A dual attack on the peroxide bond. The common principle of peroxidatic cysteine or selenocysteine residues

M. Dalla Tiezza, F. M. Bickelhaupt, L. Flohé, M. Maiorino, F. Ursini, L. Orian*

*Corresponding author for this work

Research output: Contribution to JournalArticleAcademicpeer-review

Abstract

The (seleno)cysteine residues in some protein families react with hydroperoxides with rate constants far beyond those of fully dissociated low molecular weight thiol or selenol compounds. In case of the glutathione peroxidases, we could demonstrate that high rate constants are achieved by a proton transfer from the chalcogenol to a residue of the active site [Orian et al. Free Radic. Biol. Med. 87 (2015)]. We extended this study to three more protein families (OxyR, GAPDH and Prx). According to DFT calculations, a proton transfer from the active site chalcogenol to a residue within the active site is a prerequisite for both, creating a chalcogenolate that attacks one oxygen of the hydroperoxide substrate and combining the delocalized proton with the remaining OH or OR, respectively, to create an ideal leaving group. The “parking postions” of the delocalized proton differ between the protein families. It is the ring nitrogen of tryptophan in GPx, a histidine in GAPDH and OxyR and a threonine in Prx. The basic principle, however, is common to all four families of proteins. We, thus, conclude that the principle outlined in this investigation offers a convincing explanation for how a cysteine residue can become peroxidatic.

Original languageEnglish
Article number101540
Pages (from-to)1-9
Number of pages9
JournalRedox Biology
Volume34
Early online date14 Apr 2020
DOIs
Publication statusPublished - Jul 2020

Funding

L.O. acknowledges Università degli Studi di Padova for financial support P-DiSC (BIRD2018-UNIPD) project MAD3S (Modeling Antioxidant Drugs: Design and Development of computer-aided molecular Systems). All the calculations were carried out on Galileo (CINECA:Casalecchio di Reno, Italy) thanks to the ISCRA Grant REBEL2 (REdox state role in Bio-inspired ELementary reactions 2), P.I.: L.O.. M.D.T. is grateful to Fondazione CARIPARO for financial support (PhD grant). F.M.B. acknowledges financial support by the Netherlands Organisation for Scientific Research ( NWO ).

FundersFunder number
Casalecchio di Reno
ISCRA
Fondazione Cassa di Risparmio di Padova e Rovigo
Nederlandse Organisatie voor Wetenschappelijk Onderzoek
Università degli Studi di PadovaBIRD2018-UNIPD

    Keywords

    • Density functional theory
    • DFT
    • GAPDH
    • Glyceroaldehyde dehydrogenase
    • Oxidative stress regulator
    • OxyR
    • Peroxidatic cysteine
    • Peroxiredoxin
    • Reaction mechanism

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