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Regulacja aktywności katalitycznej rybozymów HDV oraz deoksyrybozymów za pomocą antybiotyków i jonów metali

Wrzesinski J., Ciesiołka J.

Wiadomości Chemiczne

2018

[Z] 72, 7-8

397--415

This review article describes the results of a 15-year cooperation between the Department of RNA Biochemistry at the Institute of Bioorganic Chemistry, Polish Academy of Sciences in Poznań and the Medical Chemistry Team of the Faculty of Chemistry at the University of Wrocław, headed by Professor Małgorzata Jeżowska- -Bojczuk. A wide spectrum of antibiotics and other low molecular compounds and their complexes with Cu2+ ions have been tested as potential inhibitors of the HDV ribozyme catalytic reaction. Unexpectedly, it has been found that a number of compounds, depending on the conditions, exhibit inhibitory or stimulatory properties, i.e. they act as modulators of the RNA catalysis process. It was found that the effect of stimulation / inhibition of the catalytic activity of the HDV ribozyme is closely related to the degree of protonation of the antibiotics under study in given conditions. Their ability to inhibit catalysis also increases after binding the Cu2+ cation. In an environment with a higher pH, antibiotics usually stimulate the cleavage reaction, as at least some of their nitrogen centers are allowed to participate in the catalysis reaction, as proton acceptors / donors or a catalytic metal ion coordination site. During the study of one of the antibiotics, bacitracin, it was also observed that it exhibits nucleolytic properties with RNA and DNA molecules. The discovery of the hydrolytic properties of bacitracin extended the potential use of this antibiotic in antiviral therapy with the aim to destroy undesired nucleic acids in the cell. To search for DNAzymes catalyzing RNA hydrolysis, the in vitro selection method was used. In the selection experiment aimed at obtaining DNAzymes active in the presence of Cd2+ ions, variants belonging to the family of DNAzymes 8–17 previously described in the literature were obtained. Analysis of their properties showed that not only Cd2+ but also Zn2+ and Mn2+ ions support catalysis, therefore the site of catalytic metal ion coordination is not highly specific. The DNAzymes obtained in the second selection experiment showed an optimum of catalytic activity in the pH range of 4.0–4.5 and were inactive at a pH higher than 5.0. Interestingly, they do not require the presence of any divalent metal ions as cofactors in the catalysis reaction. The obtained results broaden the repertoire of DNAzymes which operate under non-physiological conditions and bring new information on the possible mechanisms of reactions catalyzed by nucleic acids.