Reactivity of Persulfides Toward Strained Bicyclo[6.1.0]nonyne Derivatives: Relevance to Chemical Tagging of Proteins

Galardon, Erwan; Padovani, Dominique

doi:10.1021/acs.bioconjchem.5b00243

Cited by 23 publications

(22 citation statements)

References 44 publications

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“…These data, particularly the cross reactivity with reduced Gpx3 Cys36-SH suggest limited applicability of BCN ( 5 ) 32 as a selective probe for detecting protein sulfenic acids. 34 – 36 …”

Section: Resultsmentioning

confidence: 99%

Profiling the reactivity of cyclic C-nucleophiles towards electrophilic sulfur in cysteine sulfenic acid

2016

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Oxidation of a protein cysteine thiol to sulfenic acid, termed S-sulfenylation, is a reversible post-translational modification that plays a crucial role in regulating protein function and is correlated with disease states. The majority of reaction-based small molecule and immunochemical probes used for detecting sulfenic acids are based on the 5,5-dimethyl-1,3-cyclohexanedione (dimedone) scaffold, which is selective, but suffers from low reactivity. In addition, mechanistic details and features that diminish or enhance nucleophile reactivity remain largely unknown. A significant hurdle to resolving the aforementioned issues has been the chemically unstable nature of small-molecule sulfenic acid models. Herein, we report a facile mass spectrometry-based assay and repurposed dipeptide-based model to screen a library of cyclic C-nucleophiles for reactivity with sulfenic acid under aqueous conditions. Observed rate constants for ~100 cyclic C-nucleophiles were obtained and, from this collection, we have identified novel compounds with more than 200-fold enhanced reactivity, as compared to dimedone. The increase in reactivity and retention of selectivity of these C-nucleophiles were validated in secondary assays, including a protein model for sulfenic acid. Together, this work represents a significant step toward developing new chemical reporters for detecting protein S-sulfenylation with superior kinetic resolution. The enhanced rates and varied composition of the C-nucleophiles should enable more comprehensive analyses of the sulfenome and serve as the foundation for reversible or irreversible nucleophilic covalent inhibitors that target oxidized cysteine residues in therapeutically important proteins.

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Section: Resultsmentioning

confidence: 99%

Profiling the reactivity of cyclic C-nucleophiles towards electrophilic sulfur in cysteine sulfenic acid

2016

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“…12f). 151 The reaction of 106 with persulfides proceeds analogously to the reaction with sulfenic acids, providing adduct 111, which can undergo subsequent rearrangement to disulfide 112 or the corresponding thioether after extrusion of sulfur (Fig. 12f).…”

Section: Alternative Chemical Probesmentioning

confidence: 99%

Chemical methods for mapping cysteine oxidation

2018

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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.

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“…For example, the strained cycloalkyne BCN-Bio1 had ~300-fold higher reactivity with protein -SOH compared with previous series of reagents. While potential reaction of strained cycloalkynes with -SSH has been revealed recently [47], these can be easily handled by effective blocking of these species as well as at the stage of MS analysis given the difference in the nature of products of BCN-Bio1 reaction with these species. This newly discovered reaction also offers the opportunity for simultaneous quantitative measurement of both -SSH and -SOH species within the same experiment, addressing a limitation with current approaches.…”

Section: Synthesis Stability Reactivity and Characterization Of mentioning

confidence: 99%

Biological chemistry and functionality of protein sulfenic acids and related thiol modifications

Devarie‐Baez

Lopez

Furdui

2015

Free Radical Research

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Selective modification of proteins at cysteine residues by reactive oxygen, nitrogen or sulfur species formed under physiological and pathological states is emerging as a critical regulator of protein activity impacting cellular function. This review focuses primarily on protein sulfenylation (-SOH), a metastable reversible modification connecting reduced cysteine thiols to many products of cysteine oxidation. An overview is first provided on the chemistry principles underlining synthesis, stability and reactivity of sulfenic acids in model compounds and proteins, followed by a brief description of analytical methods currently employed to characterize these oxidative species. The following chapters present a selection of redox-regulated proteins for which the -SOH formation was experimentally confirmed and linked to protein function. These chapters are organized based on the participation of these proteins in the regulation of signaling, metabolism and epigenetics. The last chapter discusses the therapeutic implications of altered redox microenvironment and protein oxidation in disease.

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Reactivity of Persulfides Toward Strained Bicyclo[6.1.0]nonyne Derivatives: Relevance to Chemical Tagging of Proteins

Cited by 23 publications

References 44 publications

Profiling the reactivity of cyclic C-nucleophiles towards electrophilic sulfur in cysteine sulfenic acid

Profiling the reactivity of cyclic C-nucleophiles towards electrophilic sulfur in cysteine sulfenic acid

Chemical methods for mapping cysteine oxidation

Biological chemistry and functionality of protein sulfenic acids and related thiol modifications

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