Used in high concentrations, it interferes with the formation of diverse compounds in primary and secondary metabolisms. CCR allows for the repression of the protein synthesis due to the presence of a catabolite that is generated from a rapidly metabolizable exogenous carbon source. In _S. coelicolor_, cAMP does not appear to play a role in CCR because cAMP levels do not vary [6; 9; 12]. _Streptomyces_ were shown to utilize unique CCR mechanisms to modulate the rates of carbon consumption that affect the expression of genes involved in the transport of alternative carbon sources, e.g., glycerol and arabinose, xylose, fructose and galactose [10]. Furthermore, CCR affects the production of extracellular polysaccharide-degrading enzymes, such as chitinase and amylase [13]. Carbon source availability has been demonstrated to influence antibiotic production, enzyme secretion and morphological development in streptomycetes [14]. The main carbon source in _Streptomyces_ spp. is glucose. It is predominantly transported through the GlcP transporter belonging to the MFS family [12; 15]. Subsequently, it is phosphorylated by the glucose kinase GlcA, resulting in the formation of glucose 6-phosphate (Figure 1). In _Streptomyces_, GlcA is involved in the global regulation of CCR. Glucose kinase shares identity with proteins from the ROK family (\"Repressor, ORF, Kinase\", a family of bacterial proteins including transcriptional repressors, sugar kinases and uncharacterized open reading frames). ROK proteins were demonstrated to have regulatory functions in _Streptomyces_ spp., e.g., in _S. avemitilis_[16]. Glucose kinase combines features of transcriptional regulators (a helix-turn-helix DNA-binding domain) and of kinases. Interestingly, in _S. coelicolor_, GlcA lacks the DNA-binding domain and it cannot exert a regulatory function by binding to the promoter regions of the repressed genes. It has been demonstrated that GlcA interacts with GlcP in the efficient transport and phosphorylation of glucose [17]. Recent studies demonstrated that CCR functions through two mechanisms in _S. coelicolor_: the GlcA-dependent and glucose-dependent mechanisms [18]. It has been shown that glucose-stimulated glycolysis and the pentose phosphate pathway negatively affect the enzymes involved the amino acid metabolism. Furthermore, a strong influence of GlkA on the synthesis of prodigiosins (RED) and calcium-dependent antibiotics (CDAs) was observed [18; 19]. Recent studies showed that the CCR effect is based on the combined action of GlkA and transcription factors [18]. Although GlkA plays a role in CCR, glucose also play a key role in this mechanism.