Gallium as a Therapeutic Agent: A Thermodynamic Evaluation of the Competition between Ga3+ and Fe3+ Ions in Metalloproteins

Gallium has been employed (in the form of soluble salts) to fight various forms of cancer, infectious, and inflammatory diseases. The rationale behind this lies in the ability of Ga3+ cation to mimic closely in appearance the native ferric ion, Fe3+, thus interfering with the biological processes requiring ferric cofactors. However, Ga3+ ion cannot participate in redox reactions and, when-substituting for the native Fe3+ ion in the enzyme active site, renders it inactive. Although a significant body of information on the Ga3+-Fe3+ competition in biological systems has been accumulated, the intimate mechanism of the process is still not well understood and several questions remain: What are the basic physical principles governing the competition between the two trivalent cations in proteins? What type of metal centers are the most likely targets for gallium therapy? To what extent are the Fe3+-binding sites in the key enzyme ribonucleotide reductase vulnerable to Ga3+ substitution? Here, we address these questions by studying the competition between Ga3+ and Fe3+ ions in model metal binding sites of various compositions and charge states. The results obtained are in line with available experimental data and shed light on the intimate mechanism of the Ga3+/Fe3+ selectivity in various model-metal binding sites and biological systems such as serum transferrin and ribonucleotide reductase.