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The Journal of Nutrition Mar 2004Glutathione (gamma-glutamyl-cysteinyl-glycine; GSH) is the most abundant low-molecular-weight thiol, and GSH/glutathione disulfide is the major redox couple in animal... (Review)
Review
Glutathione (gamma-glutamyl-cysteinyl-glycine; GSH) is the most abundant low-molecular-weight thiol, and GSH/glutathione disulfide is the major redox couple in animal cells. The synthesis of GSH from glutamate, cysteine, and glycine is catalyzed sequentially by two cytosolic enzymes, gamma-glutamylcysteine synthetase and GSH synthetase. Compelling evidence shows that GSH synthesis is regulated primarily by gamma-glutamylcysteine synthetase activity, cysteine availability, and GSH feedback inhibition. Animal and human studies demonstrate that adequate protein nutrition is crucial for the maintenance of GSH homeostasis. In addition, enteral or parenteral cystine, methionine, N-acetyl-cysteine, and L-2-oxothiazolidine-4-carboxylate are effective precursors of cysteine for tissue GSH synthesis. Glutathione plays important roles in antioxidant defense, nutrient metabolism, and regulation of cellular events (including gene expression, DNA and protein synthesis, cell proliferation and apoptosis, signal transduction, cytokine production and immune response, and protein glutathionylation). Glutathione deficiency contributes to oxidative stress, which plays a key role in aging and the pathogenesis of many diseases (including kwashiorkor, seizure, Alzheimer's disease, Parkinson's disease, liver disease, cystic fibrosis, sickle cell anemia, HIV, AIDS, cancer, heart attack, stroke, and diabetes). New knowledge of the nutritional regulation of GSH metabolism is critical for the development of effective strategies to improve health and to treat these diseases.
Topics: Cysteine; Glutamic Acid; Glutathione; Glycine; Health; Humans
PubMed: 14988435
DOI: 10.1093/jn/134.3.489 -
Molecular Aspects of Medicine 2009This review is the introduction to a special issue concerning, glutathione (GSH), the most abundant low molecular weight thiol compound synthesized in cells. GSH plays... (Review)
Review
This review is the introduction to a special issue concerning, glutathione (GSH), the most abundant low molecular weight thiol compound synthesized in cells. GSH plays critical roles in protecting cells from oxidative damage and the toxicity of xenobiotic electrophiles, and maintaining redox homeostasis. Here, the functions and GSH and the sources of oxidants and electrophiles, the elimination of oxidants by reduction and electrophiles by conjugation with GSH are briefly described. Methods of assessing GSH status in the cells are also described. GSH synthesis and its regulation are addressed along with therapeutic approaches for manipulating GSH content that have been proposed. The purpose here is to provide a brief overview of some of the important aspects of glutathione metabolism as part of this special issue that will provide a more comprehensive review of the state of knowledge regarding this essential molecule.
Topics: Animals; Glutamate-Cysteine Ligase; Glutathione; Humans; Molecular Structure
PubMed: 18796312
DOI: 10.1016/j.mam.2008.08.006 -
Nutrients Sep 2019Glutathione is a tripeptide that plays a pivotal role in critical physiological processes resulting in effects relevant to diverse disease pathophysiology such as... (Review)
Review
Glutathione is a tripeptide that plays a pivotal role in critical physiological processes resulting in effects relevant to diverse disease pathophysiology such as maintenance of redox balance, reduction of oxidative stress, enhancement of metabolic detoxification, and regulation of immune system function. The diverse roles of glutathione in physiology are relevant to a considerable body of evidence suggesting that glutathione status may be an important biomarker and treatment target in various chronic, age-related diseases. Yet, proper personalized balance in the individual is key as well as a better understanding of antioxidants and redox balance. Optimizing glutathione levels has been proposed as a strategy for health promotion and disease prevention, although clear, causal relationships between glutathione status and disease risk or treatment remain to be clarified. Nonetheless, human clinical research suggests that nutritional interventions, including amino acids, vitamins, minerals, phytochemicals, and foods can have important effects on circulating glutathione which may translate to clinical benefit. Importantly, genetic variation is a modifier of glutathione status and influences response to nutritional factors that impact glutathione levels. This narrative review explores clinical evidence for nutritional strategies that could be used to improve glutathione status.
Topics: Diet; Gene Expression Regulation; Glutathione; Humans; Phytochemicals
PubMed: 31484368
DOI: 10.3390/nu11092073 -
Molecular Aspects of Medicine 2009Glutathione (GSH) is a ubiquitous intracellular peptide with diverse functions that include detoxification, antioxidant defense, maintenance of thiol status, and... (Review)
Review
Glutathione (GSH) is a ubiquitous intracellular peptide with diverse functions that include detoxification, antioxidant defense, maintenance of thiol status, and modulation of cell proliferation. GSH is synthesized in the cytosol of all mammalian cells in a tightly regulated manner. The major determinants of GSH synthesis are the availability of cysteine, the sulfur amino acid precursor, and the activity of the rate-limiting enzyme, glutamate cysteine ligase (GCL). GCL is composed for a catalytic (GCLC) and modifier (GCLM) subunit and they are regulated at multiple levels and at times differentially. The second enzyme of GSH synthesis, GSH synthase (GS) is also regulated in a coordinated manner as GCL subunits and its up-regulation can further enhance the capacity of the cell to synthesize GSH. Oxidative stress is well known to induce the expression of GSH synthetic enzymes. Key transcription factors identified thus far include Nrf2/Nrf1 via the antioxidant response element (ARE), activator protein-1 (AP-1) and nuclear factor kappa B (NFkappaB). Dysregulation of GSH synthesis is increasingly being recognized as contributing to the pathogenesis of many pathological conditions. These include diabetes mellitus, pulmonary fibrosis, cholestatic liver injury, endotoxemia and drug-resistant tumor cells. Manipulation of the GSH synthetic capacity is an important target in the treatment of many of these disorders.
Topics: Animals; Glutamate-Cysteine Ligase; Glutathione; Glutathione Synthase; Humans; Models, Biological
PubMed: 18601945
DOI: 10.1016/j.mam.2008.05.005 -
Free Radical Biology & Medicine Dec 2015The multifaceted functions of reduced glutathione (gamma-glutamyl-cysteinyl-glycine; GSH) continue to fascinate plants and animal scientists, not least because of the... (Review)
Review
SIGNIFICANCE
The multifaceted functions of reduced glutathione (gamma-glutamyl-cysteinyl-glycine; GSH) continue to fascinate plants and animal scientists, not least because of the dynamic relationships between GSH and reactive oxygen species (ROS) that underpin reduction/oxidation (redox) regulation and signalling. Here we consider the respective roles of ROS and GSH in the regulation of plant growth, with a particular focus on regulation of the plant cell cycle. Glutathione is discussed not only as a crucial low molecular weight redox buffer that shields nuclear processes against oxidative challenge but also a flexible regulator of genetic and epigenetic functions.
RECENT ADVANCES
The intracellular compartmentalization of GSH during the cell cycle is remarkably consistent in plants and animals. Moreover, measurements of in vivo glutathione redox potentials reveal that the cellular environment is much more reducing than predicted from GSH/GSSG ratios measured in tissue extracts. The redox potential of the cytosol and nuclei of non-dividing plant cells is about -300 mV. This relatively low redox potential maintained even in cells experiencing oxidative stress by a number of mechanisms including vacuolar sequestration of GSSG. We propose that regulated ROS production linked to glutathione-mediated signalling events are the hallmark of viable cells within a changing and challenging environment.
CRITICAL ISSUES
The concept that the cell cycle in animals is subject to redox controls is well established but little is known about how ROS and GSH regulate this process in plants. However, it is increasingly likely that redox controls exist in plants, although possibly through different pathways. Moreover, redox-regulated proteins that function in cell cycle checkpoints remain to be identified in plants. While GSH-responsive genes have now been identified, the mechanisms that mediate and regulate protein glutathionylation in plants remain poorly defined.
FUTURE DIRECTIONS
The nuclear GSH pool provides an appropriate redox environment for essential nuclear functions. Future work will focus on how this essential thiol interacts with the nuclear thioredoxin system and nitric oxide to regulate genetic and epigenetic mechanisms. The characterization of redox-regulated cell cycle proteins in plants, and the elucidation of mechanisms that facilitate GSH accumulation in the nucleus are keep steps to unravelling the complexities of nuclear redox controls.
Topics: Animals; Cell Proliferation; Glutathione; Humans; Oxidation-Reduction; Oxidative Stress
PubMed: 26546102
DOI: 10.1016/j.freeradbiomed.2015.09.023 -
Advances in Cancer Research 2021Cisplatin has been a mainstay of cancer chemotherapy since the 1970s. Despite its broad anticancer potential, its clinical use has regularly been constrained by kidney... (Review)
Review
Cisplatin has been a mainstay of cancer chemotherapy since the 1970s. Despite its broad anticancer potential, its clinical use has regularly been constrained by kidney toxicities. This review details those biochemical pathways and metabolic conversions that underlie the kidney toxicities. A wide range of redox events contribute to the eventual physiological consequences of drug activities.
Topics: Antineoplastic Agents; Antioxidants; Cisplatin; Glutathione; Humans; Kidney; Neoplasms; Oxidative Stress
PubMed: 34353441
DOI: 10.1016/bs.acr.2021.03.008 -
Oxidative Medicine and Cellular... 2019Glutathione is the principal intracellular antioxidant buffer against oxidative stress and mainly exists in the forms of reduced glutathione (GSH) and oxidized... (Review)
Review
Glutathione is the principal intracellular antioxidant buffer against oxidative stress and mainly exists in the forms of reduced glutathione (GSH) and oxidized glutathione (GSSG). The processes of glutathione synthesis, transport, utilization, and metabolism are tightly controlled to maintain intracellular glutathione homeostasis and redox balance. As for cancer cells, they exhibit a greater ROS level than normal cells in order to meet the enhanced metabolism and vicious proliferation; meanwhile, they also have to develop an increased antioxidant defense system to cope with the higher oxidant state. Growing numbers of studies have implicated that altering the glutathione antioxidant system is associated with multiple forms of programmed cell death in cancer cells. In this review, we firstly focus on glutathione homeostasis from the perspectives of glutathione synthesis, distribution, transportation, and metabolism. Then, we discuss the function of glutathione in the antioxidant process. Afterwards, we also summarize the recent advance in the understanding of the mechanism by which glutathione plays a key role in multiple forms of programmed cell death, including apoptosis, necroptosis, ferroptosis, and autophagy. Finally, we highlight the glutathione-targeting therapeutic approaches toward cancers. A comprehensive review on the glutathione homeostasis and the role of glutathione depletion in programmed cell death provide insight into the redox-based research concerning cancer therapeutics.
Topics: Cell Death; Glutathione; Humans; Neoplasms
PubMed: 31281572
DOI: 10.1155/2019/3150145 -
Biochimica Et Biophysica Acta May 2013S-Nitrosoglutathione (GSNO) is the S-nitrosated derivative of glutathione and is thought to be a critical mediator of the down stream signaling effects of nitric oxide... (Review)
Review
BACKGROUND
S-Nitrosoglutathione (GSNO) is the S-nitrosated derivative of glutathione and is thought to be a critical mediator of the down stream signaling effects of nitric oxide (NO). GSNO has also been implicated as a contributor to various disease states.
SCOPE OF REVIEW
This review focuses on the chemical nature of GSNO, its biological activities, the evidence that it is an endogenous mediator of NO action, and implications for therapeutic use.
MAJOR CONCLUSIONS
GSNO clearly exerts its cellular actions through both NO- and S-nitrosation-dependent mechanisms; however, the chemical and biological aspects of this compound should be placed in the context of S-nitrosation as a whole.
GENERAL SIGNIFICANCE
GSNO is a central intermediate in formation and degradation of cellular S-nitrosothiols with potential therapeutic applications; thus, it remains an important molecule of study. This article is part of a Special Issue entitled Cellular functions of glutathione.
Topics: Animals; Glutathione; Humans; Nitric Oxide; Nitrosation; S-Nitrosoglutathione; S-Nitrosothiols
PubMed: 23416062
DOI: 10.1016/j.bbagen.2013.02.004 -
Current Opinion in Chemical Biology Dec 2022Metallodrugs that are redox sensitive or have labile coordination sites are particularly susceptible to inhibition by glutathione (GSH) and other endogenous thiols.... (Review)
Review
Metallodrugs that are redox sensitive or have labile coordination sites are particularly susceptible to inhibition by glutathione (GSH) and other endogenous thiols. Because GSH is an essential antioxidant, strategies to prevent thiol deactivation must consider their potential effects on normal cellular functions. In this short review, we describe general approaches for taming glutathione in metallodrug therapy and discuss their strengths and limitations. We also offer our perspectives on developing practical solutions that are effective and clinically relevant.
Topics: Glutathione; Oxidation-Reduction; Sulfhydryl Compounds; Antioxidants
PubMed: 36206677
DOI: 10.1016/j.cbpa.2022.102213 -
International Journal of Molecular... Jan 2022Extracellular glutathione (GSH) and oxidized glutathione (GSSG) can modulate the function of the extracellular calcium sensing receptor (CaSR). The CaSR has a binding... (Review)
Review
Extracellular glutathione (GSH) and oxidized glutathione (GSSG) can modulate the function of the extracellular calcium sensing receptor (CaSR). The CaSR has a binding pocket in the extracellular domain of CaSR large enough to bind either GSH or GSSG, as well as the naturally occurring oxidized derivative L-cysteine glutathione disulfide (CySSG) and the compound cysteinyl glutathione (CysGSH). Modeling the binding energies (ΔG) of CySSG and CysGSH to CaSR reveals that both cysteine derivatives may have greater affinities for CaSR than either GSH or GSSG. GSH, CySSG, and GSSG are found in circulation in mammals and, among the three, CySSG is more affected by HIV/AIDs and aging than either GSH or GSSG. The beta-carbon linkage of cysteine in CysGSH may model a new class of calcimimetics, exemplified by etelcalcetide. Circulating glutathionergic compounds, particularly CySSG, may mediate calcium-regulatory responses via receptor-binding to CaSR in a variety of organs, including parathyroids, kidneys, and bones. Receptor-mediated actions of glutathionergics may thus complement their roles in redox regulation and detoxification. The glutathionergic binding site(s) on CaSR are suggested to be a target for development of drugs that can be used in treating kidney and other diseases whose mechanisms involve CaSR dysregulation.
Topics: Animals; Biomarkers; Calcium; Cysteine; Extracellular Space; Glutathione; Glutathione Disulfide; Humans; Molecular Structure; Organ Specificity; Oxidation-Reduction; Protein Binding; Receptors, Calcium-Sensing; Structure-Activity Relationship
PubMed: 35054903
DOI: 10.3390/ijms23020717