In a recent copy of Nature Chemical Biology Davis and Halloran discuss cellular copper ion chemistry. Transition metals such as zinc, copper and iron are necessary to reach intracellular concentration of tens to hundreds of micromolar. Few if any of these ions are thought to be ‘free’ or readily accessible in terms of their thermodynamic availability or reaction chemistry. The mechanisms by which cells control the metal occupancy of a given metal-binding site—that is, how metalloenzymes acquire the correct metal ion at the right time in cellular growth—are emerging through physiochemical characterization of a range of conserved metal trafficking pathways.
The regulation of metal ion availability requires the concerted activity of numerous metal receptors, including metal transporters, metallochaperones and metalloregulatory factors.
Mechanistic and structural insights into the chemistry of cellular copper-trafficking machinery have predominately focused on cysteine (that is, thiol)-rich CuCI) sites which are associated with inherited diseases of copper metabolism.
In a series of recent studies characterizing methionine-rich domains of copper trafficking proteins, some unexpected copper-thioether chemistry is emerging. As was the case for cysteine thiolate-rich sites, the CuCI) coordination chemistry of such proteins is quite distinct from that seen in copper enzymes.
Two fundamental differences are emerging between the two classes: they each function in chemically distinct subcellular compartments, and they use quite different electrostatic contributions to achieve Cu(I) binding selectivity and transfer.
Most of the cysteine-rich copper sites characterized to date are found in reducing intracellular compartments, whereas an abundance of methionine-rich copper sites are found in the oxidizing compartments and the extracellular milieu.
One important feature of the methionine-rich sites and motifs is their selectivity against the two most abundant intracellular transition metal ions: zinc and iron. Notably, the +2 ions of these metals are not favoured for binding in the methionine-rich sites, but hundreds of examples of zinc and iron ions bound to CXXC motifs in higher-coordinate or metal-cluster sites can be found in the metalloprotein literature (for example, in zinc finger proteins and iron-sulfur proteins).
As our understanding of the methionine-rich chemistry expands to include extracytosolic proteins, a broad picture is emerging of biological cuprous coordination and ligand-exchange chemistry. Different coordination motifs seem to be tailored to different pathways and cellular environments in order to preserve copper-specific recognition within a robust metal-binding site. A corollary to this idea, however, is the consideration that metal-trafficking sites may also be responsive to changing cellular environments, as oxidative bursts may release copper or zinc ions from cysteine-rich (or methionine-rich) metal-binding sites as the ligating groups are oxidized and the metal-binding sites are disrupted. The interplay between the intimate coordination chemistry of each family of sites and the changing metabolic needs of the cell may well prove to be a key to unlocking the roles of metal ions in intracellular signaling processes.
Davis and Halloran 2008 A place for thioether chemistry in cellular copper ion recognition and trafficking Nature Chemical Biology vol 4 148-151.

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