A Catalytic Trisulfide in Human Sulfide Quinone Oxidoreductase Catalyzes Coenzyme A Persulfide Synthesis and Inhibits Butyrate Oxidation

Landry, Aaron P.; Moon, Sangjun; Kim, Hanseong; Yadav, Pramod Kumar; Guha, Arkajit; Cho, Uhn‐Soo; Banerjee, Ruma

doi:10.1016/j.chembiol.2019.09.010

Cited by 47 publications

(71 citation statements)

References 63 publications

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“…Our analysis of persulfide pKa and nucleophilicity has implications for the reaction catalyzed by the mitochondrial enzyme SQOR. It has been proposed that this enzyme contains a trisulfide (RSSSR) instead of a disulfide (RSSR) in its two active site cysteines (72). Reaction of H2S with RSSSR instead of RSSR to form two persulfides, could imply an acceleration of ~2 orders of magnitude due to persulfide being a better leaving group than thiol because of its lower pKa (3).…”

Section: Biological Implicationsmentioning

confidence: 99%

Acidity and nucleophilic reactivity of glutathione persulfide

Benchoam

Semelak

Cuevasanta

et al. 2020

Journal of Biological Chemistry

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Persulfides (RSSH/RSS-) participate in sulfur trafficking and metabolic processes, and are proposed to mediate the signaling effects of H2S. Despite their growing relevance, their chemical properties are poorly understood. Herein, we studied experimentally and computationally the formation, acidity, and nucleophilicity of glutathione persulfide (GSSH/GSS-), the derivative of the abundant cellular thiol, glutathione (GSH). We characterized the kinetics and equilibrium of GSSH formation from glutathione disulfide and H2S. A pKa of 5.45 for GSSH was determined, which is 3.49 units below that of GSH. The reactions of GSSH with the physiologically-relevant electrophiles peroxynitrite and hydrogen peroxide, as well as with the probe monobromobimane, were studied and compared with those of thiols. These reactions occurred through SN2 mechanisms. At neutral pH, GSSH reacted faster than GSH due to increased availability of the anion and, depending on the electrophile, increased reactivity. In addition, GSS- presented higher nucleophilicity with respect to a thiolate with similar basicity. This can be interpreted in terms of the so-called alpha effect, i.e. the increased reactivity of a nucleophile when the atom adjacent to the nucleophilic atom has high electron density. The magnitude of the alpha effect correlated with the Brønsted nucleophilic factor, βnuc, for the reactions with thiolates and with the ability of the leaving group. Our study constitutes the first determination of the pKa of a biological persulfide and the first examination of the alpha effect in sulfur nucleophiles, and sheds light on the chemical basis of the biological properties of persulfides.

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Section: Biological Implicationsmentioning

confidence: 99%

Acidity and nucleophilic reactivity of glutathione persulfide

Benchoam

Semelak

Cuevasanta

et al. 2020

Journal of Biological Chemistry

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“…An important enzymatic route to the biogenesis of RSS in bacteria is the sulfide:quinone oxidoreductase (SQR) (76,(123)(124)(125). SQR catalyzes the two-electron oxidation of H 2 S to sulfane sulfur fixed as organic and inorganic per-and polysulfides ( Fig.…”

Section: Biogenesis and Clearance Of Organic Rss In Bacteriamentioning

confidence: 99%

H2S and reactive sulfur signaling at the host-bacterial pathogen interface

Walsh

Giedroc

2020

Journal of Biological Chemistry

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Bacterial pathogens that cause invasive disease in the vertebrate host must adapt to host efforts to cripple their viability. Major host insults are reactive oxygen and reactive nitrogen species as well as cellular stress induced by antibiotics. Hydrogen sulfide (H2S) is emerging as an important player in cytoprotection against these stressors, which may well be attributed to downstream more oxidized sulfur species termed reactive sulfur species (RSS). In this review, we summarize recent work that suggests that H2S/RSS impacts bacterial survival in infected cells and animals. We discuss the mechanisms of biogenesis and clearance of RSS in the context of a bacterial H2S/RSS homeostasis model, and the bacterial transcriptional regulatory proteins that act as “sensors” of cellular RSS that maintain H2S/RSS homeostasis. In addition, we cover fluorescence imaging- and mass spectrometry-based approaches used to detect and quantify RSS in bacterial cells. Lastly, we discuss proteome persulfidation (S-sulfuration) as potential mediators of H2S/RSS signaling in bacteria in the context of the writer-reader-eraser paradigm, and progress toward ascribing regulatory significance to this widespread post-translational modification.

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“…The first (irreversible and committing) step is catalysed by SQR, which oxidises H 2 S and transfers the electron equivalents to coenzyme Q and the sulphur atom to an acceptor molecule that becomes persulphidated. 100,125,126 The preferred sulphur-accepting substrate is still a matter of debate, but glutathione appears to be the most effective and plausible in physiological conditions. [127][128][129][130] The resulting glutathione persulphide is a substrate for either persulphide dioxygenase, which oxidises the sulphane sulphur yielding sulphite and glutathione, or rhodanese, which generates thiosulphate.…”

Section: Regulation Of H 2 S and Rss Levelsmentioning

confidence: 99%

Cysteine metabolic circuitries: druggable targets in cancer

et al. 2020

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To enable survival in adverse conditions, cancer cells undergo global metabolic adaptations. The amino acid cysteine actively contributes to cancer metabolic remodelling on three different levels: first, in its free form, in redox control, as a component of the antioxidant glutathione or its involvement in protein s-cysteinylation, a reversible post-translational modification; second, as a substrate for the production of hydrogen sulphide (H2S), which feeds the mitochondrial electron transfer chain and mediates per-sulphidation of ATPase and glycolytic enzymes, thereby stimulating cellular bioenergetics; and, finally, as a carbon source for epigenetic regulation, biomass production and energy production. This review will provide a systematic portrayal of the role of cysteine in cancer biology as a source of carbon and sulphur atoms, the pivotal role of cysteine in different metabolic pathways and the importance of H2S as an energetic substrate and signalling molecule. The different pools of cysteine in the cell and within the body, and their putative use as prognostic cancer markers will be also addressed. Finally, we will discuss the pharmacological means and potential of targeting cysteine metabolism for the treatment of cancer.

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A Catalytic Trisulfide in Human Sulfide Quinone Oxidoreductase Catalyzes Coenzyme A Persulfide Synthesis and Inhibits Butyrate Oxidation

Cited by 47 publications

References 63 publications

Acidity and nucleophilic reactivity of glutathione persulfide

Acidity and nucleophilic reactivity of glutathione persulfide

H2S and reactive sulfur signaling at the host-bacterial pathogen interface

Cysteine metabolic circuitries: druggable targets in cancer

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