## 1 Actinobacteria and Their Primary Metabolism as Basis for Secondary Metabolism Precursor Supply
### Primary Metabolism in Actinobacteria: Sulfur Metabolism  
Sulfur is a common compound in the environment (up to 0.1% of the earth's crust). However, much of this material is inaccessible to living organisms. Sulfur is an essential element for bacterial metabolism and accounts for approx. 1% of the cell dry weight. It plays a central role in metabolic processes [58]. All bacteria require sulfur for growth. It is used in the biosynthesis of amino acids (e.g., cysteine and methionine), which are incorporated into other biomolecules [59]. Sulfur also plays an essential role in a variety of enzyme cofactors,such as coenzyme A, coenzyme M, biotin, thiamine and lipoic acid. Furthermore, sulfur is critical in redox processes as a building block for iron-sulfur centers and as the redox-active component of disulfide bonds. Furthermore, sulfane sulfur, including polysulfide and persulfide, was demonstrated to be a cellular component present in microorganisms, with reported impacts on the production of actinorhodin and spore formation in _S. coelicolor_ M145 [60]. For biosynthetic processes, sulfur is generally derived from the assimilation of inorganic sulfate in bacteria and plants, but not in animals. In bacteria, sulfur amino acid (SAA) metabolism is highly adaptive and diversified [61; 62]. In _Streptomyces_ spp., the biosynthesis of cysteine (Cys) and methionine (Met) via homocysteine (Hcy) are linked through bidirectional transsulturation pathways. Each transsulturation direction involves two sequential reactions that are catalyzed by different enzymes that often have relaxed specificities. Cysteine is the key intermediate in most pathways of sulfur metabolism. After the inorganic sulfate is transported into the cell, it is incorporated into the sulfate assimilation pathway. Sulfur is converted to 3\({}^{\prime}\)-phosphoadenosine-5\({}^{\prime}\)-phosphulfate (PAPS), and then reduced to sulfite and subsequently to sulfide. Afterwards, sulfide is transferred onto an organic moiety to yield molecules of cysteine [59; 61; 62]. The inter-conversion between homocysteine (Hcy) and methionine takes place in the activated methyl cycle (AMC), which involves ATP and additional cofactors such as cobalamin and 5-methyl-tetrahydrofolate. The function as well as metabolic branching of the AMC have been demonstrated to influence the production of bacterial metabolites (e.g., quorum-sensing molecules) that can have an impact on the bacterial physiology and the surrounding microbial community [62]. Metabolism of the sulfur-containing amino acids methionine and cysteine requires the transfer of methyl groups. Afterwards, these amino acids are converted to compounds that enter central metabolic pathways, with the following oxidation of the sulfur atom and formation of excretory forms of sulfur, as well as with the synthesis of other essential compounds. The transfer of sulfur from methionine to serine by transsulturation to synthesize cysteine is critical for methionine catabolism and sulfur excretion. Most _Streptomyces_ spp. and other actinobacteria do not have a MetA enzyme, which acylates the hydroxyl of homoserine with succinyl-CoA. Instead, a direct sulfhydrylation pathway involving _metX_ and _metY_ has been found in actinomycetes. _S. coelicolor_ apparently lacks _metA_ and _metXY_. Most actinobacterial genomes also do not have a canonical _metC_ that encodes for a cystathionine-\(\beta\)-lyase; instead, they have a _malY_ gene [58; 59; 60; 61; 62]. The knowledge of sulfur metabolism in antibiotic-producing streptomycetes is generally fragmentary. The assimilation of sulfate into methionine has only been described in the model streptomycete _S. coelicolor_. The sulfate assimilation cluster in _S. coelicolor_ was shown to be structurally and functionally similar to that of _Corynebacterium_. The genes _sco6093-sco6102_ were demonstrated to be involved in sulfate assimilation, with _sco6102_ encoding for sulfite reductase and the _sco6094-sco6096_ genes being involved in sulfate import.