Disease relevance of GSTA4

• The encoded GSTA4-4 enzyme was expressed in Escherichia coli and was found to be immunologically distinct from GSTA1-1 and to have high activity with alk-2-enals [1].
• Molecular implications of the human glutathione transferase A-4 gene (hGSTA4) polymorphisms in neurodegenerative diseases [2].
• These findings are consistent with capillary growth by subdivision being the main mechanism of glomerular hypertrophy when nephron loss occurs during childhood, and the identity of the regressions of N versus GTA4 in RN and controls suggests that compensatory hypertrophy resembles the normal glomerular growth pattern in this age group [3].

High impact information on GSTA4

• Butyrate induced GSTP1, GSTM2, and GSTA4 in HT29 as previously confirmed by other methods (northern blot/qPCR) [4].
• By searching the human genome sequence database with human hGSTA1 and hGSTA4 cDNA sequences, we identified three PAC and one BAC clones covering more than 400 kilobases and containing the entire GST alpha gene cluster [5].
• Identification of cDNAs encoding two human alpha class glutathione transferases (GSTA3 and GSTA4) and the heterologous expression of GSTA4-4 [1].
• A second cDNA, termed GSTA4, was identified in a brain cDNA library [1].
• The homodimeric protein hGSTA4-4, is involved in the detoxification of 4-hydroxynonenal and other reactive electrophiles produced by oxidative metabolism, and may have a significant role in protecting intracellular components from oxidative damage [6].

Biological context of GSTA4

• Northern analysis demonstrated the presence of hGSTA1 and/or A2 (hGSTA1/2) and hGSTA4 steady-state mRNAs in second trimester prenatal livers [7].
• Incubation of HT29 cells with butyrate (2-4 mM) significantly elicited a 1.8 to 3-fold upregulation of steady state hGSTA4 mRNA over 8-24 h after treatment [8].
• In the present study, we have investigated in HT29 cells whether hGSTA4-4, which has a high substrate specificity for HNE, was also inducible by butyrate and, thus, could contribute to the previously observed chemoresistance [8].
• We have isolated and characterized a human glutathione transferase A4 (hGSTA4) subunit gene from a yeast artificial chromosome containing several other glutathione transferase alpha genes and pseudogenes [6].
• The hGSTA4 gene spans nearly 18 kb, contains seven exons, maps onto chromosome 6p12, and lies in close proximity to the 7SK small nuclear RNA gene in a head-to-tail orientation [6].

Anatomical context of GSTA4

• Western blotting of prenatal liver proteins provided corroborating evidence via detection of an hGSTA1/2-reactive protein in both cytosol and mitochondria and of hGSTA4-4-reactive protein in mitochondria alone [7].
• We had previously demonstrated the presence of hGSTA4-4, an efficient catalyst of 4HNE detoxification, in human liver mitochondria to the exclusion of the cytosol [9].
• In early human fibrous atherosclerotic plaques, immunohistochemical studies demonstrated marked induction of hGSTA4-4 in endothelial cells overlying plaque, and in proliferating plaque vascular smooth muscle cells [10].
• Glutathione-S-transferase A4-4 modulates oxidative stress in endothelium: possible role in human atherosclerosis [10].
• Targeting of hGSTA4-4 to the mitochondrion holds implications for degenerative diseases associated with oxidative stress that arise from aerobic respiration [11].

Associations of GSTA4 with chemical compounds

• Catalytic studies demonstrated that prenatal liver cytosolic GSTs were active toward 1-chloro-2,4-dinitrobenzene (a general GST reference substrate), delta5-androstene-3,17-dione (relatively specific for hGSTA1-1), and 4-hydroxynonenal, a highly mutagenic alpha,beta-unsaturated aldehyde produced during oxidative damage and a substrate for hGSTA4-4 [7].
• Genotoxicity of 4-hydroxy-2-nonenal in human colon tumor cells is associated with cellular levels of glutathione and the modulation of glutathione S-transferase A4 expression by butyrate [8].
• One profile showed rapid increase of 45 genes immediately after transplant by week 1 with significant changes (P < .05) greater than threefold including the chemokine CXC9 and glutathione-related stress factors, GPX2 and GSTA4 [12].
• In contrast, the steady-state levels of gammaGCS-HS, hGSTA4, and bcl-2 mRNAs were not affected by phenytoin exposure [13].
• Previously, we have shown that overexpression of 4-hydroxy-2-nonenal (HNE)-detoxifying enzyme glutathione S-transferase A4-4 (hGSTA4-4) in human lens epithelial cells (HLE B-3) leads to pro-carcinogenic phenotypic transformation of these cells [R. Sharma, et al. Eur. J. Biochem. 271 (2004) 1960-1701] [14].

Other interactions of GSTA4

• 4-Hydroxynonenal induces mitochondrial oxidative stress, apoptosis and expression of glutathione S-transferase A4-4 and cytochrome P450 2E1 in PC12 cells [15].
• The pI value of hGSTA4-4 was found to be 8.4, as opposed to the pI value of 5.8 for hGST5 [16].
• In humans and rodent species, the alpha 4 subclass of glutathione S-transferases (mGSTA4-4, rGSTA4-4, hGST-5.8, and hGSTA4-4) exhibits uniquely high glutathione conjugation activity toward 4HNE and other hydroxyalkenals [11].
• 4-HNE-induced oxidative stress also caused an increase in the expression of GSTA4-4, CYP2E1 and Hsp70 proteins in the mitochondria [15].
• The intracellular concentrations of 4-HNE are regulated through a coordinated action of GSTs (GSTA4-4 and hGST5.8) which conjugate 4-HNE to GSH to form the conjugate (GS-HNE) and the transporter 76 kDa Ral-binding GTPase activating protein (RLIP76), which catalyze ATP-dependent transport of GS-HNE [17].

Analytical, diagnostic and therapeutic context of GSTA4

• Incorporation of the inactive mutant of hGSTA4-4 (Y212F) in cells by either microinjection or transfection does not cause transformation, suggesting that the activity of hGSTA4-4 toward 4-HNE is required for transformation [18].
• Early atherosclerotic plaques are studied by immunohistochemistry for an a class glutathione-S-transferase (GST) isozyme known as hGSTA4-4, which has preferential metabolic activity for a, ss -unsaturated aldehydes derived from lipid peroxidation, especially 4-hydroxy-2-nonenal [19].

References