“…This work was inspired by the early work of Allison and Benitez using water soluble cyclohexene derivatives to trap cysteine sulfenic acids and later Barton and co-workers who specifically used norbornene derivatives to trap the sulfenic acid formed during thermally induced syn-elimination of the sulfoxides of penicillin. 99,[154][155][156] The strain of the norbornene was sufficient to lead to rapid reaction with the unstable sulfenic acid. Dimedone was far less reactive and unable to trap the same short-lived cysteine sulfenic acid.…”
Cysteine residues in proteins are subject to diverse redox chemistry. Oxidation of cysteine to S-nitrosocysteine, cysteine sulfenic and sulfinic acids, disulfides and persulfides are a few prominent examples of these oxidative post-translational modifications. In living organisms, these modifications often play key roles in cell signalling and protein function, but a full account of this biochemistry is far from complete. It is therefore an important goal in chemical biology to identify what proteins are subjected to these modifications and understand their physiological function. This review provides an overview of these modifications, how they can be detected and quantified using chemical probes, and how this information provides insight into their role in biology. This survey also highlights future opportunities in the study of cysteine redox chemistry, the challenges that await chemists and biologists in this area of study, and how meeting such challenges might reveal valuable information for biomedical science.
“…This work was inspired by the early work of Allison and Benitez using water soluble cyclohexene derivatives to trap cysteine sulfenic acids and later Barton and co-workers who specifically used norbornene derivatives to trap the sulfenic acid formed during thermally induced syn-elimination of the sulfoxides of penicillin. 99,[154][155][156] The strain of the norbornene was sufficient to lead to rapid reaction with the unstable sulfenic acid. Dimedone was far less reactive and unable to trap the same short-lived cysteine sulfenic acid.…”
Cysteine residues in proteins are subject to diverse redox chemistry. Oxidation of cysteine to S-nitrosocysteine, cysteine sulfenic and sulfinic acids, disulfides and persulfides are a few prominent examples of these oxidative post-translational modifications. In living organisms, these modifications often play key roles in cell signalling and protein function, but a full account of this biochemistry is far from complete. It is therefore an important goal in chemical biology to identify what proteins are subjected to these modifications and understand their physiological function. This review provides an overview of these modifications, how they can be detected and quantified using chemical probes, and how this information provides insight into their role in biology. This survey also highlights future opportunities in the study of cysteine redox chemistry, the challenges that await chemists and biologists in this area of study, and how meeting such challenges might reveal valuable information for biomedical science.
“…Notable examples include a cyclooctyne reagent [ 25 ] typically used in strain-promoted azide-alkyne cycloaddition (SPAAC) reactions, and a trans-cycloctene derivative [ 26 ] originally used for tetrazine ligation. Norbornadiene and less strained norbornene derivatives are also purported to react with sulfenic acid [ 27 , 28 ]. Fig.…”
Cysteine sulfenic acids (Cys-SOH) are pivotal modifications in thiol-based redox signaling and central intermediates
en route
to disulfide and sulfinic acid states. A core mission in our lab is to develop bioorthogonal chemical tools with the potential to answer mechanistic questions involving cysteine oxidation. Our group, among others, has contributed to the development of nucleophilic chemical probes for detecting sulfenic acids in living cells. Recently, another class of Cys-SOH probes based on strained alkene and alkyne electrophiles has emerged. However, the use of different models of sulfenic acid and methodologies, has confounded clear comparison of these probes with respect to chemical reactivity, kinetics, and selectivity. Here, we perform a parallel evaluation of nucleophilic and electrophilic chemical probes for Cys-SOH. Among the key findings, we demonstrate that a probe for Cys-SOH based on the norbornene scaffold does not react with any of the validated sulfenic acid models in this study. Furthermore, we show that purported cross-reactivity of dimedone-like probes with electrophiles, like aldehydes and cyclic sulfenamides, is a not meaningful in a biological setting. In summary, nucleophilic probes remain the most viable tools for bioorthogonal detection of Cys-SOH.
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