Glutathione Metabolism and Its Implications for Health

Abstract

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.

Protective effect of arginine on oxidative stress in transgenic sickle mouse models

“…The higher GSH activity in BERK mice as compared with less severe NY1DD mice may be a protective response to a greater oxidative stress in this model caused by recurring ischemic-reperfusion events, increased levels of inflammatory cytokines and higher levels of protein nitration [16] that are known to enhance GSH synthesis [34]. GSH effectively scavenges reactive oxygen species directly and indirectly via enzymatic reactions [45]. Furthermore, GPx catalyzes GSH-dependent reduction of H 2 O 2 and other peroxides [20].…”

Has removal of excess cysteine led to the evolution of pheomelanin?

“…Dopaquinone then reacts with thiol groups to synthesize pheomelanin, or, in the absence of thiol groups, suffers a cyclization that leads to the synthesis of eumelanin [3]. Thiol groups that react with dopaquinone are provided by free cysteine or by the cysteine-containing tripeptide glutathione (GSH) [11], which is the main physiological reservoir of cysteine and the most important intracellular antioxidant [12]. This means that pheomelanogenesis requires a constant supply of cysteine via GSH, thus lowering the levels of this important antioxidant [13].…”

Luciferase and Luciferin Co-immobilized Mesoporous Silica Nanoparticle Materials for Intracellular Biocatalysis

“…6À8 For example, a key metabolite involved in maintaining a reduced intracellular redox milieu is the tripeptide glutathione (GSH). 9 GSH has long been suggested to be part of signaling cascades transuding environmental signals to the nucleus, and its elevated concentration in many types of tumors is often associated with an increased resistance to chemo-and radiotherapy. 8 Likewise, as biological energy, adenosine triphosphate (ATP) is involved in a multitude of important intracellular physiological processes, such as protein metabolism and cell apoptosis, the level of which is a measure of tumor cell viability and growth.…”