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Mechanisms of metal ion incorporation into metalloproteins.

Although the structure and function of protein metallocenters have been extensively characterized, much less is known about their assembly. Here, I describe several general strategies for metallocenter biosynthesis and provide literature precedents for each mechanism. The simplest mechanism involves reversible metal ion binding to amino acid ligands of the apo-protein. In a variation of this mechanism, the apo-protein first must be phosphorylated, carboxylated or otherwise covalently modified in order to create the metal ion binding site. Alternatively, passive metal ion binding may require the presence of an associated compound, such as a nucleotide, carbonate or inorganic sulfide, which is co-incorporated into the protein along with the metal ion. In addition, reversible binding may occur using a pre-formed organometallic cofactor such as a metal-tetrapyrrole. Electron transfer reactions are coupled to biosynthesis of certain metallocenters, i.e. oxidation or reduction of the metallocenter or apo-protein may be required prior to binding, or once bound the metallocenter may be oxidatively trapped in the protein. An effector molecule may bind to apo-protein to open up or stabilize the metallocenter binding site, then after the metallocenter is incorporated the effector molecule dissociates. A transferase or insertase protein first may bind the metallocenter and then incorporate it into the appropriate apo-protein. Finally, metal cofactors may be covalently attached to proteins. Regardless of the metallocenter biosynthetic mechanism, intracellular metal ion concentrations must be sufficient; hence, metal ion transport systems also are briefly discussed.