A Nuclear Spin Selective Control over the DNA Repair Key Enzyme Might Renovate the Cancer–Fight Paradigm. DNA Polymerase Beta to Engage with a Magnetic Isotope Effect

Authors

  • Oleg A. Shatalov Russian Federal Research and Clinical Center for Pediatric Hematology, Oncology and Immunology, Moscow 117997
  • Maxim E. Grigoryev N. I. Pirogov Russian National Research Medical University, Moscow 117997
  • Alexander A. Bukhvostov I. M. Sechenov Moscow State Medical University, Moscow 124327
  • Dmitry A. Kuznetsov N. I. Pirogov Russian National Research Medical University, Moscow 117997, Russia N. N. Semenov Institute for Chemical Physics of the Russian Academy of Sciences, Moscow 117997, Russia

DOI:

https://doi.org/10.24297/jac.v4i3.953

Keywords:

magnetic isotope effect, nuclear spin selectivity, DNArepair, 40Ca and 43Ca isotopes, ion-radical path in the metal – dependent enzymatic catalysis

Abstract

DNA Polymerase Beta (EC 2.7.7.7) is found to be operated by magnetic isotope effect (MIE) of Calcium once the Mg2+ ions replaced with the stable 43Ca2+ isotopes inside the enzyme catalytic sites. The isotope mentioned is the only paramagnetic species of the Calcium isotopic set with a 0.135 natural abundance value and the negative 7/2 nuclear spin providing a nuclear magnetic moment equal to 1.317 Bohr magnetons. As compared to the Mg/40Ca substitution, a 2.25-fold enzyme inhibition has been shown to provethe43Ca-MIE dependent mode of the catalysis turning down.An ion-radical mechanism based on the singlet – triplet conversion of the enzyme generated intermediates (ion-radical pairs) is found to be engaged once the paramagnetic metal isotope involved into the catalysis studied.The MIE promotes a primary reaction in DNA synthesis constituting in electron transfer between the ion – radical forming partners, [Ca(H2O)n2+] and [Ca2+(dNTP)]. Once the metal isotope substitution takes place inside just one of two DNA Polymerase Beta catalytic sites, a consequent43Ca – promoted inhibition leads to a residual synthesis of shorted DNA fragments that counts 25 – 35 nucleotides in length contrasting with the 180n – 210n DNA produced by either intact or40Ca – loaded polymerase. Being occurred simultaneously with a marked MIE – promoted enzyme inhibition, this fact itself makes possible to consider these short (“size-invalidâ€) DNA segments hardly efficient in the DNA base – excision repair. The latter is a survival factor in leukemic cells where the DNApolβ was found overexpressed. That supports a standpoint considering theDNApolβ a legitimate target for antitumor agents since its inhibition deprives the malignant cell from a DNA base – excision repair in neoplasma. A possible trend making role of these data in the current developments on a novel concept - establishing chemical background for cancer therapies is in a focus.

Downloads

Download data is not yet available.

Published

2008-12-12

How to Cite

Shatalov, O. A., Grigoryev, M. E., Bukhvostov, A. A., & Kuznetsov, D. A. (2008). A Nuclear Spin Selective Control over the DNA Repair Key Enzyme Might Renovate the Cancer–Fight Paradigm. DNA Polymerase Beta to Engage with a Magnetic Isotope Effect. JOURNAL OF ADVANCES IN CHEMISTRY, 4(3), 554-562. https://doi.org/10.24297/jac.v4i3.953

Issue

Section

Articles