期刊
JOURNAL OF PHYSICAL CHEMISTRY B
卷 123, 期 26, 页码 5444-5451出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jpcb.9b03145
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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 redox-silent gallium in the enzyme active site. Recently, another hypothesis for the Ga3+ curative effect has been put forward: the metal cation can deactivate the enzyme by entrapping its substrates (nucleotide diphosphates; NDPs) into Ga3+-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.
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