title: Gallium as a Therapeutic Agent: A Thermodynamic Evaluation of the Competition between Ga(3+) and Fe(3+) Ions in Metalloproteins.
abstract: 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 Ga(3+) cation to mimic closely in appearance the native ferric ion, Fe(3+), thus interfering with the biological processes requiring ferric cofactors. However, Ga(3+) ion cannot participate in redox reactions and, when substituting for the "native" Fe(3+) ion in the enzyme active site, renders it inactive. Although a significant body of information on the Ga(3+)-Fe(3+) 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 Fe(3+)-binding sites in the key enzyme ribonucleotide reductase vulnerable to Ga(3+) substitution? Here, we address these questions by studying the competition between Ga(3+) and Fe(3+) 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 Ga(3+)/Fe(3+) selectivity in various model metal binding sites and biological systems such as serum transferrin and ribonucleotide reductase.
authors.affiliation: Faculty of Chemistry and Pharmacy, Sofia University "St. Kl. Ohridski" , 1164 Sofia, Bulgaria.
authors.forename: Valia
authors.initials: V
authors.lastname: Nikolova
authors.affiliation: Institute of Organic Chemistry with Centre of Phytochemistry, Bulgarian Academy of Sciences , 1113 Sofia, Bulgaria.
authors.forename: Silvia
authors.initials: S
authors.lastname: Angelova
authors.affiliation: Faculty of Chemistry and Pharmacy, Sofia University "St. Kl. Ohridski" , 1164 Sofia, Bulgaria.
authors.forename: Nikoleta
authors.initials: N
authors.lastname: Markova
authors.affiliation: Faculty of Chemistry and Pharmacy, Sofia University "St. Kl. Ohridski" , 1164 Sofia, Bulgaria.
authors.forename: Todor
authors.initials: T
authors.lastname: Dudev
mesh_terms: D005290:Ferric Compounds / Q000737:chemistry*; D005708:Gallium / Q000737:chemistry* / Q000627:therapeutic use; D007093:Imidazoles / Q000737:chemistry; D008024:Ligands; D008667:Metalloproteins / Q000737:chemistry*; D010636:Phenols / Q000737:chemistry; D012264:Ribonucleotide Reductases / Q000737:chemistry; D013816:Thermodynamics
chemical_list: D005290:Ferric Compounds; D007093:Imidazoles; D008024:Ligands; D008667:Metalloproteins; D010636:Phenols; D005708:Gallium; D012264:Ribonucleotide Reductases