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The kinetic analysis of recognition of the damaged nucleotides by mutant forms of the 8-oxoguanine DNA glycosylase hOGG1

Abstract

We have investigated the role of Tyr-203, His-270, and Lys-249 amino acid residues from the 8-oxoguanine glycosylase (hOGG1) active site in the process of recognition of 7,8-dihydro-8-oxoguanine (oxoG) damaged nucleotide and in the catalytic stages of enzymatic reaction. The pre-steady state kinetic analysis of conformational transitions of mutant forms of the enzyme and model DNA substrates during the enzymatic process revealed that the studied amino acid residues are involved in the specific binding of DNA substrates. The Tyr-203 is responsible for recognition of the damaged nucleotide; interaction between His-270 and DNA is necessary for the formation of the catalytically active complex with the oxoG-containing DNA. The Lys-249 acts not only as one of the catalytically important amino acids of the active site of the enzyme, but also plays a significant role in the formation of specific enzyme–substrate complex. The present study significantly complements the molecular-kinetic model of the enzymatic reaction and helps to clarify the origin of the high specificity of hOGG1 to oxidized bases in DNA.

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Abbreviations

hOGG1:

human 8-oxoguanine-DNA-glycosylase

BER:

base excision repair

oxoGua:

7,8-dihydro-8-oxoguanine

АР-site:

apurinic/apyrimidinic site

F-site:

(2R, 3S)-2-(hydroxy methyl)-3-hydroxytetrahydrofuran residue

ROS:

reactive oxygen species

FRET:

fluorescence resonance energy transfer

aPu:

2- aminopurine

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Correspondence to N. A. Kuznetsov or O. S. Fedorova.

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Original Russian Text © M.V. Lukina, A.A. Kuznetsova, N.A. Kuznetsov, O.S. Fedorova, 2017, published in Bioorganicheskaya Khimiya, 2017, Vol. 43, No. 1, pp. 4–17.

The paper is based on the materials of the “Chemical Biology 2016” conference; Novosibirsk, Russia, July 24–29, 2016.

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Lukina, M.V., Kuznetsova, A.A., Kuznetsov, N.A. et al. The kinetic analysis of recognition of the damaged nucleotides by mutant forms of the 8-oxoguanine DNA glycosylase hOGG1. Russ J Bioorg Chem 43, 1–12 (2017). https://doi.org/10.1134/S1068162017010058

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  • DOI: https://doi.org/10.1134/S1068162017010058

Keywords

  • human 8-oxoguanine DNA glycosylase
  • specificity
  • conformational changes
  • mechanism of recognition
  • pre-steady state kinetics