Several isozymes are encoded by different genes, which vary in cellular location and substrate specificity. Glutathione peroxidase 1 is the most abundant version, found in the cytoplasm of nearly all mammalian tissues, whose preferred substrate is hydrogen peroxide. Glutathione peroxidase 4 has a high preference for lipid hydroperoxides; it is expressed in nearly every mammalian cell, though at much lower levels. Glutathione peroxidase 2 is an intestinal and extracellular enzyme, while glutathione peroxidase 3 is extracellular, especially abundant in plasma. So far, eight different isoforms of glutathione peroxidase have been identified in humans.
The main reaction that glutathione peroxidase catalyzes is: where GSH represents reduced monomeric glutathione, and GS–SG represents glutathione disulfide. The mechanism involves oxidation of the selenol of a selenocysteine residue by hydrogen peroxide. This process gives the derivative with a selenenic acid group. The selenenic acid is then converted back to the selenol by a two step process that begins with reaction with GSH to form the GS-SeR and water. A second GSH molecule reduces the GS-SeR intermediate back to the selenol, releasing GS-SG as the by-product. A simplified representation is shown below: Glutathione reductase then reduces the oxidized glutathione to complete the cycle:
Structure
Mammalian GPx1, GPx2, GPx3, and GPx4 have been shown to be selenium-containing enzymes, whereas GPx6 is a selenoprotein in humans with cysteine-containing homologues in rodents. GPx1, GPx2, and GPx3 are homotetrameric proteins, whereas GPx4 has a monomeric structure. As the integrity of the cellular and subcellular membranes depends heavily on glutathione peroxidase, its antioxidative protective system itself depends heavily on the presence of selenium.
Animal models
Mice genetically engineered to lack glutathione peroxidase 1 are grossly phenotypically normal and have normal lifespans, indicating this enzyme is not critical for life. However, Gpx1−/− mice develop cataracts at an early age and exhibit defects in muscle satellite cell proliferation. Gpx1 −/− mice showed up to 16 dB higher auditory brainstem response thresholds than control mice. After 110 dB noise exposure for one hour, Gpx1 −/− mice had up to 15 dB greater noise-induced hearing loss compared with control mice." Mice with knockouts for GPX3 or GPX2 also develop normally However, glutathione peroxidase 4 knockout mice die during early embryonic development. Some evidence, though, indicates reduced levels of glutathione peroxidase 4 can increase life expectancy in mice. The bovine erythrocyte enzyme has a molecular weight of 84 kDa.
Discovery
Glutathione peroxidase was discovered in 1957 by Gordon C. Mills.
Clinical significance
It has been shown that low levels of glutathione peroxidase as measured in the serum may be a contributing factor to vitiligo. Lower plasma glutathione peroxide levels were also observed in patients with type 2 diabetes with macroalbuminuria and this was correlated to the stage of diabetic nephropathy. In one study, the activity of glutathione peroxidase along with other antioxidant enzymes such as superoxide dismutase and catalase was not associated with coronary heart disease risk in women. Glutathione peroxidase activity was found to be much lower in patients with relapsing-remitting multiple sclerosis. One study has suggested that glutathione peroxidase and superoxide dismutase polymorphisms play a role in the development of celiac disease.
