Competition between abiogenic and biogenic metal cations in biological systems: Mechanisms of gallium‘s anticancer and antibacterial effect

• Published in: Journal of inorganic biochemistry Vol. 214; p. 111309
• Main Authors: Kircheva, Nikoleta, Dudev, Todor
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 01-01-2021
• Subjects: Antibacterial therapy; Anticancer therapy; DFT calculations; Gallium; Ribonucleotide reductase; Siderophores; Siderophores; Gallium; Ribonucleotide reductase; Anticancer therapy; Antibacterial therapy; DFT calculations
• ISSN: 0162-0134; 1873-3344
• DOI: 10.1016/j.jinorgbio.2020.111309

Metal cations are key players in a plethora of essential biological processes. Over the course of evolution specific biological functions have been bestowed upon two dozen of (biogenic) metal species, some of the most frequently found being sodium, potassium, magnesium, calcium, zinc, manganese, iron, and copper. On the other hand, there is a group of less studied abiogenic metals like lithium, strontium and gallium that possess not known functions in living organisms, but, by mimicking the native ions and/or competing with them for binding to key metalloenzymes, may exert beneficial effect on humans in particular medical conditions. This review summarizes and critically examines the mechanisms of gallium's therapeutic action in anticancer and antibacterial therapies by exploiting the tools of molecular modeling and experimental biochemistry. These approaches allow for identifying key factors for Ga3+ beneficial effect such as the electrostatic interactions with the protein ligands, substrates or bacterial siderophores, intramolecular hydrogen bond formation, and pH and dielectric properties of the medium. Several intriguing questions concerning the gallium competition with the native ferric ion have found their answers.
The mechanisms of gallium's therapeutic action in anticancer and antibacterial therapies have been examined by employing the tools of molecular modeling and experimental biochemistry. [Display omitted]
•Light is shed on gallium's therapeutic effects.•Ga3+ can displace Fe3+ from ribonucleotide reductase (RR), thus silencing the enzyme.•Ga3+ can form complexes with the substrates of RR leading to enzyme starvation.•By disrupting the cellular iron uptake Ga3+ leads to RR inhibition.•Ga3+ is a potent competitor of Fe3+ for bacterial siderophores.