Thiol redox biochemistry: insights from computer simulations

A small-molecule cysteine sulfenic acid (Cys–SOH) was synthesized and isolated as stable crystals, for the first time, by utilizing a nanosized molecular cavity as a protective cradle. The cradled Cys–SOH was synthesized by direct oxidation of the corresponding cysteine thiol with H2O2 under basic conditions and its structure was established by X-ray crystallographic analysis. In the reaction of the cradled Cys–SOH with a thiol to produce the disulfide, a remarkable acceleration was observed upon the addition of an amine base. This suggests the important role of base in the reaction of Cys–SOH with thiols in biological systems. The cradled Cys–SOH was reduced to the cysteine thiol by dithiothreitol or triphenylphosphine. The high stability and sufficient reactivity of the cradled Cys–SOH indicate its usefulness as a small-molecule model compound for better understanding the chemical behavior of Cys–SOH in biological systems.

Sulfenic acid

Thiol

Dithiothreitol

Reactivity

10.1080/10426507.2023.2195650

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Posttranslational glutathiolation of aldose reductase (AKR1B1): A possible mechanism of protein recovery from S-nitrosylation

Chemico-Biological Interactions (2008)

Shahid P. Baba Karin Wetzelberger Joseph David Hoetker Aruni Bhatnagar

S-Nitrosylation

Thiol

Nitrosylation

Sulfenic acid

10.1016/j.cbi.2008.11.007

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Citations (33)

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

Free Radical Research (2015)

Nelmi O. Devarie‐Baez Elsa I. Silva Lopez Cristina M. Furdui

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.

Sulfenic acid

Thiol

Posttranslational modification

10.3109/10715762.2015.1090571

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Citations (78)

Reactions of Oxidants with Disulfide Bonds: Evidence for Selective Reactivity at Specific Sites

Free Radical Biology and Medicine (2015)

Marta T. Ignasiak Maryam Karimi David I. Pattison Michael J. Davies

Hypochlorous acid

Sulfenic acid

Glyceraldehyde 3-phosphate dehydrogenase

Thiocyanate

Thiol

10.1016/j.freeradbiomed.2015.10.321

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Structural Consensus Rules for Cysteine Protease Inhibition by NO(-Donors)

Current Enzyme Inhibition (2005)

Paolo Ascenzi Alessio Bocedi Fabio Polticelli Martino Bolognesi

Nitric oxide (NO) exerts its action in several physiological and pathological events. The great propensity for Cys(NO)-(de)nitrosylation represents a mechanism which modulates cysteine protease action. Cys(NO)-(de)nitrosylation is assisted by basic and acid residues, within the environment of the Cys catalytic residue. In particular, Cys-nitrosylation is catalyzed by amino acid residues which stabilize the reactive deprotonated form of the Cys Sγ atom. By contrast, CysNO-denitrosylation is assisted by amino acid residues which facilitate the protonation of the Cys Sγ atom with the concomitant NO release. Note that Cysnitrosylated residues may undergo oxidation giving rise to sulfenic, sulfinic or sulfonic acid and lead to the formation of disulfide bridges. These structural consensus rules apply not only to cysteine proteases, but represent a generally accepted mechanism for (macro)molecular Cys(NO)-(de)nitrosylation. Keywords: nitric oxide, cysteine protease, enzyme inhibition, cys-nitrosylation, cysno-denitrosylation, acid-base catalysis, structural consensus rules

S-Nitrosylation

Sulfenic acid

Nitrosylation

Cysteine protease

10.2174/157340805774580448

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Regulation of Protein Nitrosylation by Thioredoxin 1

Springer eBooks (2016)

Narayani Nagarajan Junichi Sadoshima

S-Nitrosylation

Nitrosylation

Peroxiredoxin

10.1007/978-3-319-45865-6_11

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Redox Active Thiol Sensors of Oxidative and Nitrosative Stress

Antioxidants and Redox Signaling (2012)

Andrés Vázquez‐Torres

The reactivity of the thiol in the side chain of cysteines is exploited by bacterial regulatory proteins that sense and respond to reactive oxygen and nitrogen species.Charged residues and helix dipoles diminish the pKa of redox active cysteines, resulting in a thiolate that is stabilized by neighboring polar amino acids. The reaction of peroxides with thiolates generates a sulfenic acid (-SOH) intermediate that often gives rise to a reversible disulfide bond. Peroxide-induced intramolecular and intermolecular disulfides and intermolecular mixed disulfides modulate the signaling activity of members of the LysR/OxyR, MarR/OhrR, and RsrA family of transcriptional regulators. Thiol-dependent regulators also help bacteria resist the nitrosative and nitroxidative stress. -SOHs, mixed disulfides, and S-nitrosothiols are some of the post-translational modifications induced by nitrogen oxides in the thiol groups of OxyR and SsrB bacterial regulatory proteins. Sulfenylation, disulfide bond formation, S-thiolation, and S-nitrosylation are reversible modifications amenable to feedback regulation by antioxidant and antinitrosative repair systems. The structural and functional changes engaged in the thiol-dependent sensing of reactive species have been adopted by several regulators to foster bacterial virulence during exposure to products of NADPH phagocyte oxidase and inducible nitric oxide synthase.Investigations with LysR/OxyR, MarR/OhrR, and RsrA family members have helped in an understanding of the mechanisms by which thiols in regulatory proteins react with reactive species, thereby activating antioxidant and antinitrosative gene expression.To define the determinants that provide selectivity of redox active thiolates for some reactive species but not others is an important challenge for future investigations.

Reactive nitrogen species

Sulfenic acid

S-Nitrosylation

Thiol

Nitrosylation

S-Nitrosoglutathione

10.1089/ars.2012.4522

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Citations (84)