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Glutathione homeostasis and functions: potential targets for medical interventions.

Lushchak VI - J Amino Acids (2012)

Bottom Line: The ancillary goals are to provide up-to-date knowledge of GSH biosynthesis, hydrolysis, and utilization; intracellular compartmentalization and interorgan transfer; elimination of endogenously produced toxicants; involvement in metal homeostasis; glutathione-related enzymes and their regulation; glutathionylation of sulfhydryls.Special attention is paid to compounds mainly of a natural origin (phytochemicals) which affect GSH-related processes.The paper provides starting points for development of novel tools and provides a hypothesis for investigation of the physiology and biochemistry of glutathione with a focus on human and animal health.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry and Biotechnology, Vassyl Stefanyk Precarpathian National University, 57 Shevchenko Street, Ivano-Frankivsk 76025, Ukraine.

ABSTRACT
Glutathione (GSH) is a tripeptide, which has many biological roles including protection against reactive oxygen and nitrogen species. The primary goal of this paper is to characterize the principal mechanisms of the protective role of GSH against reactive species and electrophiles. The ancillary goals are to provide up-to-date knowledge of GSH biosynthesis, hydrolysis, and utilization; intracellular compartmentalization and interorgan transfer; elimination of endogenously produced toxicants; involvement in metal homeostasis; glutathione-related enzymes and their regulation; glutathionylation of sulfhydryls. Individual sections are devoted to the relationships between GSH homeostasis and pathologies as well as to developed research tools and pharmacological approaches to manipulating GSH levels. Special attention is paid to compounds mainly of a natural origin (phytochemicals) which affect GSH-related processes. The paper provides starting points for development of novel tools and provides a hypothesis for investigation of the physiology and biochemistry of glutathione with a focus on human and animal health.

No MeSH data available.


Related in: MedlinePlus

Oxidation of protein cysteine residues to sulfenic, sulfinic, or sulfonic derivatives and formation of glutathionylated proteins. In biological systems, sulfenic and sulfinic derivatives may be reduced by thioredoxin (TR) and sulfiredoxin (Srx), respectively, whereas sulfonic moieties cannot be reduced. Glutathionylated proteins are formed by direct interaction of GSH with sulfenic acid derivatives, exchange between cysteine residues and GSSG, or interaction with oxidized glutathione forms.
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fig6: Oxidation of protein cysteine residues to sulfenic, sulfinic, or sulfonic derivatives and formation of glutathionylated proteins. In biological systems, sulfenic and sulfinic derivatives may be reduced by thioredoxin (TR) and sulfiredoxin (Srx), respectively, whereas sulfonic moieties cannot be reduced. Glutathionylated proteins are formed by direct interaction of GSH with sulfenic acid derivatives, exchange between cysteine residues and GSSG, or interaction with oxidized glutathione forms.

Mentions: An increase in cellular levels of mixed disulfides formed between GSH and protein thiols, a process called glutathionylation, was demonstrated to be caused by oxidative stress about three decades ago [169–171]. Since that time many studies of the role of glutathionylation have been carried out. Work from the laboratory of Sies and others implicated the process in the regulation of the activity of specific enzymes and certain regulatory pathways [6, 172–176]. From this, glutathionylation was recognised as one of the physiologically relevant mechanisms of posttranslational modification of certain proteins. Exposure of cysteine residues of proteins to ROS leads to their oxidation with the consequent formation of stable sulfenic, sulfinic, or sulfonic acid derivatives and unstable transient forms (Figure 6). Sulfenic acid may be returned to the original cysteine form by several reductases ([6, 177] and cited therein) whereas sulfinic acid can be reduced only by the specific action of sulfiredoxin [178–181]. It is believed that sulfonic acid cannot be reduced in living organisms. Cysteine oxidation to sulfenic acid may be used for ROS sensing and in this case it plays a positive role in cell adaptation. However, more frequently the oxidation may inhibit certain proteins if the oxidized cysteine residues are important for protein function. Therefore, in addition to direct reduction of sulfenic acid to cysteine, living organisms possess other ways of dealing with this moiety (Figure 6). Sulfenic acid residues may interact with reduced glutathione forming mixed disulfides [182, 183]. This issue is not so straightforward, because formation of this dithiol can be implicated in the regulation of some metabolic pathways. Many proteins are subject to glutathionylation and some of them lose biological activity as the result, whereas others may be activated [182]. In human T lymphocytes, Fratelli and colleagues [184] found that cell exposure to oxidants (diamide and H2O2) enhanced glutathionylation of certain proteins. These included cytoskeletal proteins (vimentin, myosin, tropomyosin, cofilin, profilin, and actin), metabolic enzymes (enolase, aldolase, 6-phosphoglucolactonase, adenylate kinase, ubiquitin-conjugating enzyme, phosphoglycerate kinase, triose phosphate isomerase and pyrophosphatase), redox enzymes (peroxiredoxin 1, protein disulfide isomerase, and cytochrome c oxidase), cyclophilin, stress proteins (HSP70 and HSP60), nucleophosmin, transgelin, galectin, and fatty acid binding protein. S-Glutathionylation is thought to be one of the mechanisms preventing ROS-induced irreversible protein inactivation under oxidative stress insults. During recovery, GSH residues can be removed from the glutathionylated proteins resulting in restoration of their functional activity.


Glutathione homeostasis and functions: potential targets for medical interventions.

Lushchak VI - J Amino Acids (2012)

Oxidation of protein cysteine residues to sulfenic, sulfinic, or sulfonic derivatives and formation of glutathionylated proteins. In biological systems, sulfenic and sulfinic derivatives may be reduced by thioredoxin (TR) and sulfiredoxin (Srx), respectively, whereas sulfonic moieties cannot be reduced. Glutathionylated proteins are formed by direct interaction of GSH with sulfenic acid derivatives, exchange between cysteine residues and GSSG, or interaction with oxidized glutathione forms.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3303626&req=5

fig6: Oxidation of protein cysteine residues to sulfenic, sulfinic, or sulfonic derivatives and formation of glutathionylated proteins. In biological systems, sulfenic and sulfinic derivatives may be reduced by thioredoxin (TR) and sulfiredoxin (Srx), respectively, whereas sulfonic moieties cannot be reduced. Glutathionylated proteins are formed by direct interaction of GSH with sulfenic acid derivatives, exchange between cysteine residues and GSSG, or interaction with oxidized glutathione forms.
Mentions: An increase in cellular levels of mixed disulfides formed between GSH and protein thiols, a process called glutathionylation, was demonstrated to be caused by oxidative stress about three decades ago [169–171]. Since that time many studies of the role of glutathionylation have been carried out. Work from the laboratory of Sies and others implicated the process in the regulation of the activity of specific enzymes and certain regulatory pathways [6, 172–176]. From this, glutathionylation was recognised as one of the physiologically relevant mechanisms of posttranslational modification of certain proteins. Exposure of cysteine residues of proteins to ROS leads to their oxidation with the consequent formation of stable sulfenic, sulfinic, or sulfonic acid derivatives and unstable transient forms (Figure 6). Sulfenic acid may be returned to the original cysteine form by several reductases ([6, 177] and cited therein) whereas sulfinic acid can be reduced only by the specific action of sulfiredoxin [178–181]. It is believed that sulfonic acid cannot be reduced in living organisms. Cysteine oxidation to sulfenic acid may be used for ROS sensing and in this case it plays a positive role in cell adaptation. However, more frequently the oxidation may inhibit certain proteins if the oxidized cysteine residues are important for protein function. Therefore, in addition to direct reduction of sulfenic acid to cysteine, living organisms possess other ways of dealing with this moiety (Figure 6). Sulfenic acid residues may interact with reduced glutathione forming mixed disulfides [182, 183]. This issue is not so straightforward, because formation of this dithiol can be implicated in the regulation of some metabolic pathways. Many proteins are subject to glutathionylation and some of them lose biological activity as the result, whereas others may be activated [182]. In human T lymphocytes, Fratelli and colleagues [184] found that cell exposure to oxidants (diamide and H2O2) enhanced glutathionylation of certain proteins. These included cytoskeletal proteins (vimentin, myosin, tropomyosin, cofilin, profilin, and actin), metabolic enzymes (enolase, aldolase, 6-phosphoglucolactonase, adenylate kinase, ubiquitin-conjugating enzyme, phosphoglycerate kinase, triose phosphate isomerase and pyrophosphatase), redox enzymes (peroxiredoxin 1, protein disulfide isomerase, and cytochrome c oxidase), cyclophilin, stress proteins (HSP70 and HSP60), nucleophosmin, transgelin, galectin, and fatty acid binding protein. S-Glutathionylation is thought to be one of the mechanisms preventing ROS-induced irreversible protein inactivation under oxidative stress insults. During recovery, GSH residues can be removed from the glutathionylated proteins resulting in restoration of their functional activity.

Bottom Line: The ancillary goals are to provide up-to-date knowledge of GSH biosynthesis, hydrolysis, and utilization; intracellular compartmentalization and interorgan transfer; elimination of endogenously produced toxicants; involvement in metal homeostasis; glutathione-related enzymes and their regulation; glutathionylation of sulfhydryls.Special attention is paid to compounds mainly of a natural origin (phytochemicals) which affect GSH-related processes.The paper provides starting points for development of novel tools and provides a hypothesis for investigation of the physiology and biochemistry of glutathione with a focus on human and animal health.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry and Biotechnology, Vassyl Stefanyk Precarpathian National University, 57 Shevchenko Street, Ivano-Frankivsk 76025, Ukraine.

ABSTRACT
Glutathione (GSH) is a tripeptide, which has many biological roles including protection against reactive oxygen and nitrogen species. The primary goal of this paper is to characterize the principal mechanisms of the protective role of GSH against reactive species and electrophiles. The ancillary goals are to provide up-to-date knowledge of GSH biosynthesis, hydrolysis, and utilization; intracellular compartmentalization and interorgan transfer; elimination of endogenously produced toxicants; involvement in metal homeostasis; glutathione-related enzymes and their regulation; glutathionylation of sulfhydryls. Individual sections are devoted to the relationships between GSH homeostasis and pathologies as well as to developed research tools and pharmacological approaches to manipulating GSH levels. Special attention is paid to compounds mainly of a natural origin (phytochemicals) which affect GSH-related processes. The paper provides starting points for development of novel tools and provides a hypothesis for investigation of the physiology and biochemistry of glutathione with a focus on human and animal health.

No MeSH data available.


Related in: MedlinePlus