H2S Signals Through Protein S-Sulfhydration

By A. Mustafa, Moataz M. Gadalla, N. Sen, Seyun Kim, W. Mu, Sadia K. Gazi, R. Barrow, Guangdong Yang, Rui Wang, S. Snyder. Science Signaling, 2009

1,214 citations recorded by the source corpus.

The gaseous messenger hydrogen sulfide regulates target proteins through S-sulfhydration of cysteine residues. Battling for the Same Cysteine? Recent evidence suggests that hydrogen sulfide (H2S)—a gas perhaps best known for its scent of rotten eggs—has joined nitric oxide (NO) and carbon monoxide in the select ranks of gases that act as physiologic messenger molecules. Although H2S is enzymatically generated in vivo and mediates various physiologic functions, including acting as a vasorelaxant and eliciting hibernation states, the mechanisms through which it affects its targets have been unclear. Here, Mustafa et al. show that endogenous H2S modifies cysteine residues in many proteins, including glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and actin, converting cysteine -SH groups to -SSH groups in a process the authors call S-sulfhydration. Intriguingly, H2S enhanced GAPDH activity through sulfhydration of a cysteine residue that is also a target of nitrosylation by NO, which inhibits GAPDH activity, suggesting that some targets might be subject to regulation through competitive nitrosylation and sulfhydration of the same cysteine residues. Hydrogen sulfide (H2S), a messenger molecule generated by cystathionine γ-lyase, acts as a physiologic vasorelaxant. Mechanisms whereby H2S signals have been elusive. We now show that H2S physiologically modifies cysteines in a large number of proteins by S-sulfhydration. About 10 to 25% of many liver proteins, including actin, tubulin, and glyceraldehyde-3-phosphate dehydrogenase (GAPDH), are sulfhydrated under physiological conditions. Sulfhydration augments GAPDH activity and enhances actin polymerization. Sulfhydration thus appears to be a physiologic posttranslational modification for proteins.

Subfields: Biochemistry, Cardiology and Cardiovascular Medicine, Endocrine and Autonomic Systems

View Paper: https://www.semanticscholar.org/paper/6c126c0201a27085fa587e2997724a08e90bd9a2

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Biochemistry

1. Rui Wang
2. B. Paul
3. S. Snyder
4. C. Winterbourn
5. P. Nagy
6. Ling-Xia Li
7. P. Moore
8. P. Rose

In Cardiology and Cardiovascular Medicine

1. Rui Wang
2. C. Szabó

In Endocrine and Autonomic Systems

1. Rui Wang
2. C. Winterbourn
3. P. Nagy
4. S. Snyder
5. P. Moore
6. Ling-Xia Li
7. B. Paul
8. C. Szabó

Citations in the corpus

• Hydrogen sulfide-linked sulfhydration of NF-κB mediates its anti-apoptotic actions (2012, methodology): “We monitored sulfhydration of p65 in liver lysates of TNFa-treated mice by the modified biotin switch assay (Mustafa et al., 2009a).”
• Hydrogen sulfide: a versatile regulator of environmental stress in plants (2015, background): “H 2 S can modify specific targets through protein sulfhydration which involves the posttranslational modification of protein cysteine residues (Mustafa et al. 2009).”
• Reactive cysteine persulfides and S-polythiolation regulate oxidative stress and redox signaling (2014, neutral): “(24) relied on the nucleophilicity of a protein thiol for reaction with an electrophile (Smethyl methanethiosulfonate) and assumed that a protein hydropersulfide would not react.”
• Hydrogen sulfide and cell signaling. (2011, background): “HYDROGEN SULFIDE IN CELL SIGNALING—THE ROLE OF S-SULFHYDRATION H2S causes S-sulfhydration of a large number of cellular proteins (71); this process is potentially significant because it provides a possible mechanism by which H2S alters the function of a wide range of cellular proteins and enzymes.”
• Hydrogen sulfide mediates ion fluxes inducing stomatal closure in response to drought stress in Arabidopsis thaliana (2017, background): “H2S works through a mechanism called sulfhydration in mammals (Mustafa et al. 2009; Yang 2014) and in higher plants (Aroca et al. 2015).”
• Physiological implications of hydrogen sulfide: a whiff exploration that blossomed. (2012, methodology): “Striking similarities between S-sulfhydration and S-nitrosylation have been noticed as both involved the covalent modification of cysteines and both are reversible by reducing agents, such as dithiothreitol (DTT) (420).”
• Tumor-derived hydrogen sulfide, produced by cystathionine-β-synthase, stimulates bioenergetics, cell proliferation, and angiogenesis in colon cancer (2013, background): “(GAPDH activity in wild-type and CBS silenced cells amounted to 6.2 ± 0.2 units/mL and 4.0 ± 0.1 units/mL, respectively, n = 3, P 0.01).”
• Redox chemistry of biological thiols (2010, background): “The recent discovery that H2S exerts its signaling properties via interacting with protein thiols to form persulfides opens up a new aspect of thiol biochemistry [233].”