GSTA4 explained

Glutathione S-transferase A4, also known as GSTA4, is an enzyme which in humans is encoded by the GSTA4 gene.^{[1] [2] [3]}

Function

Cytosolic and membrane-bound forms of glutathione S-transferase are encoded by two distinct supergene families. These enzymes are involved in cellular defense against toxic, carcinogenic, and pharmacologically active electrophilic compounds. At present, eight distinct classes of the soluble cytoplasmic mammalian glutathione S-transferases have been identified: alpha, kappa, mu, omega, pi, sigma, theta and zeta. This gene encodes a glutathione S-transferase belonging to the alpha class. The alpha class genes, which are located in a cluster on chromosome 6, are highly related and encode enzymes with glutathione peroxidase activity that function in the detoxification of lipid peroxidation products.^[1]

GSTA4 shows very high activity with reactive carbonyl compounds such as alk-2-enals.^[2] GSTA4 is highly effective in catalyzing the conjugate addition of reduced glutathione to 4-hydroxynonenal, an important product of peroxidative degradation of arachidonic acid and a commonly used biomarker for oxidative damage in tissue.^[3]

Clinical significance

Reactive electrophiles produced by oxidative metabolism have been linked to a number of degenerative diseases including Parkinson's disease, Alzheimer's disease, cataract formation, and atherosclerosis hence reduced expression of the GSTA4 enzyme may have pathophysiological consequences.^[1] The expression of this gene is decreased drastically among burn and trauma victims.

Further reading

• Ketterer B . A bird's eye view of the glutathione transferase field . Chem. Biol. Interact. . 138 . 1 . 27–42 . 2001 . 11640913 . 10.1016/S0009-2797(01)00277-0 . 2001CBI...138...27K .
• Hubatsch I, Ridderström M, Mannervik B . Human glutathione transferase A4-4: an alpha class enzyme with high catalytic efficiency in the conjugation of 4-hydroxynonenal and other genotoxic products of lipid peroxidation . Biochem. J. . 330 . Pt 1. 175–9 . 1998 . 9461507 . 10.1042/bj3300175. 1219124 .
• Board PG . Identification of cDNAs encoding two human alpha class glutathione transferases (GSTA3 and GSTA4) and the heterologous expression of GSTA4-4 . Biochem. J. . 330 . Pt 2. 827–31 . 1998 . 9480897 . 10.1042/bj3300827. 1219212 .
• Liu S, Stoesz SP, Pickett CB . Identification of a novel human glutathione S-transferase using bioinformatics . Arch. Biochem. Biophys. . 352 . 2 . 306–13 . 1998 . 9587421 . 10.1006/abbi.1998.0608 .
• Desmots F, Rauch C, Henry C, etal . Genomic organization, 5'-flanking region and chromosomal localization of the human glutathione transferase A4 gene . Biochem. J. . 336 . Pt 2. 437–42 . 1999 . 9820822 . 10.1042/bj3360437. 1219889 .
• Bruns CM, Hubatsch I, Ridderström M, etal . Human glutathione transferase A4-4 crystal structures and mutagenesis reveal the basis of high catalytic efficiency with toxic lipid peroxidation products . J. Mol. Biol. . 288 . 3 . 427–39 . 1999 . 10329152 . 10.1006/jmbi.1999.2697 .
• Gardner JL, Gallagher EP . Development of a peptide antibody specific to human glutathione S-transferase alpha 4-4 (hGSTA4-4) reveals preferential localization in human liver mitochondria . Arch. Biochem. Biophys. . 390 . 1 . 19–27 . 2001 . 11368510 . 10.1006/abbi.2001.2352 .
• Nilsson LO, Mannervik B . Improved heterologous expression of human glutathione transferase A4-4 by random silent mutagenesis of codons in the 5' region . Biochim. Biophys. Acta . 1528 . 2–3 . 101–6 . 2001 . 11687296 . 10.1016/s0304-4165(01)00177-5.
• Desmots F, Rissel M, Loyer P, etal . Immunohistological analysis of glutathione transferase A4 distribution in several human tissues using a specific polyclonal antibody . J. Histochem. Cytochem. . 49 . 12 . 1573–80 . 2002 . 11724905 . 10.1177/002215540104901211. 3114685 .
• Gustafsson A, Nilsson LO, Mannervik B . Hybridization of alpha class subunits generating a functional glutathione transferase A1-4 heterodimer . J. Mol. Biol. . 316 . 2 . 395–406 . 2002 . 11851347 . 10.1006/jmbi.2001.5345 .
• Desmots F, Rissel M, Gilot D, etal . Pro-inflammatory cytokines tumor necrosis factor alpha and interleukin-6 and survival factor epidermal growth factor positively regulate the murine GSTA4 enzyme in hepatocytes . J. Biol. Chem. . 277 . 20 . 17892–900 . 2002 . 11884396 . 10.1074/jbc.M112351200 . free .
• Gallagher EP, Gardner JL . Comparative expression of two alpha class glutathione S-transferases in human adult and prenatal liver tissues . Biochem. Pharmacol. . 63 . 11 . 2025–36 . 2002 . 12093480 . 10.1016/S0006-2952(02)01017-1 .
• Strausberg RL, Feingold EA, Grouse LH, etal . Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences . Proc. Natl. Acad. Sci. U.S.A. . 99 . 26 . 16899–903 . 2003 . 12477932 . 10.1073/pnas.242603899 . 139241 . 2002PNAS...9916899M . free .
• Mungall AJ, Palmer SA, Sims SK, etal . The DNA sequence and analysis of human chromosome 6 . Nature . 425 . 6960 . 805–11 . 2003 . 14574404 . 10.1038/nature02055 . 2003Natur.425..805M . free .
• Ota T, Suzuki Y, Nishikawa T, etal . Complete sequencing and characterization of 21,243 full-length human cDNAs . Nat. Genet. . 36 . 1 . 40–5 . 2004 . 14702039 . 10.1038/ng1285 . free .
• Engle MR, Singh SP, Czernik PJ, etal . Physiological role of mGSTA4-4, a glutathione S-transferase metabolizing 4-hydroxynonenal: generation and analysis of mGsta4 null mouse . Toxicol. Appl. Pharmacol. . 194 . 3 . 296–308 . 2004 . 14761685 . 10.1016/j.taap.2003.10.001 .
• Gerhard DS, Wagner L, Feingold EA, etal . The Status, Quality, and Expansion of the NIH Full-Length cDNA Project: The Mammalian Gene Collection (MGC) . Genome Res. . 14 . 10B . 2121–7 . 2004 . 15489334 . 10.1101/gr.2596504 . 528928 .
• Patrick B, Li J, Jeyabal PV, etal . Depletion of 4-hydroxynonenal in hGSTA4-transfected HLE B-3 cells results in profound changes in gene expression . Biochem. Biophys. Res. Commun. . 334 . 2 . 425–32 . 2005 . 16005854 . 10.1016/j.bbrc.2005.06.099 .
• Coppedè F, Armani C, Bidia DD, etal . Molecular implications of the human glutathione transferase A-4 gene (hGSTA4) polymorphisms in neurodegenerative diseases . Mutat. Res. . 579 . 1–2 . 107–14 . 2005 . 16054170 . 10.1016/j.mrfmmm.2005.02.020 .

Notes and References

1. Web site: Entrez Gene: GSTA4 glutathione S-transferase A4.
2. Board PG . Identification of cDNAs encoding two human alpha class glutathione transferases (GSTA3 and GSTA4) and the heterologous expression of GSTA4-4 . Biochem. J. . 330 . Pt 2. 827–31 . March 1998 . 9480897 . 1219212 . 10.1042/bj3300827.
3. Hubatsch I, Ridderström M, Mannervik B . Human glutathione transferase A4-4: an alpha class enzyme with high catalytic efficiency in the conjugation of 4-hydroxynonenal and other genotoxic products of lipid peroxidation . Biochem. J. . 330 . Pt 1. 175–9 . February 1998 . 9461507 . 1219124 . 10.1042/bj3300175.