## 3 Utilization of Precursor Compounds from Primary Metabolism in Secondary Metabolism
### Supply of Key Precursors Carbon, Nitrogen, Phosphate and Sulfur for Secondary Metabolism
#### 3.2.3 Supply of Phosphate for Secondary Metabolism  
Phosphate (inorganic phosphate PO43-) plays essential roles in cells, such as maintaining the structure of DNA and RNA, cell membrane composition, ATP formation, etc. [23; 54]. It is necessary for the synthesis of the main macromolecules of the cell, such as nucleic acids and phospholipids. Phosphate plays signaling roles via phospho-transfer reactions. Furthermore, it is a constituent of high-energy molecules, such as ATP, GTP and polyphosphate, which are essential for most metabolic processes [54; 110]. Phosphate is necessary for the initial primary phase of growth, and its depletion may become a limiting component for growth, transition into the stationary phase and the start of antibiotic production. The initial concentrations of phosphate are also critical: in the initial medium, an excess of phosphate drives a higher biomass production and a larger mycelium formation. At the same time, the stationary phase is delayed and the production of a large number of antibiotics is inhibited [100; 101; 102; 103; 104; 105; 106; 107; 108; 109; 110; 111]. For example, a 4.6 mM phosphate concentration was shown to support of the growth of _S. coelicolor_ A3(2) M145 and to boost antibiotic production. In combination with glucose, this provides sufficient energy and reducing power to maintain a high growth rate [111]. Phosphate is found as a linear polymer of variable length, from ten to hundreds of phosphate molecules linked by high-energy phosphoanhydride bonds, which are essential for bacterial survival and adaptation to stress. Bacteria have evolved mechanisms to sequester and store phosphate. The cellular adaptations to phosphate availability are controlled by the two-component system PhoR-PhoP. The genes controlled by this system include genes involved in nitrogen intake, oxidative phosphorylation, nucleotide biosynthesis, glycogen catabolism, antibiotic biosynthesis and morphological differentiation. PhoP is a master regulator since it activates phosphate scavenging, transport, storage and mobilization [26].  
Phosphate and phosphate-containing compounds are important precursors of secondary metabolites, providing building blocks for compounds containing phosphate, e.g., fosfomycin isolated from _Streptomyces fradiae_ (ATCC 21096) [112] and phosphinothricin tripeptide (PTT) from _Streptomyces viridochromogenes_[113]. The essential precursor for the fosfomycin biosynthesis is the phosphate-containing compound phosphonate, and for the PTT biosynthesis, it is phosphoenolpyruvate (PEP). Phosphonate/phosphate transport systems are common in _Streptomyces_ species and are encoded by _plnCDE_ genes. Phosphonates utilization also requires the _plnCDE_ genes, which include those that code for the subunits of C-P lyase [48]. Phosphate precursor supplementation coupled with medium optimization has been demonstrated to be a wise strategy for improving the yield of antibiotics, e.g., the cyclic lipopeptide antibiotic daptomycin produced by _Streptomyces roseosporus_[114].