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Oral Diseases Nov 2017All living tissues require essential nutrients such as amino acids, fatty acids, carbohydrates, minerals, vitamins, and water. The skeleton requires nutrients for... (Review)
Review
All living tissues require essential nutrients such as amino acids, fatty acids, carbohydrates, minerals, vitamins, and water. The skeleton requires nutrients for development, maintaining bone mass and density. If the skeletal nutritional requirements are not met, the consequences can be quite severe. In recent years, there has been growing interest in promotion of bone health and inhibition of vascular calcification by vitamin K2. This vitamin regulates bone remodeling, an important process necessary to maintain adult bone. Bone remodeling involves removal of old or damaged bone by osteoclasts and its replacement by new bone formed by osteoblasts. The remodeling process is tightly regulated, when the balance between bone resorption and bone formation shifts to a net bone loss results in the development of osteoporosis in both men and women. In this review, we focus on our current understanding of the effects of vitamin K2 on bone cells and its role in prevention and treatment of osteoporosis.
Topics: Animals; Bone Development; Bone Remodeling; Bone and Bones; Calcium-Binding Proteins; Extracellular Matrix Proteins; Humans; Osteoblasts; Osteocalcin; Osteoclasts; Osteocytes; Protein S; Vitamin K 2; Matrix Gla Protein
PubMed: 27976475
DOI: 10.1111/odi.12624 -
Open Biology Apr 2022Protein S-acylation, more commonly known as protein palmitoylation, is a biological process defined by the covalent attachment of long chain fatty acids onto cysteine... (Review)
Review
Protein S-acylation, more commonly known as protein palmitoylation, is a biological process defined by the covalent attachment of long chain fatty acids onto cysteine residues of a protein, effectively altering the local hydrophobicity and influencing its stability, localization and overall function. Observed ubiquitously in all eukaryotes, this post translational modification is mediated by the 23-member family of zDHHC protein acyltransferases in mammals. There are thousands of proteins that are S-acylated and multiple zDHHC enzymes can potentially act on a single substrate. Since its discovery, numerous methods have been developed for the identification of zDHHC substrates and the individual members of the family that catalyse their acylation. Despite these recent advances in assay development, there is a persistent gap in knowledge relating to zDHHC substrate specificity and recognition, that can only be thoroughly addressed through reconstitution. Herein, we will review the various methods currently available for reconstitution of protein S-acylation for the purposes of identifying enzyme-substrate pairs with a particular emphasis on the advantages and disadvantages of each approach.
Topics: Acetyltransferases; Acylation; Animals; Mammals; Protein Processing, Post-Translational; Protein S; Substrate Specificity
PubMed: 35414257
DOI: 10.1098/rsob.210390 -
Yakugaku Zasshi : Journal of the... 2016Nitric oxide (NO) plays a pivotal function in neurotransmission, vasodilation, proliferation, and apoptosis in various types of cells via protein S-nitrosylation.... (Review)
Review
Nitric oxide (NO) plays a pivotal function in neurotransmission, vasodilation, proliferation, and apoptosis in various types of cells via protein S-nitrosylation. Previously we demonstrated that protein disulfide isomerase (PDI) is S-nitrosylated in brains manifesting sporadic neurodegenerative diseases. This modification results in dysfunction of its enzymatic activity and consequently the accumulation of unfolded/misfolded proteins in the endoplasmic reticulum (ER). The aim of this study was to clarify the detailed function of NO on unfolded protein response (UPR) branches. We here found that the ER stress sensor IRE1α is S-nitrosylated. Interestingly, NO specifically abrogates ribonuclease activity, but not oligomerization or autophosphorylation of IRE1α. Site-directed mutagenesis revealed that Cys 931 and Cys951 in IRE1 are targets for S-nitrosylation. These mutants expressing in IRE1α knockout MEF showed a resistant role to the inhibition of nuclease activity by NO. Thus, we elucidated the effects of S-nitrosylation on ER stress sensors that mediate the UPR, and thus contribute to cell death pathways.
Topics: Animals; Apoptosis; Brain; Endoplasmic Reticulum; Endoplasmic Reticulum Stress; Endoribonucleases; Mutagenesis, Site-Directed; Neurodegenerative Diseases; Nitric Oxide; Protein Disulfide-Isomerases; Protein S; Protein Serine-Threonine Kinases; Ribonucleases; Unfolded Protein Response
PubMed: 27252058
DOI: 10.1248/yakushi.15-00292-1 -
Oral and Maxillofacial Surgery Clinics... Nov 2016Thrombophilia or hypercoagulable conditions can be thought of as either inherited or acquired. The inherited disorders include deficiencies of antithrombin, protein C,... (Review)
Review
Thrombophilia or hypercoagulable conditions can be thought of as either inherited or acquired. The inherited disorders include deficiencies of antithrombin, protein C, or protein S or the common disorders of factor V Leiden and prothrombin G20210A gene mutation. All these disorders are inherited as autosomal dominant and predispose individuals primarily to venous thrombosis. Acquired thrombophilic conditions are seen in individuals with cancer, phospholipid antibodies, and a whole host of other conditions that alter endothelial function, change blood levels of coagulant or anticoagulant proteins, activate platelets, or have other effects on coagulation proteins, platelet function, or the endothelium.
Topics: Antithrombin Proteins; Blood Coagulation Disorders, Inherited; Humans; Mutation; Oral Surgical Procedures; Protein C Deficiency; Protein S Deficiency; Risk Factors; Thrombophilia; Venous Thrombosis
PubMed: 27745619
DOI: 10.1016/j.coms.2016.06.002 -
Journal of the American Chemical Society Aug 2021HS and HO are two redox regulating molecules that play important roles in many physiological and pathological processes. While each of them has distinct biosynthetic...
HS and HO are two redox regulating molecules that play important roles in many physiological and pathological processes. While each of them has distinct biosynthetic pathways and signaling mechanisms, the crosstalk between these two species is also known to cause critical biological responses such as protein S-persulfidation. So far, many chemical tools for the studies of HS and HO have been developed, such as the donors and sensors for HS and HO. However, these tools are normally targeting single species (e.g., only HS or only HO). As such, the crosstalk and synergetic effects between HS and HO have hardly been studied with those tools. In this work, we report a unique HS/HO dual donor system by employing 1-thio-β-d-glucose and glucose oxidase (GOx) as the substrates. This enzymatic system can simultaneously produce HS and HO in a slow and controllable fashion, without generating any bio-unfriendly byproducts. This system was demonstrated to cause efficient S-persulfidation on proteins. In addition, we expanded the system to thiolactose and thioglucose-disulfide; therefore, additional factors (β-galactosidase and cellular reductants) could be introduced to further control the release of HS/HO. This dual release system should be useful for future research on HS and HO.
Topics: Glucose; Glucose Oxidase; Humans; Hydrogen Peroxide; Hydrogen Sulfide; Protein S
PubMed: 34383487
DOI: 10.1021/jacs.1c06372 -
Antioxidants & Redox Signaling Sep 2017Trypanosomatids have a unique trypanothione-based thiol redox metabolism. The parasite-specific dithiol is synthesized from glutathione and spermidine, with...
AIMS
Trypanosomatids have a unique trypanothione-based thiol redox metabolism. The parasite-specific dithiol is synthesized from glutathione and spermidine, with glutathionylspermidine as intermediate catalyzed by trypanothione synthetase. In this study, we address the oxidative stress response of African trypanosomes with special focus on putative protein S-thiolation.
RESULTS
Challenging bloodstream Trypanosoma brucei with diamide, HO or hypochlorite results in distinct levels of reversible overall protein S-thiolation. Quantitative proteome analyses reveal 84 proteins oxidized in diamide-stressed parasites. Fourteen of them, including several essential thiol redox proteins and chaperones, are also enriched when glutathione/glutaredoxin serves as a reducing system indicating S-thiolation. In parasites exposed to HO, other sets of proteins are modified. Only three proteins are S-thiolated under all stress conditions studied in accordance with a highly specific response. HO causes primarily the formation of free disulfides. In contrast, in diamide-treated cells, glutathione, glutathionylspermidine, and trypanothione are almost completely protein bound. Remarkably, the total level of trypanothione is decreased, whereas those of glutathione and glutathionylspermidine are increased, indicating partial hydrolysis of protein-bound trypanothione. Depletion of trypanothione synthetase exclusively induces protein S-glutathionylation. Total mass analyses of a recombinant peroxidase treated with T(SH) and either diamide or hydrogen peroxide verify protein S-trypanothionylation as stable modification.
INNOVATION
Our data reveal for the first time that trypanosomes employ protein S-thiolation when exposed to exogenous and endogenous oxidative stresses and trypanothione, despite its dithiol character, forms protein-mixed disulfides.
CONCLUSION
The stress-specific responses shown here emphasize protein S-trypanothionylation and S-glutathionylation as reversible protection mechanism in these parasites. Antioxid. Redox Signal. 27, 517-533.
Topics: Diamide; Glutathione; Humans; Hydrogen Peroxide; Hypochlorous Acid; Oxidative Stress; Protein S; Proteome; Protozoan Proteins; Spermidine; Sulfhydryl Compounds; Trypanosoma brucei brucei
PubMed: 28338335
DOI: 10.1089/ars.2016.6947 -
Clinical Chemistry and Laboratory... Nov 2015Gestational age-specific reference values are essential for the accurate interpretation of haemostatic tests during pregnancy.
BACKGROUND
Gestational age-specific reference values are essential for the accurate interpretation of haemostatic tests during pregnancy.
METHODS
Our 1-year prospective study included 40 healthy pregnant women with a median age of 30 (range 22-40) years; the subjects were followed in order to establish the gestational age dependent values for endogenous thrombin potential (ETP), D-dimer and protein S (activity and free).
RESULTS
During the first trimester 50% of studied women had ETP >100% (reference values out of pregnancy); in the second trimester an ETP over 100% was observed in all women; ETP values remained unchanged during the third trimester. In the first trimester, the median D-dimer concentration of 0.30 mg/L, in the second 0.91 mg/L and in the third of 1.45 mg/L were observed. During the first trimester 14/40 subjects had protein S activity below reference range (<59%, out of pregnancy); the median value of 61.35; interquartile range (IQR) 20.38; in the second 21/37; the median value of 53.1 (IQR 15.65); in the third trimester 28/37 had low level of protein S activity with the median value of 49.0 (IQR 18.8). Free protein S showed a slight decrease from the first trimester; it remained almost stable during the rest of pregnancy, with the equal number of pregnant women with reduced free protein S.
CONCLUSIONS
Related to the gestational age, a significant increase of ETP and D-dimer, from the second trimester was observed; the decrease of protein S was observed already from the early pregnancy, with more pronounced variability of protein S activity.
Topics: Adult; Female; Fibrin Fibrinogen Degradation Products; Gestational Age; Humans; Pregnancy; Pregnancy Trimesters; Prospective Studies; Protein S; Thrombin; Young Adult
PubMed: 25945720
DOI: 10.1515/cclm-2014-1030 -
Research and Practice in Thrombosis and... Jan 2018FV-Short is a normal splice variant of Factor V (FV) having a short B domain, which exposes a high affinity-binding site for tissue factor pathway inhibitor α (TFPIα)....
BACKGROUND
FV-Short is a normal splice variant of Factor V (FV) having a short B domain, which exposes a high affinity-binding site for tissue factor pathway inhibitor α (TFPIα). FV-Short and TFPIα circulate in complex in plasma.
OBJECTIVES
The aim was to elucidate whether FV-Short affects TFPIα as inhibitor of coagulation FXa and to test whether the TFPIα-cofactor activity of protein S is influenced by FV-Short.
METHODS
Recombinant FV, wild-type FV-Short and a FV-Short thrombin-cleavage resistant variant were expressed and purified. The influence of FV and FV-Short variants and/or protein S on the FXa inhibitory activity of TFPIα was monitored both in a purified system and in a plasma-based thrombin generation assay.
RESULTS
FV-Short had intrinsically weak TFPIα-cofactor activity but with protein S present, FV-Short yielded efficient inactivation of FXa. Protein S alone did not promote full TFPIα-activity. Intact FV was inefficient at low protein S concentrations and had 10-fold lower activity compared to FV-Short at physiological protein S levels. Activation of FV-Short by thrombin resulted in the loss of the TFPIα-cofactor activity. The synergistic TFPIα-cofactor activity of FV-Short and protein S was also demonstrated in plasma using a thrombin generation assay.
CONCLUSIONS
FV-Short and protein S are highly efficient, synergistic cofactors to TFPIα in the regulation of FXa activity, whereas full length FV has lower activity. Our results suggest the formation of an efficient FXa-inhibitory complex between FV-Short, TFPIα and protein S on the surface of negatively charged phospholipids.
PubMed: 30046712
DOI: 10.1002/rth2.12057 -
Cells Dec 2022It has been four decades since protein S-glutathionylation was proposed to serve as a regulator of cell metabolism. Since then, this redox-sensitive covalent... (Review)
Review
BACKGROUND
It has been four decades since protein S-glutathionylation was proposed to serve as a regulator of cell metabolism. Since then, this redox-sensitive covalent modification has been identified as a cell-wide signaling platform required for embryonic development and regulation of many physiological functions.
SCOPE OF THE REVIEW
Mitochondria use hydrogen peroxide (HO) as a second messenger, but its availability must be controlled to prevent oxidative distress and promote changes in cell behavior in response to stimuli. Experimental data favor the function of protein S-glutathionylation as a feedback loop for the inhibition of mitochondrial HO production.
MAJOR CONCLUSIONS
The glutathione pool redox state is linked to the availability of HO, making glutathionylation an ideal mechanism for preventing oxidative distress whilst playing a part in desensitizing mitochondrial redox signals.
GENERAL SIGNIFICANCE
The biological significance of glutathionylation is rooted in redox status communication. The present review critically evaluates the experimental evidence supporting its role in negating mitochondrial HO production for cell signaling and prevention of electrophilic stress.
Topics: Hydrogen Peroxide; Protein S; Mitochondria; Glutathione; Oxidation-Reduction
PubMed: 36611901
DOI: 10.3390/cells12010107 -
[Rinsho Ketsueki] the Japanese Journal... Mar 2016Congenital thrombophilia is a thrombotic diathesis caused by a variety of genetic abnormalities in blood coagulation factors or their inhibitory factors associated with...
Congenital thrombophilia is a thrombotic diathesis caused by a variety of genetic abnormalities in blood coagulation factors or their inhibitory factors associated with physiological thrombus formation. Patients with congenital thrombophilia often present with unusual clinical episodes of venous thrombosis (occasionally combined with pulmonary embolism, known as venous thromboembolism) at a young age and recurrence in atypical vessels, such as the mesenteric vein and superior sagittal sinus, often with a family history of this condition. Studies in Japan as well as in western countries have shown congenital thrombophilia to be caused by a wide variety of genetic abnormalities in natural anticoagulant proteins, such as antithrombin, protein C, and protein S. However, there may still be many unknown causes of hereditary thrombosis. We recently reported a case of hereditary thrombosis induced by a novel mechanism of antithrombin resistance, that is, congenital thrombophilia caused by a gain-of-function mutation in the gene encoding the coagulation factor prothrombin.
Topics: Antithrombins; Humans; Mutation; Protein C; Protein S; Thrombin; Thrombophilia
PubMed: 27076244
DOI: 10.11406/rinketsu.57.315