Cysteine perthiosulfenic acid (Cys-SSOH): A novel intermediate in thiol-based redox signaling?

Abstract

The reversible oxidation of protein cysteine residues (Cys-SH) is a key reaction in cellular redox signaling involving initial formation of sulfenic acids (Cys-SOH), which are commonly detected using selective dimedone-based probes. Here, we report that significant portions of dimedone-tagged proteins are susceptible to cleavage by DTT reflecting the presence of perthiosulfenic acid species (Cys-SSOH) due to similar oxidation of hydropersulfides (Cys-SSH), since Cys-S-dimedone adducts are stable toward DTT. Combined studies using molecular modeling, mass spectrometry, and cell-based experiments indicate that Cys-SSH are readily oxidized to Cys-SSOH, which forms stable adducts with dimedone-based probes. We additionally confirm the presence of Cys-SSH within protein tyrosine kinases such as EGFR, and their apparent oxidation to Cys-SSOH in response NADPH oxidase activation, suggesting that such Cys-SSH oxidation may represent a novel, as yet uncharacterized, event in redox-based signaling.

Speciation of reactive sulfur species and their reactions with alkylating agents: do we have any clue about what is present inside the cell?

“…We recently proposed that a major fraction of the dimedone‐labelled protein pool may represent perthiosulfenic acid derivatives. Ab initio calculations suggested that dimedone is not reactive towards polysulfide species, only towards sulfenic, persulfenic or polysulfenic acid derivatives (Heppner et al ., ), which is consistent with this hypothesis. In order to test these assumptions in a relevant biological context, we incubated isolated GAPDH that was pretreated either with inorganic polysulfides, H 2 O 2 or left untreated.…”

Biological hydropersulfides and related polysulfides – a new concept and perspective in redox biology

“…It will now be equally important to consider the analogous reaction with hydropersulfides under those same conditions. That is, oxidation of a hydropersulfide to the corresponding perthiosulfenic acid (RSSOH) is an equally likely, if not more likely, fate for hydropersulfides [64]. It is unnecessary to list all of the biologically relevant thiol modification reactions but yet important to indicate that any type of thiol modification reaction (many of which have been associated with thiol-based signaling) can occur and are likely with hydropersulfides, possibly with important signaling/biochemical consequences.…”

The Emerging Roles of Nicotinamide Adenine Dinucleotide Phosphate Oxidase 2 in Skeletal Muscle Redox Signaling and Metabolism

“…Color images are available online. compared with corresponding sulfhydryl species (34, 71,157) and it has been proposed that they might represent important targets for H 2 O 2 , leading to the intermediate formation of perthiosulfenic acid species (143).…”