The urgency of finding novel antibacterial drugs (not only antibiotics), exhibiting different mechanisms of therapeutic action, is significant and has served as a premise for recognizing bacteria's siderophores as a plausible drug target. Bacteria secrete siderophores in order to sequester iron(III) from the surrounding medium by binding the essential metal with high affinity. Gallium, on the other hand, is an "abiogenic" ion, known for its anticancer, antibacterial, and anti-inflammatory action. The rationale behind its therapeutic effect lies in its close mimicry of the ferric ion. Since both ions share various physicochemical characteristics, it is of particular interest to understand if gallium could compete with the native ferric ion for binding siderophores and to decipher which molecular characteristics favor Ga 3+ binding over Fe 3+ binding. It is also well-known that some bacteria are susceptible to gallium-based therapy, while others are not. Therefore, many questions arise such as the following: (1) Which main group/groups building the siderophores promote gallium's attack? (2) Does the combination of the building blocks affect the preference toward a metal? (3) Does the environment play a crucial role? (4) Could the pH of the medium influence the balance between the ions? We try to address these questions by evaluating the free energy of the competition between Ga 3+ and Fe 3+ ions for siderophore ligands of various structures, denticities, and charge states by employing the tools of the computational chemistry at the DFT/SMD level. Our results not only fall in line with recent experimental data but also complement our knowledge about "Trojan horse" gallium-based therapy.
The broadly accepted mechanism of gallium's therapeutic action postulates the inactivation of the upregulated/hyperactive enzyme ribonucleotide reductase (RNR) in cancer cells by substituting the redox-active iron by redoxsilent gallium in the enzyme active site. Recently, another hypothesis for the Ga 3+ curative effect has been put forward: the metal cation can deactivate the enzyme by entrapping its substrates (nucleotide diphosphates; NDPs) into Ga 3+ −NDP complexes, lowering the free substrate levels in the cell. Several questions arise: Does gallium readily form complexes with NDPs? What are the preferable modes of metal binding to NDPs? Does, and if so, to what extent, the metal binding alter the native conformation of the substrate, thus influencing the process of substrate−enzyme recognition? Here, by employing density functional theory (DFT)/polarizable continuum model (PCM) calculations, we attempt to answer these questions. The results, which are in line with the available experimental data, lay support to the recent hypothesis about the curative effect of gallium, revealing that, by engaging the free NDPs in forming metal complexes, on the one side, and producing metal constructs that are not/poorly recognizable by the host enzyme, on the other side, gallium deprives RNR from its substrates, thus reducing the enzyme activity in malignant cells.
Metal cations are required for the proper function of a great amount of biological processes, as they are indispensable cofactors participating in up to 40% of the active sites of the proteins. In the case of some diseases, however, metal cations could exhibit a dual function. As an example, the role of the zinc cation in the development of Retinitis pigmentosa could be given. Experimental works indicate the loss of thermostability of the rhodopsin protein, subjected to the combination oftypical for the diseasemutations and increased quantity of Zn 2+ . Two structural networks in the intradiscal domain surrounding His100 and His195 are supposed to be susceptible to pathophysiological changes in trace metal concentrations. From a thermodynamic point of view, it is of particular interest to decipher the foundations of the observed outcome, as well as to closely characterize the intimate interactions between the "native" cation and the building amino acid residues of the studied centers. Therefore, the powerful, but fundamentally limited, tools of computational chemistry were applied on simplified models of rhodopsin metal centers in order to shed light on the following aspects: (1) what is the preferred geometry of the Zn 2+ -containing complexes with the amino acid ligands from the binding pockets; (2) what is the role of the mutations for the interactions between Zn 2+ and the examined centers; (3) could other divalent cations such as Ca 2+ and Cu 2+ substitute for the native zinc; (4) how does the dielectric constant of the environment affect the processes? The obtained results illuminate some aspects of the zinc coordination to amino acid residues and zinc biochemistry related to the presumed pathogenesis of Retinitis pigmentosa.
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