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

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• 作者：Valia Nikolova ; Silvia Angelova ; Nikoleta Markova ; Todor Dudev
• 刊名：Journal of Physical Chemistry B
• 出版年：2016
• 出版时间：March 10, 2016
• 年：2016
• 卷：120
• 期：9
• 页码：2241-2248
• 全文大小：482K
• ISSN：1520-5207

文摘

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.