Glutathione is a universally distributed tripeptide composed of three amino acids: glycine, cysteine and glutamic acid. The thiol group of cysteine is the key functional component of the molecule responsible for its biological activity. The structure of glutathione is unique in that the N-terminal glutamate and cysteine residues are bonded through the γ-carboxyl group of glutamate, rather than utilizing the α-carboxyl group to form the traditional peptide bond in proteins. The presence of this bond therefore makes glutathione relatively stable and resistant to intracellular degradation.
Initially, it was thought that this unusual bond could only be hydrolyzed by γ-glutamyl transpeptidase (GGT), an essential enzyme located in the plasma membrane of specific cell types. However, it has been shown that the CHAC1 protein, found in higher eukaryotes, has γ-glutamylcyclotransferase activity and also specifically degrades intracellular glutathione.
In most cells, glutathione is found at concentrations of 1-10 mM in the cytoplasm and at lower concentrations in subcellular organelles, including the nucleus, mitochondria, and endoplasmic reticulum. The tripeptide exists predominantly in the reduced (GSH) and oxidized (GSSG) forms, and the ratio between them (GSH:GSSG) is used as a marker to determine the presence of oxidative stress. In addition, the GSH:GSSG ratio is critical for creating cellular compartments with unique redox characteristics. For example, in the active reducing environment of the cytoplasm, it is difficult to form intramolecular and intermolecular protein disulfides when the GSH:GSSG ratio exceeds 100:1. However, the endoplasmic reticulum, with GSH:GSSG ratios ranging from 1:1 to 3:1, provides a much more oxidizing environment to allow oxidative protein folding . Therefore, an optimal GSH/GSSG ratio must be maintained for physiological processes to occur.
Glutathione plays important intracellular roles including, but not limited to, antioxidant defense, maintenance of redox potential, redox signaling, and regulation of cell growth and death. pK a of the GSH thiol group is approximately 9.6, conferring low reactivity to the molecule. Thus, although glutathione can directly scavenge ROS and exogenous substances, enzyme-catalyzed elimination is faster. Glutathione S-transferase (GST) lowers the pKa of the GSH thiol group to catalyze the nucleophilic addition of tripeptides to xenobiotics. Similarly, most of the glutathione in the antioxidant defense is utilized by glutathione peroxidases. These enzymes catalyze the reduction of H 2 O 2 to H 2 O through the coupled oxidation of GSH to GSSG, which is subsequently reduced back to GSH by glutathione reductase and NADPH.Other enzymes that require thiol-reducing equivalents, such as peroxiredoxins and glutaredoxins, also utilize glutathione as a reductant, restoring their oxidation-sensitive active sites to their reduced state by maintaining them in a Enzyme function.
The aging process is a complex phenomenon, broadly defined as the progressive decline of physiological functions accompanied by a variety of pathological conditions. Several theories have been proposed to explain the aging process, including the oxidative stress theory, which proposes that the elevated levels of ROS that accompany aging lead to altered function of cellular macromolecules. In addition to increased ROS production, a study by Zhu et al. showed that GSH levels as well as GSH:GSSG ratios were significantly reduced in the brains of aged rats.
Glutathione as a dietary supplement has a variety of systemic effects, such as improving liver abnormalities, ameliorating diabetic complications, and preventing viral infections, among others, and studies have shown that glutathione supplementation can help to reverse the signs of premature aging caused by free radical damage.
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