## 5 Cellular Metal Metabolism as a Part of Metabolic Pathways and Signal Transduction Networks  
The next important aspect is that the metal homeostatic systems do not work in isolation. They are part of the intracellular metabolic pathways and signaling networks and thus are intrinsic to processes that often do not seem to have any connection to a metal ion at first glance. Each metal ion has to be made available or withdrawn specifically in biological time and space depending on the developmental stage, metabolic state and cell fate. Thus any signal that changes the functional state of a cell is potentially linked to signals for re-distribution of metal ions. Distribution, re-distribution and controlling availability of metal ions for their functions in cytoplasmic or organellar proteins includes specific chemical and biochemical principles. In the case of iron, redox chemistry is critically important and determines whether iron is mobile in the form of the ferrous ion (Fe\({}^{2+}\)) or immobilized in the form of the ferric ion (Fe\({}^{3+}\)). One pathway of iron uptake is receptor-mediated endocytosis of iron [26]. The transferrin receptor binds transferrin with its bound ferric ions. The complex is taken up by cells into endosomes, where the ferric ions are reduced to ferrous ions, which are then released from transferrin and translocated to the cytosol, followed by recycling of the transferrin receptor and transferrin. Ferrous ions can also be released from ferritin, which may receive Fe\({}^{2+}\) from a metallochaperone, oxidizes Fe\({}^{2+}\) to Fe\({}^{3+}\) at a ferrooxidase site and stores iron in a core of iron oxide containing up to 4500 ferric ions surrounded by the protein shell [27; 28]. Zinc, sodium, potassium, magnesium and calcium ions, in contrast to iron or copper ions, are redox inert in biology [29]. Zinc remains in the +2 oxidation state, i.e., Zn\({}^{2+}\). The cellular availability of zinc(II) ions is controlled by membrane transporters and by release from vesicular stores or from metallothioneineins, which are relatively small cysteine sulfur-rich proteins that contain up to seven bound zinc(II) ions and are highly dynamic in their metal binding and regulation [30]. In the process of zinc dissociation from metallothioneinein, redox reactions do have a role. In coordination environments with cysteine sulfur ligands, the ligands are redox active and oxidation of the sulfur donor can mobilize zinc(II) ions from sites where they bind with high affinity [31]. The mobilization of metal ions from proteins or subcellular organelles draws attention to the pool of metal ions that are not bound to proteins, referred to as the labile iron pool in the case of iron or the free or mobile zinc pool in the case of zinc. Only indirectly and by inference do we have knowledge about the biological molecules or metabolites binding these metal ions as ligands in these pools as their very nature of exchanging ligands makes the chemical characterization with a speciation analysis very challenging. In _E. coli_, sulfur-containing amino acids along with mono- and dinucleotides have been identified as candidate ligands [32]. Glutathione has been suggested to be a ligand for Fe\({}^{2+}\) while multiple ligands have been discussed for Zn\({}^{2+}\)[33; 34]. The terms \"free\", \"labile\" and \"mobile\" are all problematic as they are operational definitions and there is no chemical characterization in vivo. \"Free\" indicates that the zinc ions are not protein bound, but they are certainly not free in the sense that they do not have any ligands. The terms \"labile\" and \"mobile\" are employed to indicate that these metal complexes exchange their ligands. The chemical characteristics differ for each metal ion. An understanding of the differences in coordination chemistry and properties of the metal ions is needed along with how metal ions in complexes with low-molecular-weight ligands are handled with uniquely biological features that ascertain the performance of their functions.