GSTA1 (glutathione S-transferase alpha 1)

2014-01-01   Ana Savic-Radojevic , Tanja Radic 

Institute of Medical, Clinical Biochemistry, Faculty of Medicine, University of Belgrade, Serbia

Identity

HGNC
LOCATION
6p12.2
LOCUSID
ALIAS
GST-epsilon,GST2,GSTA1-1,GTH1
FUSION GENES

DNA/RNA

Note

The human alpha class genes are located in a cluster on chromosome 6p12 and comprise five functional genes (GSTA1, GSTA2, GSTA3, GSTA4, GSTA5) and seven pseudogenes (Morel et al., 2002).
Atlas Image
GSTA1 gene. The GSTA1 gene spans a region of 12,5 kb composed of the seven exons (red) and six introns (green). Exons 1, 2, 3, 4, 5, 6 and 7 are 59 bp, 117 bp, 52 bp, 133 bp, 142 bp, 132 bp and 198 bp in length, respectively.

Description

The GSTA1 gene is approximately 12 kb in length and is closely flanked by other alpha class gene sequences. The complete sequence of the 1,7-kb intergenic region between exon 7 of an upstream pseudogene and exon 1 of the GSTA1 gene has been determined (Suzuki et al., 1993).

Transcription

The 1276-nucleotide transcript encodes a protein of 222 amino acid residues.

Pseudogene

An additional gene that encodes an uncharacterized Alpha class GST has been identified. The protein derived from this gene would have 19 amino acid substitutions compared with the GSTA1 isoenzyme. Several pseudogenes with single-base and/or complete exon deletions have been identified, but no reverse-transcribed pseudogenes have been detected (Suzuki et al., 1993).
Polymorphisms: GSTA1 has a functional three apparently linked single nucleotide polymorphisms (SNPs) in an SP1-responsive element within the proximal promoter (G-52A, C-69T and T-567G), plus at least four SNPs further upstream and a silent SNP A-375G. Two variants, GSTA1*A (-567T, -69C,-52G) and GSTA1*B (-67G, -69T, -52A), have been named according to the linked functional SNPs. Specifically, these substitutions result in differential expression with lower transcriptional activation of variant GSTA1*B than common GSTA1*A allele. It has been suggested that this genetic variation can change an individuals susceptibility to carcinogens and toxins, as well as, affect the efficacy of some drugs (Coles and Kadlubar, 2003). In addition, the linkage disequilibrium between GSTA1*A/GSTA1*B and GSTA2G335C (Ser112Thr) has been shown in Caucasians: specifically, GSTA1*A/GSTA2C335 (Thr112) and GSTA1*B/GSTA2G335 (Ser112) (Ning et al., 2004). It seems that the higher hepatic expression of GSTA1 enzyme in homozygous GSTA1 individuals is associated with the lower hepatic expression of GSTA2 in GSTA2C335 (Thr112) individuals (Coles et al., 2001a; Ning et al., 2004). Other haplotypes within this nomenclature but including SNPs C-115T, T-631G, and C-1142G also have been proposed (Bredschneider et al., 2002; Guy et al., 2004). Polymorphisms upstream of G-52C seem to have little effect on GSTA1 expression (Morel et al., 2002).

Proteins

Note

Glutathione S-transferase A1 is N-terminally processed.
Amino acids: 222.
Calculated molecular mass: 25,63 kDa.
Atlas Image
Crystal structure of human glutathione transferase (GST) A1-1 in complex with glutathione. Adapted from PDB (Grahn et al., 2006).

Description

The active GSTA1-1 enzyme is a homodimer, with each subunit containing a GSH-binding site (G-site) and a second adjacent hydrophobic binding site for the electrophilic substrate (H-site) (Wilce and Parker, 1994). The C-terminal region of GSTA1-1 contributes to the catalytic and noncatalytic ligand-binding functions of the enzyme, while the conserved G-site is located in the N-terminal domain (Balogh et al., 2009). Protein flexibility and dynamics in a molten globule-active site including the C-terminal α9 helix and the protruding ends of the α4-α5 helices result in achieving remarkable catalytic promiscuity of GSTA1-1 (Wu and Dong, 2012; Honaker et al., 2013). It has been proposed that the α9 helix may function as a mobile gate to the active-site cavity, controlling substrate access and product release.
Atlas Image
Structure determination and refinement of human alpha class glutathione transferase A1-1, and a comparison with the MU and PI class enzymes. Adapted from PDB (Sinning et al., 1993).

Expression

GSTA1-1 is highly expressed (as mRNA and protein) in liver, intestine, kidney, adrenal gland, pancreas and testis, while expression in a wide range of tissues is low (Hayes and Pulford, 1995; Coles et al., 2001a). Both positive and negative regulatory regions are present in the 5` noncoding region of GSTA1, including a polymorphic SP1-binding site within the proximal promoter. Binding of the transcription factor AP1 has been suggested as a common mechanism for up-regulation of GSTs (Hayes and Pulford, 1995). The results of recent study also implied the role of a Kelch-like ECH-associated protein 1 (Keap1)-dependent signaling pathway for the induction of the constitutive GSTA1 expression during epithelial cell differentiation (Kusano et al., 2008). Regarding GSH-dependent Δ54 isomerase activity of this class of enzyme, it has been shown that steroidogenic factor 1 (SF-1) is involved in regulation of expression of GSTA genes (Matsumura et al., 2013). Aberrant overexpression has been observed in various malignancies such as colorectal (Hengstler et al., 1998) and lung cancer (Carmichael et al., 1988), while decrease in alpha class GSTs has been observed in stomach and liver tumors (Howie et al., 1990). A detailed recent review on GSTA1 can be found in Wu and Dong, 2012.

Localisation

Cytosolic.

Function

Human GSTA1-1 enzyme catalyzes the GSH-dependent detoxification of electrophiles showing highly promiscuous substrate selectivity for many structurally unrelated chemicals, including environmental carcinogens (e.g. benzo(a)pyrene diol epoxides), several alkylating chemotherapeutic agents (such as busulfan, chlorambucil, melphalan, phosphoramide mustard, cyclophosphamide, thiotepa), as well as, steroids and products of lipid degradation. GSTA1-1 is the most highly expressed GST of the liver and could therefore, be critical for "systemic" detoxification of electrophilic xenobiotics including carcinogens and drugs (Coles and Kadlubar, 2005). In addition to enzymatic detoxification, GSTA1 acts as modulator of mitogen-activated protein kinase (MAPK) signal transduction pathway via a mechanism involving protein-protein interactions. Namely, GSTA1 forms complexes with c-Jun N-terminal kinase (JNK), modifying JNK activation during cellular stress (Adnan et al., 2012). Thus, it is possible that GSTA1 confer drug resistance by two distinct means: by direct inactivation (detoxification) of chemotherapeutic drugs and by acting as inhibitors of MAPK pathway.

Homology

The alpha class GSTs is showing strong intra-class sequence similarity (Balogh et al., 2009).

Mutations

Germinal

None described so far.

Somatic

36 mutations (COSMIC): 26 substitution-missense, 4 substitution-nonsense, 5 substitution-coding silent, 1 unknown type.

Implicated in

Entity name
Colorectal cancer
Note
Regarding the role of GSTA1 polymorphism in the risk of colorectal cancer, the results of epidemiological studies are still inconclusive. Several studies showed that GSTA1*B genotype (low hepatic expression) is associated with increased susceptibility to colorectal cancer, which imply the possible inefficient hepatic detoxification of food-derived carcinogen metabolite N-acetoxy-PhIP (Coles et al., 2001b; Sweeney et al., 2002). In contrast, meta-analysis of Economopoulos representing the pooled analysis of four studies (1648 cases, 2039 controls) does not confer this association.
Entity name
Breast cancer
Note
The role of GSTA1 polymorphism in breast cancer risk was mainly based on investigation on response to chemotherapeutic drugs in these patients. In breast cancer patients on cyclophosphamide containing chemotherapy carriers of GSTA1*B/*B genotype showed significantly reduced five years risk of death in comparison to GSTA1*A homozygous carriers. This association was likely caused by decreased detoxification of the therapeutic metabolites of cyclophosphamide in GSTA1*B/*B patients (Sweeney et al., 2003).
Entity name
Bladder cancer
Note
Recent investigation indicates that the GSTA1-low activity genotype in combination with the GSTM1-null genotype significantly increases the risk of bladder cancer in smokers (Matic et al., 2013). In addition, it seems that GSTA1 polymorphism may influence vulnerability to oxidative DNA damage, thereby contributing to the malignant potential of transitional cell carcinoma (Savic-Radojevic et al., 2013).
Entity name
Myeloid leukemia
Note
Aberant overexpression of both GSTA1 and GSTA2 proteins was found in blast cells derived from acute myeloid leukemia patients, showing resistance to doxorubicin in vitro (Sargent et al., 1999). In addition, GSTA1 and CYP39A1 (member of cytochrome P450 family) polymorphisms were found to be associated with pharmacokinetics of busulfan, which is used in preparative regimens prior to stem cell transplantation in pediatric patients (ten Brink et al., 2013).
Entity name
Prostate cancer
Note
Genetic variants of GSTA1 and GSTT1 may modify prostate cancer risk, especially among smokers (Komiya et al., 2005).
Entity name
Asthma
Note
Genetic alterations in GST enzymes may influence the detoxification of environmental toxic substances in airway and increase the risk of asthma. Thus, it has been shown that subjects with at least one allele -69T in the GSTA1 genotype have an increased risk of asthma (Polimanti et al., 2010).

Bibliography

Pubmed IDLast YearTitleAuthors
229064942012The effect of menadione on glutathione S-transferase A1 (GSTA1): c-Jun N-terminal kinase (JNK) complex dissociation in human colonic adenocarcinoma Caco-2 cells.Adnan H et al
196189652009Structural analysis of a glutathione transferase A1-1 mutant tailored for high catalytic efficiency with toxic alkenals.Balogh LM et al
120873512002Genetic polymorphisms of glutathione S-transferase A1, the major glutathione S-transferase in human liver: consequences for enzyme expression and busulfan conjugation.Bredschneider M et al
34094651988Glutathione S-transferase isoenzymes and glutathione peroxidase activity in normal and tumour samples from human lung.Carmichael J et al
115352432001The role of human glutathione S-transferases (hGSTs) in the detoxification of the food-derived carcinogen metabolite N-acetoxy-PhIP, and the effect of a polymorphism in hGSTA1 on colorectal cancer risk.Coles B et al
163993772005Human alpha class glutathione S-transferases: genetic polymorphism, expression, and susceptibility to disease.Coles BF et al
116920742001Effect of polymorphism in the human glutathione S-transferase A1 promoter on hepatic GSTA1 and GSTA2 expression.Coles BF et al
202075352010GSTM1, GSTT1, GSTP1, GSTA1 and colorectal cancer risk: a comprehensive meta-analysis.Economopoulos KP et al
164214512006New crystal structures of human glutathione transferase A1-1 shed light on glutathione binding and the conformation of the C-terminal helix.Grahn E et al
151280502004Promoter polymorphisms in glutathione-S-transferase genes affect transcription.Guy CA et al
87705361995The glutathione S-transferase supergene family: regulation of GST and the contribution of the isoenzymes to cancer chemoprotection and drug resistance.Hayes JD et al
96528001998Resistance factors in colon cancer tissue and the adjacent normal colon tissue: glutathione S-transferases alpha and pi, glutathione and aldehyde dehydrogenase.Hengstler JG et al
236496282013Enzymatic detoxication, conformational selection, and the role of molten globule active sites.Honaker MT et al
23111891990Glutathione S-transferase and glutathione peroxidase expression in normal and tumour human tissues.Howie AF et al
156168292005Human glutathione S-transferase A1, T1, M1, and P1 polymorphisms and susceptibility to prostate cancer in the Japanese population.Komiya Y et al
184767232008Keap1 regulates the constitutive expression of GST A1 during differentiation of Caco-2 cells.Kusano Y et al
240753582013GSTA1, GSTM1, GSTP1, and GSTT1 polymorphisms and susceptibility to smoking-related bladder cancer: a case-control study.Matic M et al
236501892013Human glutathione S-transferase A (GSTA) family genes are regulated by steroidogenic factor 1 (SF-1) and are involved in steroidogenesis.Matsumura T et al
120426652002The human glutathione transferase alpha locus: genomic organization of the gene cluster and functional characterization of the genetic polymorphism in the hGSTA1 promoter.Morel F et al
151280492004Human glutathione S-transferase A2 polymorphisms: variant expression, distribution in prostate cancer cases/controls and a novel form.Ning B et al
203742582010GSTA1, GSTO1 and GSTO2 gene polymorphisms in Italian asthma patients.Polimanti R et al
105007951999Evidence for the involvement of the glutathione pathway in drug resistance in AML.Sargent JM et al
233943112013GSTM1-null and GSTA1-low activity genotypes are associated with enhanced oxidative damage in bladder cancer.Savic-Radojevic A et al
83316571993Structure determination and refinement of human alpha class glutathione transferase A1-1, and a comparison with the Mu and Pi class enzymes.Sinning I et al
83075791993Structure and organization of the human alpha class glutathione S-transferase genes and related pseudogenes.Suzuki T et al
125161032003Association between a glutathione S-transferase A1 promoter polymorphism and survival after breast cancer treatment.Sweeney C et al
125052892002Novel markers of susceptibility to carcinogens in diet: associations with colorectal cancer.Sweeney C et al
81424731994Structure and function of glutathione S-transferases.Wilce MC et al
231218342012Human cytosolic glutathione transferases: structure, function, and drug discovery.Wu B et al
241921172013Effect of genetic variants GSTA1 and CYP39A1 and age on busulfan clearance in pediatric patients undergoing hematopoietic stem cell transplantation.ten Brink MH et al

Other Information

Locus ID:

NCBI: 2938
MIM: 138359
HGNC: 4626
Ensembl: ENSG00000243955

Variants:

dbSNP: 2938
ClinVar: 2938
TCGA: ENSG00000243955
COSMIC: GSTA1

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000243955ENST00000334575P08263
ENSG00000243955ENST00000334575A0A140VJK4

Expression (GTEx)

0
100
200
300
400
500
600
700
800

Pathways

PathwaySourceExternal ID
Glutathione metabolismKEGGko00480
Metabolism of xenobiotics by cytochrome P450KEGGko00980
Drug metabolism - cytochrome P450KEGGko00982
Glutathione metabolismKEGGhsa00480
Metabolism of xenobiotics by cytochrome P450KEGGhsa00980
Drug metabolism - cytochrome P450KEGGhsa00982
Chemical carcinogenesisKEGGhsa05204
Chemical carcinogenesisKEGGko05204
MetabolismREACTOMER-HSA-1430728
Biological oxidationsREACTOMER-HSA-211859
Phase II conjugationREACTOMER-HSA-156580
Glutathione conjugationREACTOMER-HSA-156590
Platinum drug resistanceKEGGko01524
Platinum drug resistanceKEGGhsa01524
Fluid shear stress and atherosclerosisKEGGko05418
Fluid shear stress and atherosclerosisKEGGhsa05418

Protein levels (Protein atlas)

Not detected
Low
Medium
High

PharmGKB

Entity IDNameTypeEvidenceAssociationPKPDPMIDs
PA134850491TransplantationDiseaseClinicalAnnotationassociatedPK24192117
PA160680212Lymphoma, Large B-Cell, DiffuseDiseaseClinicalAnnotationassociatedPD19448608, 29938344
PA443340AnemiaDiseaseClinicalAnnotationassociatedPD22188361
PA444823Lupus NephritisDiseaseClinicalAnnotationassociatedPKPD26222310
PA445204Ovarian NeoplasmsDiseaseClinicalAnnotationassociatedPD22188361
PA445594SarcomaDiseaseClinicalAnnotationassociatedPD24215845
PA448691busulfanChemicalClinicalAnnotation, PathwayassociatedPK24192117
PA449014cisplatinChemicalClinicalAnnotationassociatedPD22188361
PA449165cyclophosphamideChemicalClinicalAnnotationassociatedPKPD19448608, 22188361, 26222310, 29938344
PA449412doxorubicinChemicalClinicalAnnotationassociatedPD19448608, 24215845, 29938344
PA451100prednisoneChemicalClinicalAnnotationassociatedPD19448608, 29938344
PA451261rituximabChemicalClinicalAnnotationassociatedPD19448608, 29938344
PA451879vincristineChemicalClinicalAnnotationassociatedPD19448608, 29938344

References

Pubmed IDYearTitleCitations
157461602005Constitutional short telomeres are strong genetic susceptibility markers for bladder cancer.83
184961312008Influence of polymorphisms of drug metabolizing enzymes (CYP2B6, CYP2C9, CYP2C19, CYP3A4, CYP3A5, GSTA1, GSTP1, ALDH1A1 and ALDH3A1) on the pharmacokinetics of cyclophosphamide and 4-hydroxycyclophosphamide.44
197869802010Genetic polymorphisms and the efficacy and toxicity of cisplatin-based chemotherapy in ovarian cancer patients.43
202075352010GSTM1, GSTT1, GSTP1, GSTA1 and colorectal cancer risk: a comprehensive meta-analysis.33
202075352010GSTM1, GSTT1, GSTP1, GSTA1 and colorectal cancer risk: a comprehensive meta-analysis.33
116920742001Effect of polymorphism in the human glutathione S-transferase A1 promoter on hepatic GSTA1 and GSTA2 expression.32
116920742001Effect of polymorphism in the human glutathione S-transferase A1 promoter on hepatic GSTA1 and GSTA2 expression.32
180657252008Genetic variants of glutathione S-transferase as possible risk factors for hepatocellular carcinoma: a HuGE systematic review and meta-analysis.32
189921482008Low-penetrance alleles predisposing to sporadic colorectal cancers: a French case-controlled genetic association study.32
165990072004Polymorphisms in glutathione-related genes affect methylmercury retention.29

Citation

Ana Savic-Radojevic ; Tanja Radic

GSTA1 (glutathione S-transferase alpha 1)

Atlas Genet Cytogenet Oncol Haematol. 2014-01-01

Online version: http://atlasgeneticsoncology.org/gene/40764/gsta1