Stability constants of bio-relevant, redox-active metals with amino acids: The challenges of weakly binding ligands

Metal ion interactions with weakly coordinating ligands, such as amino acids, are dependent on several factors, including metal ion availability, metal ion propensity for hydrolysis, ligand availability, and thermodynamic stability, as measured by stability constants. Metal ions in biological systems are often controlled by highly specific chaperone, transport, and storage proteins. Disruption in the homeostasis of redox active metal ions, such as Cu(I), Cu(II), Fe(II), and Fe(III), has been linked to increased oxidative damage and disease. Weakly binding ligands such as amino acids may play an active role in mitigating this metal-mediated damage, but a comprehensive understanding of the availability and thermodynamic likelihood of coordination must be understood to accurately predict complex formation in a competitive environment. This review presents an overview of amino acid stability constants with Cu(I), Cu(II), Fe(II), and Fe(III), the most common redox-active metal ions in biological systems. Specific attention is given to sulfur- and selenium-containing amino acids, since their interactions with Cu(I) and Fe(II) is of particular biological interest. This review also describes methods available for stability constant determination, with particular attention to specific difficulties encountered when working with weakly binding ligands and each of these four metal ions. Finally, the potential biological implications of these results are discussed based on reported stability constants as well as amino acid, copper, and iron bioavailability.