Theoretical studies of the reactions of the sulfur-sulfur bond. 1. General heterolytic mechanisms

Pappas, Jan A.

doi:10.1021/ja00451a013

Cited by 50 publications

(32 citation statements)

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“…The thiol-disulfide exchange occurred with little geometry modifications. The ∼90°amplitude for the C-S-S ox /C ox -S ox -S angles (104.7°/101.2°to 107.6°/105.5°) and CS-S ox C ox dihedral (−74.4°t o 99.0°) was maintained between GSSG and GSH ox -Cys53, in agreement with earlier studies that pointed out that hyperconjugation between the SC bond and the SS bond played an important role in the arrangement of SS dihedral angles (47,49). Moreover, an analysis of the CS and SS natural bond orbitals indicated that the SS bond was a single bond formed by sp hybridization of sulfur valence orbitals (with p orbitals accounting for ∼90% of the interaction); the same occurred for CS bonds (p orbitals accounted for ∼80% of the interaction).…”

Section: Resultssupporting

confidence: 92%

“…Moreover, an analysis of the CS and SS natural bond orbitals indicated that the SS bond was a single bond formed by sp hybridization of sulfur valence orbitals (with p orbitals accounting for ∼90% of the interaction); the same occurred for CS bonds (p orbitals accounted for ∼80% of the interaction). The predominant contributions of p orbitals for the binding might also explain why the CS-SC dihedral and the CSS angles were mostly orthogonal (47,49).…”

Section: Resultsmentioning

confidence: 99%

“…It has been observed also that the near orthogonality of the CSS angles in the disulfide results from a hyperconjugation effect from the interacting p orbitals involved in CS and SS bonds, whereas d orbitals from sulfur mostly do not interact. This effect is proposed to strengthen the disulfide bond (47,49). For the particular case of the thiol-disulfide exchange between the Cys53-thiolate and the disulfide of GSSG, a secondorder turnover rate of 191 M −1 ·s −1 has been determined (13).…”

Section: Gsh/gssg Buffer In Catalysis By Hpdimentioning

confidence: 99%

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Mechanistic insights on the reduction of glutathione disulfide by protein disulfide isomerase

Neves

Fernandes

Ramos

2017

Proc. Natl. Acad. Sci. U.S.A.

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We explore the enzymatic mechanism of the reduction of glutathione disulfide (GSSG) by the reduced a domain of human protein disulfide isomerase (hPDI) with atomistic resolution. We use classical molecular dynamics and hybrid quantum mechanics/molecular mechanics calculations at the mPW1N/6-311+G(2d,2p):FF99SB//mPW1N/6-31G(d): FF99SB level. The reaction proceeds in two stages: (i) a thiol-disulfide exchange through nucleophilic attack of the Cys53-thiolate to the GSSG-disulfide followed by the deprotonation of Cys56-thiol by Glu47-carboxylate and (ii) a second thiol-disulfide exchange between the Cys56-thiolate and the mixed disulfide intermediate formed in the first step. The Gibbs activation energy for the first stage was 18.7 kcal·mol, and for the second stage, it was 7.2 kcal·mol ). Our results also suggest that the catalysis by protein disulfide isomerase (PDI) and thiol-disulfide exchange is mostly enthalpy-driven (entropy changes below 2 kcal·mol −1 at all stages of the reaction). Hydrogen bonds formed between the backbone of His55 and Cys56 and the Cys56-thiol result in an increase in the Gibbs energy barrier of the first thiol-disulfide exchange. The solvent plays a key role in stabilizing the leaving glutathione thiolate formed. This role is not exclusively electrostatic, because an explicit inclusion of several water molecules at the density-functional theory level is a requisite to form the mixed disulfide intermediate. In the intramolecular oxidation of PDI, a transition state is only observed if hydrogen bond donors are nearby the mixed disulfide intermediate, which emphasizes that the thermochemistry of thiol-disulfide exchange in PDI is influenced by the presence of hydrogen bond donors.PDI | GSH/GSSG buffer | thiol-disulfide exchange | protein folding | ONIOM

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Section: Resultssupporting

confidence: 92%

Section: Resultsmentioning

confidence: 99%

Section: Gsh/gssg Buffer In Catalysis By Hpdimentioning

confidence: 99%

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Mechanistic insights on the reduction of glutathione disulfide by protein disulfide isomerase

Neves

Fernandes

Ramos

2017

Proc. Natl. Acad. Sci. U.S.A.

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“…It is known that disulphide bond reduction proceeds by means of an S N 2 mechanism. This reaction is highly directional, proceeding via a transition state in which the three involved sulphur atoms form an ~180° angle [20][21][22] . Thus, the relative positions of these sulphur atoms must be important for efficient Trx catalysis.…”

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confidence: 99%

Probing the chemistry of thioredoxin catalysis with force

Wiita

Pérez-Jiménez²,

Walther³

et al. 2007

Nature

255

313

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Thioredoxins are enzymes that catalyse disulphide bond reduction in all living organisms 1 . Although catalysis is thought to proceed through a substitution nucleophilic bimolecular (S N 2) reaction 1,2 , the role of the enzyme in modulating this chemical reaction is unknown. Here, using single-molecule force-clamp spectroscopy 3,4 , we investigate the catalytic mechanism of Escherichia coli thioredoxin (Trx). We applied mechanical force in the range of 25-600 pN to a disulphide bond substrate and monitored the reduction of these bonds by individual enzymes. We detected two alternative forms of the catalytic reaction, the first requiring a reorientation of the substrate disulphide bond, causing a shortening of the substrate polypeptide by 0.79 ± 0.09 Å (± s.e.m.), and the second elongating the substrate disulphide bond by 0.17 ± 0.02 Å (±s.e.m.). These results support the view that the Trx active site regulates the geometry of the participating sulphur atoms with sub-ångström precision to achieve efficient catalysis. Our results indicate that substrate conformational changes may be important in the regulation of Trx activity under conditions of oxidative stress and mechanical injury, such as those experienced in cardiovascular disease 5,6 . Furthermore, single-molecule atomic force microscopy techniques, as shown here, can probe dynamic rearrangements within an enzyme's active site during catalysis that cannot be resolved with any other current structural biological technique.One of the principal challenges of understanding enzyme catalysis, a central problem in biology, is resolving the dynamics of enzyme-substrate interactions with sub-ångström resolution-the length scale at which chemistry occurs 7 . Although nuclear magnetic resonance (NMR) and X-ray crystallography determinations of protein structures can reach down to the sub-ångström level, they cannot yet provide dynamic information about enzyme

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“…A peptide-binding groove is identified on the surface of the protein close to the catalytic cysteine. It is known that the reduction of a disulfide bond proceeds via an S n 2 mechanism, in which the three participating sulfur atoms form an ϳ180°angle (47,48). Given the fact that the disulfide bond in 1MDI forms an angle of ϳ70°with respect to the axis of the groove, it is evident that the target disulfide bond must rotate with respect to the pulling axis to acquire the correct geometry for reaction (Fig.…”

Section: Force As a New Probe Of Enzyme Catalysismentioning

confidence: 99%

Single-molecule Force Spectroscopy Approach to Enzyme Catalysis

Alegre-Cebollada¹,

Pérez-Jiménez²,

Kosuri

et al. 2010

Journal of Biological Chemistry

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Enzyme catalysis has been traditionally studied using a diverse set of techniques such as bulk biochemistry, x-ray crystallography, and NMR. Recently, single-molecule force spectroscopy by atomic force microscopy has been used as a new tool to study the catalytic properties of an enzyme. In this approach, a mechanical force ranging up to hundreds of piconewtons is applied to the substrate of an enzymatic reaction, altering the conformational energy of the substrate-enzyme interactions during catalysis. From these measurements, the force dependence of an enzymatic reaction can be determined. The force dependence provides valuable new information about the dynamics of enzyme catalysis with sub-angstrom resolution, a feat unmatched by any other current technique. To date, singlemolecule force spectroscopy has been applied to gain insight into the reduction of disulfide bonds by different enzymes of the thioredoxin family. This minireview aims to present a perspective on this new approach to study enzyme catalysis and to summarize the results that have already been obtained from it. Finally, the specific requirements that must be fulfilled to apply this new methodology to any other enzyme will be discussed.

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Theoretical studies of the reactions of the sulfur-sulfur bond. 1. General heterolytic mechanisms

Cited by 50 publications

References 1 publication

Mechanistic insights on the reduction of glutathione disulfide by protein disulfide isomerase

Mechanistic insights on the reduction of glutathione disulfide by protein disulfide isomerase

Probing the chemistry of thioredoxin catalysis with force

Single-molecule Force Spectroscopy Approach to Enzyme Catalysis

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