Abstract
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.
Published Version
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
