## 2 Specialized Metabolic Pathways for Supply of Alternative Precursors for Secondary Metabolism
### Alternative Metabolism in Actinobacteria--Polyamine Metabolism  
In nature, polyamine metabolism can provide nitrogen and carbon in environments with unfavorable conditions. Moreover, recently, polyamines were reported to directly impact secondary metabolism in _Streptomyces_[8]. The metabolism of polyamines is shaped by evolutionary processes, such as gene duplication, loss, fusion and horizontal gene transfer [64]. Polyamines are aliphatic polycations with polycarbon chains and multiple amino groups. Natural polyamines that are widely distributed in bacteria are putrescine, cadaverine, spermidine and spermine [65]. Polyamines have been demonstrated to play important roles in bacterial cells, influencing cellular growth, developmental processes and environmental stress responses. Polyamines are predominantly derived from the amino acids ornithine and methionine, but can be also synthesized from arginine and lysine as secondary sources [65]. In _S. coelicolor_, low concentrations of putrescine, cadaverine, spermidine and spermine (ca. 0.05-0.1 mmol/g) were detected after incubation in a complex medium. Furthermore, putrescine, spermidine and diaminobenz biosynthesis can occur in _S. coelicolor_ in the late stationary phase, while cadaverine is synthesized under iron limitation conditions [66]. Polyamines are present in soil, where they are released after the decomposition of organic matter. The average polyamine concentrations per gram of humus were determined in an analysis of soils and different sources of humic acids. Putrescine ranged between 0.28 and 0.56 nmol/g, spermidine was between 0.23 and 0.62 nmol/g, and spermine was between 0.16 and 0.43 nmol/g [67]. Polyamines can be acquired from the extracellular environment and assimilated as a nitrogen and carbon source. In the Actinobacteria _S. coelicolor_, this occurs via the gamma-glutamyl pathway [8]. The initial step of polyamine utilization is catalyzed by GlnA2 and/or GlnA3 enzymes that are able to glutamylate the polyamines putrescine, cadaverine, spermidine and spermine [38]. Sequence alignments and transcriptional analysis indicated that glutamylated products can be further metabolized to aminovalerate and GABA, a process involving a gamma-glutamylpolyamine oxidoreductase, dehydrogenases and hydrolases. Subsequently, a GABA aminotransferase catalyzes the production of glutarate semialdehyde or succinate semialdehyde (Figure 4). Succinic semialdehyde dehydrogenase converts these to succinate or glutamate that feeds the tricarboxylic acid (TCA) cycle [38]. Alternatively, in _S. coelicolor_, polyamines may be utilized via the aminotransferase pathway involving an amidotransferaseerase. Elevated polyamine concentrations can lead to bacterial cell death; for instance, 200 mM of exogenous putrescine was shown to be toxic to _S. coelicolor_[38]. Elevated polyamine levels occur in soil on sites with high amounts of decomposed organic matter. Thus, in the first step of the polyamine utilization pathway, polyamines are detoxified by glutamylation [38]. Besides their role as precursors, polyamines can influence secondary metabolism in a different way. In _S. coelicolor_ grown in defined media with added exogenous polyamines as the sole nitrogen source, putrescine, cadaverine, spermidine and spermine caused delayed aerial mycelium development and spore formation. Furthermore, polyamines induced the production of prodigiosin and abolished the production of actinorhorodin in _S. coelicolor_ M145 [38]. Deletion of the essential gene for polyamine utilization, _glnA3 (sco6962)_, caused defects in aerial mycelium formation as well as sporulation in medium with glutamate as the nitrogen source. In media with nitrate, glutamine and ammonium as the nitrogen sources, increased actinorhodin and prodigiosin production was observed in the _S. coelicolor AgInA3_ mutant [38; 68]. In _S. tsukubaensis,_ the presence of polyamines in the tacrolimus (FK-506) production medium resulted in inhibited biomass accumulation and FK-506 production. Poor growth of _S.