Proton Transfer and SN 2 Reactions as Steps of Fast Selenol and Thiol Oxidation in Proteins: A Model Molecular Study Based on GPx.

ChemPlusChem
M Dalla TiezzaL Orian

Abstract

The so-called peroxidatic cysteines and selenocysteines in proteins reduce hydroperoxides through a dual attack to the peroxide bond in a two-step mechanism. First, a proton dislocation from the thiol/selenol to a close residue of the enzymatic pocket occurs. Then, a nucleophilic attack of the anionic cysteine/selenocysteine to one O atom takes place, while the proton is shuttled back to the second O atom, promoting the formation of a water molecule. In this computational study, we use a molecular model of GPx to demonstrate that the enzymatic environment significantly lowers the barrier of the latter SN 2 step. Particularly, in our Se-based model the energy barriers for the two steps are 29.82 and 2.83 kcal mol-1 , both higher than the corresponding barriers computed in the enzymatic cluster, i. e., 21.60 and null, respectively. Our results, obtained at SMD-B3LYP-D3(BJ)/6-311+G(d,p), cc-pVTZ//B3LYP-D3(BJ)/6-311G(d,p), cc-pVTZ level of theory, show that the mechanistic details can be well reproduced using an oversimplified model, but the energetics is definitively more favorable in the GPx active site. In addition, we pinpoint the role of the chalcogen in the peroxide reduction process, rooting the advantages of the presence of...Continue Reading

References

Jun 1, 1972·Hoppe-Seyler's Zeitschrift für physiologische Chemie·L FlohéE Eichele
Sep 15, 1988·Physical Review A: General Physics·A D Becke
Apr 21, 2009·Biochimica Et Biophysica Acta·Stefano ToppoMatilde Maiorino
May 22, 2010·Organic & Biomolecular Chemistry·Willem-Jan van Zeist, F Matthias Bickelhaupt
Mar 4, 2011·Journal of Computational Chemistry·Stefan GrimmeLars Goerigk
Jul 15, 2015·Free Radical Biology & Medicine·Laura OrianFulvio Ursini
Mar 8, 2016·ACS Chemical Biology·Hans J Reich, Robert J Hondal
Apr 20, 2016·Journal of Computational Chemistry·Francesco ZaccariaLaura Orian
Dec 10, 2016·Chemistry : a European Journal·Giovanni RibaudoLaura Orian
Apr 28, 2017·Angewandte Chemie·F Matthias Bickelhaupt, Kendall N Houk
Aug 25, 2017·Chemphyschem : a European Journal of Chemical Physics and Physical Chemistry·Marco BortoliLaura Orian
Aug 2, 2018·Physical Chemistry Chemical Physics : PCCP·Marco BortoliLaura Orian
Jan 12, 2020·Nature Protocols·Pascal VermeerenTrevor A Hamlin

❮ Previous
Next ❯

Citations


❮ Previous
Next ❯

Related Concepts

Related Feeds

Basal Ganglia

Basal Ganglia are a group of subcortical nuclei in the brain associated with control of voluntary motor movements, procedural and habit learning, emotion, and cognition. Here is the latest research.