## 3 Utilization of Precursor Compounds from Primary Metabolism in Secondary Metabolism
### Secondary Metabolism in Actinobacteria
Basic units or preliminary stages are defined by a systematic mechanical, regulated production process to form a biologically active molecule [92]. There are various fundamentally similar synthesis methods for macromolecules of secondary metabolism, such as polyketide synthases (PKSs), NRPSs, aminoglycos and others (e.g., RiPPs). Ribosomally synthesized and post-translationally modified peptides (RiPPs) are a superfamily of natural products that exhibits a range of structures, which begin as gene-encoded precursor peptides that are linear chains ofamino acids produced by ribosomes. Polyketides are an important source of naturally occurring small molecules used for medicine. PKSs produce most of the commonly used antibiotics. Currently, three different mechanisms of polyketide biosynthesis are known and they are similar to the fatty acid biosynthesis mechanism. PKSs are classified into three types according to their biosynthesis mechanism: type I PKSs (modular type; non-iterative type), type II PKSs (iterative type), and type III PKSs (chalcone synthase type). Polyketide biosynthesis begins with an activated starter molecule, such as acetyl-CoA. The elongation of the molecule happens through activated extension units, usually malonyl-CoA. Different polyketide intermediate forms are possible. All polyketide biosynthetic mechanisms synthesize a basic body, which is then used for modifications or it serves as a precursor for further biosynthesis processes [94]. There are many other synthesis pathways, but their products do not produce such large compound families. The synthesis of secondary metabolites depends on the nutrient conditions in the cell. The key elements of life are macronutrients (C, H, O, P and S), major cations (K, Mg and Ca) and micronutrients (metal ions). In _Streptomyces_, complex pathway-specific regulatory mechanisms influence the transition from primary to secondary metabolism in response to environmental conditions, such as temperature, pH, oxygenation and nutrient source availability. Actinobacteria are faced with large changes in the sources of oxygen, carbon, nitrogen, phosphate, sulfur, iron and other nutrients. This requires a strict control of primary and secondary metabolisms to avoid imbalances that could have undesirable consequences for cell growth and secondary metabolite biosynthesis [95; 96]. The regulation of secondary metabolism in _Streptomyces_ is complex. It is coordinated at different levels and requires extra- and intracellular effector molecules as the central components of the global and cluster-specific regulatory cascades. The transition from primary to secondary metabolism is connected to the morphological and physiological differentiation of _Streptomyces_. The precursor supply is also regulated in the cell through reduction of phosphate levels, catabolite repression and stringent control via ppGpp. It has been demonstrated that low concentrations of phosphate as well as a lack of amino acids, which is sensed by the effector molecule ppGpp, can act as a trigger for secondary metabolite production [97]. Moreover, an interconnection between elevated levels of cAMP (cyclic adenosine monophosphate) and the increased production of secondary metabolites, such as antibiotics and other biologically active substances, has been shown [31; 32]. \(\gamma\)-butyloxtonotes, which are effector molecules, are also involved in the regulation of secondary metabolism and morphological differentiation [98]. In addition to the global regulatory mechanisms, there is biosynthetic cluster-specific regulation. Specific regulatory proteins can activate the transcription of the genes of the associated gene clusters [99; 45]. Enzymes involved in antibiotic synthesis, such as phosphatases, become active when the organism's growth is in stagnation due to nutrient deficiency. Interestingly, Antibiotic production usually co-occurs with the growth of a producer strain, which has been observed for epidermis, nisin and gallidermin, but not for mersacidin, which is produced only after active growth [100; 101].