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British Journal of Pharmacology Apr 2018Hydrogen sulfide (H S), independently of any specific transporters, has a number of biological effects on the cardiovascular system. However, until now, the detailed... (Review)
Review
UNLABELLED
Hydrogen sulfide (H S), independently of any specific transporters, has a number of biological effects on the cardiovascular system. However, until now, the detailed mechanism of H S was not clear. Recently, a novel post-translational modification induced by H S, named S-sulfhydration, has been proposed. S-sulfhydration is the chemical modification of specific cysteine residues of target proteins by H S. There are several methods for detecting S-sulfhydration, such as the modified biotin switch assay, maleimide assay with fluorescent thiol modifying regents, tag-switch method and mass spectrometry. H S induces S-sulfhydration on enzymes or receptors (such as p66Shc, phospholamban, protein tyrosine phosphatase 1B, mitogen-activated extracellular signal-regulated kinase 1 and ATP synthase subunit α), transcription factors (such as specific protein-1, kelch-like ECH-associating protein 1, NF-κB and interferon regulatory factor-1), and ion channels (such as voltage-activated Ca channels, transient receptor potential channels and ATP-sensitive K channels) in the cardiovascular system. Although significant progress has been achieved in delineating the role of protein S-sulfhydration by H S in the cardiovascular system, more proteins with detailed cysteine sites of S-sulfhydration as well as physiological function need to be investigated in further studies. This review mainly summarizes the role and possible mechanism of S-sulfhydration in the cardiovascular system. The S-sulfhydrated proteins may be potential novel targets for therapeutic intervention and drug design in the cardiovascular system, which may accelerate the development and application of H S-related drugs in the future.
LINKED ARTICLES
This article is part of a themed section on Spotlight on Small Molecules in Cardiovascular Diseases. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.8/issuetoc.
Topics: Animals; Cardiovascular System; Humans; Hydrogen Sulfide; Protein Processing, Post-Translational; Protein S
PubMed: 28432761
DOI: 10.1111/bph.13825 -
Plant Physiology and Biochemistry : PPB Feb 2024Abiotic stress is one of the main threats affecting crop growth and production. Nitric oxide (NO), an important signaling molecule involved in wide range of plant growth... (Review)
Review
Abiotic stress is one of the main threats affecting crop growth and production. Nitric oxide (NO), an important signaling molecule involved in wide range of plant growth and development as well as in response to abiotic stress. NO can exert its biological functions through protein S-nitrosylation, a redox-based posttranslational modification by covalently adding NO moiety to a reactive cysteine thiol of a target protein to form an S-nitrosothiol (SNO). Protein S-nitrosylation is an evolutionarily conserved mechanism regulating multiple aspects of cellular signaling in plant. Recently, emerging evidence have elucidated protein S-nitrosylation as a modulator of plant in responses to abiotic stress, including salt stress, extreme temperature stress, light stress, heavy metal and drought stress. In addition, significant mechanism has been made in functional characterization of protein S-nitrosylated candidates, such as changing protein conformation, and the subcellular localization of proteins, regulating protein activity and influencing protein interactions. In this study, we updated the data related to protein S-nitrosylation in plants in response to adversity and gained a deeper understanding of the functional changes of target proteins after protein S-nitrosylation.
Topics: Plants; Nitric Oxide; Plant Development; Signal Transduction; Stress, Physiological; Protein Processing, Post-Translational
PubMed: 38184883
DOI: 10.1016/j.plaphy.2023.108329 -
Ageing Research Reviews Apr 2022Hydrogen sulfide (HS) and hydrogen polysulfides (HS) are essential regulatory signaling molecules generated by the entire body, including the central nervous system.... (Review)
Review
Hydrogen sulfide (HS) and hydrogen polysulfides (HS) are essential regulatory signaling molecules generated by the entire body, including the central nervous system. Researchers have focused on the classical HS signaling from the past several decades, whereas the last decade has shown the emergence of HS-induced protein S-sulfhydration signaling as a potential therapeutic approach. Cysteine S-persulfidation is a critical paradigm of post-translational modification in the process of HS signaling. Additionally, studies have shown the cross-relationship between S-sulfhydration and other cysteine-induced post-translational modifications, namely nitrosylation and carbonylation. In the central nervous system, S-sulfhydration is involved in the cytoprotection through various signaling pathways, viz. inflammatory response, oxidative stress, endoplasmic reticulum stress, atherosclerosis, thrombosis, and angiogenesis. Further, studies have demonstrated HS-induced S-sulfhydration in regulating different biological processes, such as mitochondrial integrity, calcium homeostasis, blood-brain permeability, cerebral blood flow, and long-term potentiation. Thus, protein S-sulfhydration becomes a crucial regulatory molecule in cerebrovascular and neurodegenerative diseases. Herein, we first described the generation of intracellular HS followed by the application of HS in the regulation of cerebral blood flow and blood-brain permeability. Further, we described the involvement of S-sulfhydration in different biological and cellular functions, such as inflammatory response, mitochondrial integrity, calcium imbalance, and oxidative stress. Moreover, we highlighted the importance of S-sulfhydration in cerebrovascular and neurodegenerative diseases.
Topics: Brain; Calcium; Cysteine; Humans; Hydrogen Sulfide; Prospective Studies; Protein S
PubMed: 35124235
DOI: 10.1016/j.arr.2022.101579 -
European Journal of Cell Biology Jun 2018Protein S-palmitoylation refers to a post-translational modification (PTM) wherein palmitic acid, a 16-carbon long saturated fatty acid gets covalently attached to Cys... (Review)
Review
Protein S-palmitoylation refers to a post-translational modification (PTM) wherein palmitic acid, a 16-carbon long saturated fatty acid gets covalently attached to Cys sidechain of a protein. It has been known to the literature for almost 50 years and in general, this PTM is believed to facilitate membrane attachments of proteins for the obvious hydrophobicity of the palmitoyl group. But after the discovery of the protein palmitoyl acyltransferases (PATs, also known as DHHC-PATs), a major paradigm shift has been observed in the field of protein S-palmitoylation. A family of 23 mammalian DHHC-PATs has been identified and the majority of them are associated with many human diseases spanning from neuropsychiatric diseases to cancers. Novel unique and essential role of DHHC-mediated protein S-palmitoylation has been revealed apart from its membrane trafficking role. Biomedical importance of DHHCs has also been reiterated with small molecule inhibitors for DHHCs as well as in DHHC-knockout mice or mouse Xenograft models. In this review, we present recent advances in the field of protein S-palmitoylation and the involvement of individual DHHC isoforms in human diseases. In addition, the recent development of the analytical tools to study S-palmitoylation and their inhibitors are discussed in detail. We also highlight the issues that need to be addressed in detail to further develop our understanding on protein S-palmitoylation and strongly believe that pharmacological modulation of DHHC-mediated protein S-palmitoylation has a massive potential to emerge as a novel therapeutic strategy for human diseases. It will not be surprising if reversible protein S-palmitoylation prove to be an indispensable PTM that regulates a host of cellular processes, just like protein phosphorylation or ubiquitination.
Topics: Acyltransferases; Animals; Humans; Lipoylation; Palmitic Acid; Protein S
PubMed: 29602512
DOI: 10.1016/j.ejcb.2018.03.005 -
Ageing Research Reviews Jun 2023Mitochondria-associated endoplasmic reticulum membranes (MAMs) are dynamic coupling structures between mitochondria and the endoplasmic reticulum (ER). As a new... (Review)
Review
Mitochondria-associated endoplasmic reticulum membranes (MAMs) are dynamic coupling structures between mitochondria and the endoplasmic reticulum (ER). As a new subcellular structure, MAMs combine the two critical organelle functions. Mitochondria and the ER could regulate each other via MAMs. MAMs are involved in calcium (Ca) homeostasis, autophagy, ER stress, lipid metabolism, etc. Researchers have found that MAMs are closely related to metabolic syndrome and neurodegenerative diseases (NDs). The formation of MAMs and their functions depend on specific proteins. Numerous protein enrichments, such as the IP3R-Grp75-VDAC complex, constitute MAMs. The changes in these proteins govern the interaction between mitochondria and the ER; they also affect the biological functions of MAMs. S-palmitoylation is a reversible protein post-translational modification (PTM) that mainly occurs on protein cysteine residues. More and more studies have shown that the S-palmitoylation of proteins is closely related to their membrane localization. Here, we first briefly describe the composition and function of MAMs, reviewing the component and biological roles of MAMs mediated by S-palmitoylation, elaborating on S-palmitoylated proteins in Ca flux, lipid rafts, and so on. We try to provide new insight into the molecular basis of MAMs-related diseases, mainly NDs. Finally, we propose potential drug compounds targeting S-palmitoylation.
Topics: Humans; Mitochondrial Membranes; Protein S; Lipoylation; Neurodegenerative Diseases; Mitochondria; Endoplasmic Reticulum; Endoplasmic Reticulum Stress
PubMed: 37004843
DOI: 10.1016/j.arr.2023.101920 -
Amino Acids Jan 2023Some glycoproteins contain carbohydrates S-linked to cysteine (Cys) residues. However, relatively few S-glycosylated proteins have been detected, due to the lack of an...
Some glycoproteins contain carbohydrates S-linked to cysteine (Cys) residues. However, relatively few S-glycosylated proteins have been detected, due to the lack of an effective research methodology. This work outlines a general concept for the detection of S-glycosylation sites in proteins. The approach was verified by exploratory experiments on a model mixture of β-S-glucosylated polypeptides obtained by the chemical transformation of lysozyme P00698. The model underwent two processes: (1) oxidative hydrolysis of S-glycosidic bonds under alkaline conditions to expose the thiol group of Cys residues; (2) thiol S-alkylation leading to thiol S-adduct formation at the former S-glycosylation sites. Oxidative hydrolysis was conducted in aqueous urea, dimethyl sulfoxide, or trifluoroethanol, with silver nitrate as the reaction promoter, in the presence of triethylamine and/or pyridine. The concurrent formation of stable protein silver thiolates, gluconic acid, and silver nanoclusters was observed. The essential de-metalation of protein silver thiolates using dithiothreitol preceded the S-labeling of Cys residues with 4-vinyl pyridine or a fluorescent reagent. The S-labeled model was sequenced by tandem mass spectrometry to obtain data on the modifications and their distribution over the protein chains. This enabled the efficiency of both S-glycosidic bonds hydrolysis and S-glycosylation site labeling to be evaluated. Suggestions are also given for testing this novel strategy on real proteomic samples.
Topics: Glycosylation; Cysteine; Protein S; Glycosides; Hydrolysis; Proteomics; Proteins; Oxidative Stress
PubMed: 36460841
DOI: 10.1007/s00726-022-03208-7 -
Biomedical Journal 2015Cancer is a worldwide health problem leading to a high incidence of morbidity and mortality. Malignant transformation can occur by expression of oncogenes,... (Review)
Review
Cancer is a worldwide health problem leading to a high incidence of morbidity and mortality. Malignant transformation can occur by expression of oncogenes, over-expression and deregulated activation of proto-oncogenes, and inactivation of tumor suppressor genes. These cellular actions occur through stimulation of oncogenic signaling pathways. Nitric oxide (NO) can induce genetic changes in cells and its intracellular generation can lead to tumor formation and progression. It can also promote anti-tumor activities. The pro- and anti-tumor activities of NO are dependent on its intracellular concentration, cell compartmentalization, and cell sensitivity. NO affects a number of oncogenic signaling pathways. This review focuses on two oncogenic signaling pathways: NO-EGFR-Src-FAK and NO-Ras-EGFR-ERK1/2 MAP kinases. In these pathways, low to intermediate concentrations of NO/S-nitrosothiols (RSNOs) stimulate oncogenic signaling, while high concentrations of NO/RSNO stimulate anti-oncogenic signaling. Increasing knowledge on pro- and anti-tumorigenic activities of NO and related reactive species such as RSNOs has fostered the research and synthesis of novel NO-based chemotherapeutic agents. RSNOs, effective as NO donors and trans-nitrosylating agents under appropriate conditions, may operate as potential chemotherapeutic agents.
Topics: Animals; Humans; Neoplasms; Nitric Oxide; Phosphorylation; Protein S; Signal Transduction; Tyrosine
PubMed: 26068128
DOI: 10.4103/2319-4170.158624 -
Journal of the American Chemical Society May 2020Per--acetylated unnatural monosaccharides containing a bioorthogonal group have been widely used for metabolic glycan labeling (MGL) in live cells for two decades, but...
Per--acetylated unnatural monosaccharides containing a bioorthogonal group have been widely used for metabolic glycan labeling (MGL) in live cells for two decades, but it is only recently that we discovered the existence of an artificial "S-glycosylation" between protein cysteines and per--acetylated sugars. While efforts are being made to avoid this nonspecific reaction in MGL, the reaction mechanism remains unknown. Here, we present a detailed mechanistic investigation, which unveils the "S-glycosylation" being an atypical glycosylation termed S-glyco-modification. In alkaline protein microenvironments, per--acetylated monosaccharides undergo base-promoted β-elimination to form thiol-reactive α,β-unsaturated aldehydes, which then react with cysteine residues via Michael addition. This S-glyco-modification produces 3-thiolated sugars in hemiacetal form, rather than typical glycosides. The elimination-addition mechanism guides us to develop 1,6-di--propionyl--azidoacetylgalactosamine (1,6-PrGalNAz) as an improved unnatural monosaccharide for MGL.
Topics: Glycosylation; Molecular Structure; Monosaccharides; Protein S
PubMed: 32339456
DOI: 10.1021/jacs.0c02110 -
Frontiers in Cardiovascular Medicine 2021Plasma levels of the anticoagulant cofactor protein S and PROS1 mutation are reported to impart increased risk of thromboembolism in European and south east Asian...
Plasma levels of the anticoagulant cofactor protein S and PROS1 mutation are reported to impart increased risk of thromboembolism in European and south east Asian populations, but the relationship is not yet documented in Han Chinese in population-based study. Therefore, we undertook a case-control study of this relationship among patients with venous thromboembolism, and probed the genetic factors contributing to low protein S deficiency. Among the 603 consecutively recruited venous thromboembolism patients, 51 (8.5%) proved to be deficient in free protein S antigen (lower than 38.6 U/dl), among whom 30 cases were identified to have a causative mutation by direct sequencing. In contrast, six cases (1.0%) of the 584 healthy controls had low free antigen levels, among whom direct sequencing confirmed disease-causing gene mutations in four controls (0.7%). After adjusting for age and gender, the odds ratio of developing venous thromboembolism in individuals with protein S deficiency based on free protein S tests was 8.1 (95% CI = 3.6-19.9, < 0.001). Gene sequencing yielded 24 different heterozygous mutations in the 34 participants, of which 13 were newly described. 17 (50%) of the 34 mutations in our study cohort occurred in exons 12 and 13, indicating the LGR2 domain to be a hotspot mutation region for the protein. These findings are conducive to the clinical application of protein S assays for the molecular diagnosis of thrombophilia.
PubMed: 35815065
DOI: 10.3389/fcvm.2021.796755 -
The FEBS Journal Feb 2022The lipid post-translational modification S-palmitoylation is a vast developing field, with the modification itself and the enzymes that catalyse the reversible reaction... (Review)
Review
The lipid post-translational modification S-palmitoylation is a vast developing field, with the modification itself and the enzymes that catalyse the reversible reaction implicated in a number of diseases. In this review, we discuss the past and recent advances in the experimental tools used in this field, including pharmacological tools, animal models and techniques to understand how palmitoylation controls protein localisation and function. Additionally, we discuss the obstacles to overcome in order to advance the field, particularly to the point at which modulating palmitoylation may be achieved as a therapeutic strategy.
Topics: Animals; Humans; Lipid Metabolism; Lipids; Lipoylation; Protein S
PubMed: 33624421
DOI: 10.1111/febs.15781