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Literature summary for 2.5.1.18 extracted from
- Glutathione transferases, regulators of cellular metabolism and physiology (2013), Biochim. Biophys. Acta, 1830, 3267-3288.
Cloned(Commentary)
| Cloned (Comment) | Organism |
|---|---|
| gene GSTA1, localized at 6p12.2, phylogenetic classification of the cytosolic GSTs, overview. Expression in HepG2, GLC4 and Caco-2 cell lines | Homo sapiens |
| gene GSTA2, localized at 6p12.2, phylogenetic classification of the cytosolic GSTs, overview | Homo sapiens |
| gene GSTA3, localized at 6p12.2, phylogenetic classification of the cytosolic GSTs, overview | Homo sapiens |
| gene GSTA4, localized at 6p12.2, phylogenetic classification of the cytosolic GSTs, overview | Homo sapiens |
| gene GSTA5, localized at 6p12.2, phylogenetic classification of the cytosolic GSTs, overview | Homo sapiens |
| gene GSTM1, localized at 1p13.3, phylogenetic classification of the cytosolic GSTs, overview | Homo sapiens |
| gene GSTM2, localized at 1p13.3, phylogenetic classification of the cytosolic GSTs, overview | Homo sapiens |
| gene GSTM3, localized at 1p13.3, phylogenetic classification of the cytosolic GSTs, overview | Homo sapiens |
| gene GSTM4, localized at 1p13.3, phylogenetic classification of the cytosolic GSTs, overview | Homo sapiens |
| gene GSTM5, localized at 1p13.3, phylogenetic classification of the cytosolic GSTs, overview | Homo sapiens |
| gene GSTO1, localized at 10q25.1, phylogenetic classification of the cytosolic GSTs, overview | Homo sapiens |
| gene GSTO2, localized at 10q25.1, phylogenetic classification of the cytosolic GSTs, overview | Homo sapiens |
| gene GSTP1, localized at 11p13.3, phylogenetic classification of the cytosolic GSTs, overview | Homo sapiens |
| gene GSTS1, localized at 4q22.3, phylogenetic classification of the cytosolic GSTs, overview | Homo sapiens |
| gene GSTT1, localized at 22q11.23, phylogenetic classification of the cytosolic GSTs, overview | Homo sapiens |
| gene GSTZ1, localized at 14q24.3, phylogenetic classification of the cytosolic GSTs, overview | Homo sapiens |
| genes GSTT2 and GSTT2B, localized at 22q11.23, phylogenetic classification of the cytosolic GSTs, overview | Homo sapiens |
Protein Variants
| Protein Variants | Comment | Organism |
|---|---|---|
| A140D | naturally occuring mutation, most common missense polymorphism found in each of the populations studied so far, the substitution involves a charge change it does not seem to have a significant effect on enzymatic activity with a range of substrates | Homo sapiens |
| A236V | naturally occuring mutation, the substitution occurs in individuals from Chile and Mexico | Homo sapiens |
| A85S | a naturally occuring polymorphism in Caucasian population | Homo sapiens |
| C130Y | naturally occuring mutation, the substitution is rare and may generate unstable protein | Homo sapiens |
| C32Y | naturally occuring mutation at the primary active site residue, the rare C32Y substitution is identified in Europeans and appears to degrade rapidly. This variant does not catalyze the typical thioltransferase and reductase reactions that are a feature of the Omega class GSTs | Homo sapiens |
| D43N | naturally occuring mutation, the mutant is expressed at low levels causing GSTT1 deficiency | Homo sapiens |
| delE155 | naturally occuring mutation, the polymorphic deletion of E155, from the deletion of AGG from the 5' splice donor site of exon 4, occurs at a low frequency in most populations and is strongly linked to K208 in Europeans and to E208 in Chinese individuals. Although active enzyme can be expressed in Escherichia coli, the delE155 enzyme appears to be unstable in vivo. T47D cells that are hemizygous for the GSTO1delE155 allele are completely deficient in GSTO1-1 activity. Variable protein expression in platelets found evidence that the delE155 enzyme is present in platelets obtained from subjects that are heterozygous for the GSTO1delE155, K208 allele | Homo sapiens |
| E208K | naturally occuring mutation, the single E208K substitution alone, created independently of the E155 deletion, does not have a significant impact on activity. Variable protein expression in platelets found evidence that the delE155 enzyme is present in platelets obtained from subjects that are heterozygous for the GSTO1delE155, K208 allele | Homo sapiens |
| E210A | naturally occuring polymorphism | Homo sapiens |
| G147W | the natural polymorphism occurs in a rare variant in Chinese individual | Homo sapiens |
| G147W/V224I | site-directed mutagenesis, the double mutation results in a gain of function with a three fold increase in the specific activity with 1-chloro-2,4-dinitrobenzene as a substrate. This increase in activity appears to result from a decrease in the Km GSH and a large increase in the catalytic efficiency of the enzyme | Homo sapiens |
| K196N | naturally occuring polymorphism | Homo sapiens |
| L158I | naturally occuring mutation, the substitution is rare and may generate unstable protein | Homo sapiens |
| additional information | a single naturally occuring SNP causing an I71L substitution causes diminished activity with several substrates including CDNB and 7-chloro-4-nitrobenz-2-oxa-1,3-diazole as a result of an elevation in its Km for GSH, but the specific activity towards DELTA5-androsten-3,17-dione and the Km GSH of the L71 variant are not changed | Homo sapiens |
| additional information | at least 66 naturally occuring polymorphisms in the GSTO2 gene with most variations occurring in non-coding regions. Four non-synonymous SNPs are characterized | Homo sapiens |
| additional information | four SNPs encoding the substitutions P110S, S112T, K196N and E210A are identified in the coding sequence of GSTA2, these SNPs occur in five haplotypes, but the K196N substitution can represent a real allele or may be a cDNA sequencing error | Homo sapiens |
| additional information | naturally occuring polymorphisms at K173, N173, and S85. A duplication of the GSTM1 gene occurs in the Saudi Arabian population | Homo sapiens |
| additional information | naturally occuring polymorphisms at positions 104, 43, 65, 141, 169, and 173. GSTT1-1 deficiency as the result of a gene deletion is common and is not deleterious. A deletion of nucleotide G412 causes a frame shift also resulting in GSTT1 deficiency | Homo sapiens |
| additional information | naturally occuring polymorphisms at positions 105 and 114 | Homo sapiens |
| additional information | naturally occuring polymorphisms at positions 139 and 139. Relatively common deletion of the GSTT2b pseudogene | Homo sapiens |
| additional information | naturally occuring polymorphisms at positions 140, 208, 32, 236, and 155 | Homo sapiens |
| additional information | naturally occuring polymorphisms at positions 147, and 224 | Homo sapiens |
| additional information | naturally occuring polymorphisms at positions 8, 32, 42, and 82, 10 SNPs in a region extending 1.5 kb upstream of the GSTZ1 transcription start site in African and European individuals | Homo sapiens |
| additional information | no naturally occuring polymorphisms in GSTA4 | Homo sapiens |
| additional information | no naturally occuring polymorphisms in GSTM2 | Homo sapiens |
| additional information | no naturally occuring polymorphisms in GSTM4 | Homo sapiens |
| additional information | no naturally occuring polymorphisms in GSTM5, so far no validated SNPs identified in the coding region, although several SNPs that contribute to six haplotypes in the 5'proximal promoter, none of it altering basal expression | Homo sapiens |
| N142D | naturally occuring mutation, the N142D substitution is the most frequent in all populations studied so far and does not appear to influence catalytic activity or stability | Homo sapiens |
| P110S | naturally occuring polymorphism | Homo sapiens |
| S112T | naturally occuring polymorphism, recombinant enzyme containing the S110 allele has elevated activity towards 4-nitrophenylacetate and azathioprene and lower activity with 1-chloro-2,4-dinitrobenzene and organic hydroperoxides compared to the wild-type. The T112 substitution causes a reduction in levels of GSTA2-2 to around 25% of those associated with the other haplotypes | Homo sapiens |
| T104P | the GSTT12B allele results from the relatively rare T104P substitution in Scandinavian individuals, and appears to destabilize the protein and result in GSTT1-1 deficiency | Homo sapiens |
| T65M | naturally occuring mutation, the mutant is expressed at low levels causing GSTT1 deficiency | Homo sapiens |
| V169 | naturally occuring mutation, the mutant is expressed at low levels causing GSTT1 deficiency | Homo sapiens |
| V224I | a naturally occuring polymorphism common in African, Asian and European individuals | Homo sapiens |
| V41I | naturally occuring mutation, catalytic activity of the V41I substitution is not evaluated but the expressed protein appears to be stable. | Homo sapiens |
Inhibitors
| Inhibitors | Comment | Organism | Structure |
|---|---|---|---|
| Dichloroacetic acid | i.e. DC, used to treat lactic acidosis and has also been proposed as a novel anticancer agent is both a substrate and a mechanism-based inactivator of GSTZ1-1. Treatment with DCA progressively inactivates GSTZ1-1 and increases the elimination half-life of subsequent doses of DCA. recombinant GSTZ1*A protein is relatively resistant to DCA mediated inactivation when compared with the other isoforms | Homo sapiens |  |
Localization
| Localization | Comment | Organism | GeneOntology No. | Textmining |
|---|---|---|---|---|
| cytosol | - |
Homo sapiens | 5829 | - |
Natural Substrates/ Products (Substrates)
| Natural Substrates | Organism | Comment (Nat. Sub.) | Natural Products | Comment (Nat. Pro.) | Rev. | Reac. |
|---|---|---|---|---|---|---|
| additional information | Homo sapiens | GSTO2-2 has strikingly high dehydroascobate reductase activity | ? | - |
? | |
| additional information | Homo sapiens | GSTZ1 G42R mutant is shown to have high specific activity with the (R)-enantiomer of 2-chloropropionic acid and low activity with the (S)-enantiomer | ? | - |
? | |
| additional information | Homo sapiens | interaction between GSTM monomers and ASK1 | ? | - |
? | |
| additional information | Homo sapiens | thioltransferase and reductase reactions that are a feature of the Omega class GSTs | ? | - |
? | |
Organism
| Organism | UniProt | Comment | Textmining |
|---|---|---|---|
| Homo sapiens | O15217 | isozyme GSTA4-4 | - |
| Homo sapiens | O43708 | isozyme GSTZ1-1 | - |
| Homo sapiens | O60760 | isozyme GSTS1-1 | - |
| Homo sapiens | P08263 | isozyme GSTA1-1 | - |
| Homo sapiens | P09210 | isozyme GSTA2-2 | - |
| Homo sapiens | P09211 | isozyme GSTP1-1, encoded by a single functional GSTP gene termed GSTP1 that maps to chromosome 11q13 | - |
| Homo sapiens | P09211 | isozyme GSTT1-1 | - |
| Homo sapiens | P09488 | isozyme GSTM1-1 | - |
| Homo sapiens | P0CG30 | isozyme GSTT2-2 | - |
| Homo sapiens | P21266 | isozyme GSTM3-3 | - |
| Homo sapiens | P28161 | isozyme GSTM2-2 | - |
| Homo sapiens | P46439 | isozyme GSTM5-5 | - |
| Homo sapiens | P78417 | isozyme GSTO1-1 | - |
| Homo sapiens | Q03013 | isozyme GSTM4-4 | - |
| Homo sapiens | Q16772 | isozyme GSTA3-3 | - |
| Homo sapiens | Q7RTV2 | isozyme GSTA5-5 | - |
| Homo sapiens | Q9H4Y5 | isozyme GSTO2-2 | - |
Reaction
| Reaction | Comment | Organism | Reaction ID |
|---|---|---|---|
| RX + glutathione = HX + R-S-glutathione | active site structure and catalytic mechanism, overview | Homo sapiens |
Source Tissue
| Source Tissue | Comment | Organism | Textmining |
|---|---|---|---|
| brain | - |
Homo sapiens | - |
| liver | high expression level | Homo sapiens | - |
| additional information | expression of GSTP1-1 in many tumors | Homo sapiens | - |
| additional information | tissue-specific expression of Mu class isozymes | Homo sapiens | - |
| additional information | tissue-specific expression of Mu class isozymes, GSTM1-1 is expressed strongly in the liver and to a lesser extent in other tissues | Homo sapiens | - |
| additional information | tissue-specific expression of Mu class isozymes, GSTM3-3 is expressed predominantly in the testis and brain | Homo sapiens | - |
| muscle | GSTM2-2 is largely muscle specific | Homo sapiens | - |
| testis | - |
Homo sapiens | - |
Substrates and Products (Substrate)
| Substrates | Comment Substrates | Organism | Products | Comment (Products) | Rev. | Reac. |
|---|---|---|---|---|---|---|
| 1-chloro-2,4-dinitrobenzene + glutathione | - |
Homo sapiens | S-(2,4-dinitrophenyl)glutathione + HCl | - |
? | |
| 1-chloro-2,4-dinitrobenzene + glutathione | - |
Homo sapiens | 2,4-dinitrophenyl-glutathione + HCl | - |
? | |
| 7-chloro-4-nitrobenzo-2-oxa-1,3-diazole + glutathione | - |
Homo sapiens | ? | - |
? | |
| ethacrynic acid + glutathione | - |
Homo sapiens | ? | - |
? | |
| additional information | GSTO2-2 has strikingly high dehydroascobate reductase activity | Homo sapiens | ? | - |
? | |
| additional information | GSTZ1 G42R mutant is shown to have high specific activity with the (R)-enantiomer of 2-chloropropionic acid and low activity with the (S)-enantiomer | Homo sapiens | ? | - |
? | |
| additional information | interaction between GSTM monomers and ASK1 | Homo sapiens | ? | - |
? | |
| additional information | thioltransferase and reductase reactions that are a feature of the Omega class GSTs | Homo sapiens | ? | - |
? | |
Subunits
| Subunits | Comment | Organism |
|---|---|---|
| dimer | - |
Homo sapiens |
| monomer or dimer | the class GST occurs in a monomer-dimer equilibrium | Homo sapiens |
Synonyms
| Synonyms | Comment | Organism |
|---|---|---|
| Alpha class GST | - |
Homo sapiens |
| GST | - |
Homo sapiens |
| GST1 | formerly | Homo sapiens |
| GST4 | - |
Homo sapiens |
| GST5 | - |
Homo sapiens |
| GSTA1-1 | - |
Homo sapiens |
| GSTA2-2 | - |
Homo sapiens |
| GSTA3-3 | - |
Homo sapiens |
| GSTA4-4 | - |
Homo sapiens |
| GSTA5-5 | - |
Homo sapiens |
| GSTM1-1 | - |
Homo sapiens |
| GSTM2-2 | - |
Homo sapiens |
| GSTM3-3 | - |
Homo sapiens |
| GSTM4-4 | - |
Homo sapiens |
| GSTM5-5 | - |
Homo sapiens |
| GSTO1-1 | - |
Homo sapiens |
| GSTO2-2 | - |
Homo sapiens |
| GSTP1-1 | - |
Homo sapiens |
| GSTS1-1 | - |
Homo sapiens |
| GSTT1-1 | - |
Homo sapiens |
| GSTT2-2 | - |
Homo sapiens |
| GSTT2B-2B | - |
Homo sapiens |
| GSTZ1-1 | - |
Homo sapiens |
| Mu class GST | - |
Homo sapiens |
| Omega class GST | - |
Homo sapiens |
| Pi class GST | - |
Homo sapiens |
| Sigma class GST | - |
Homo sapiens |
| theta class GST | - |
Homo sapiens |
| Zeta class GST | - |
Homo sapiens |
Temperature Stability [°C]
| Temperature Stability Minimum [°C] | Temperature Stability Maximum [°C] | Comment | Organism |
|---|---|---|---|
| 45 | 50 | the I105 variant and the V105 variant show different stability | Homo sapiens |
General Information
| General Information | Comment | Organism |
|---|---|---|
| evolution | the cytosolic glutathione transferases, GSTs, comprise a super family of proteins that can be categorized into multiple classes with a mixture of highly specific and overlapping functions | Homo sapiens |
| evolution | the cytosolic glutathione transferases, GSTs, comprise a superfamily of proteins that can be categorized into multiple classes with a mixture of highly specific and overlapping functions | Homo sapiens |
| malfunction | a single SNP causing an I71L substitution in African subjects causes diminished activity with several substrates including CDNB and 7-chloro-4-nitrobenz-2-oxa-1,3-diazole as a result of an elevation in its Km for GSH, but the specific activity towards DELTA5-androsten-3,17-dione and the Km GSH of the L71 variant are not changed | Homo sapiens |
| malfunction | associations between GSTO1 polymorphisms and vascular dementia and stroke. A236V polymorphism: the V236 variant protein has low specific activity with a range of substrates and shows marked heat instability. It seems highly likely that this substitution leads to GSTO1-1 deficiency in homozygotes. E155 deletion causes a significant folding defectthat may explain the deficiency associated with this deletion. The V236 variant protein has low specific activity with a range of substrates and shows marked heat instability | Homo sapiens |
| malfunction | differences in the catalytic activity of the V105 and I105 variants to carcinogenic diolepoxides may underlie the associations between these alleles and cancer susceptibility | Homo sapiens |
| malfunction | GSTM1-1 deficiency contributes significantly to survival after chemotherapy for childhood leukemia | Homo sapiens |
| malfunction | natural mutations D43N, T65M and T104P, and a frame shift mutation at G412 cause GSTT1-1 deficiency | Homo sapiens |
| malfunction | the GSTT12B allele results from the relatively rare T104P substitution in Scandinavian individuals, and appears to destabilize the protein and result in GSTT1-1 deficiency. The relatively common deletion of the GSTT2b pseudogene is associated with an altered risk of esophageal squamous cell carcinoma | Homo sapiens |
| malfunction | the GSTZ1-A protein has relatively high activity with (±)-2-bromo-3-(4-nitrophenyl)propanoic acid but it has low isomerase activity with its natural substrate maleylacetoacetate | Homo sapiens |
| malfunction | two rare intronic variants (IVS2+11A>C and IVS3+13T>C) are reported, the intron-2 SNP is significantly transmitted to asthma-affected children | Homo sapiens |
| additional information | GSTT1-1 deficiency as the result of a gene deletion is common and is not deleterious | Homo sapiens |
| physiological function | all the catalytically active GSTs contribute to the glutathione conjugation or glutathione dependant-biotransformation of xenobiotics and many catalyze glutathione peroxidase or thiol transferase reactions. GSTs also catalyze glutathione dependent isomerization reactions required for the synthesis of several prostaglandins and steroid hormones and the catabolism of tyrosine, additional GST physiological functions, overview | Homo sapiens |
| physiological function | all the catalytically active GSTs contribute to the glutathione conjugation or glutathione dependant-biotransformation of xenobiotics and many catalyze glutathione peroxidase or thiol transferase reactions. GSTs also catalyze glutathione dependent isomerization reactions required for the synthesis of several prostaglandins and steroid hormones and the catabolism of tyrosine, additional GST physiological functions, overview. Because of its highly specialized activity the Sigma class GST is generally known as hemopoietic prostaglandin D synthase, HPGDS | Homo sapiens |
| physiological function | all the catalytically active GSTs contribute to the glutathione conjugation or glutathione dependant-biotransformation of xenobiotics and many catalyze glutathione peroxidase or thiol transferase reactions. GSTs also catalyze glutathione dependent isomerization reactions required for the synthesis of several prostaglandins and steroid hormones and the catabolism of tyrosine, additional GST physiological functions, overview. Because of its highly specialized role catalyzing the penultimate step in the catabolism of tyrosine, GSTZ1-1 is also known as maleylacetoacetate isomerase, MAAI | Homo sapiens |
| physiological function | all the catalytically active GSTs contribute to the glutathione conjugation or glutathione dependant-biotransformation of xenobiotics and many catalyze glutathione peroxidase or thiol transferase reactions. GSTs also catalyze glutathione dependent isomerization reactions required for the synthesis of several prostaglandins and steroid hormones and the catabolism of tyrosine, additional GST physiological functions, overview. GSTA1-1 is likely to play a significant role in binding hydrophobic ligands such as bilirubin and steroid hormones | Homo sapiens |
| physiological function | all the catalytically active GSTs contribute to the glutathione conjugation or glutathione dependant-biotransformation of xenobiotics and many catalyze glutathione peroxidase or thiol transferase reactions. GSTs also catalyze glutathione dependent isomerization reactions required for the synthesis of several prostaglandins and steroid hormones and the catabolism of tyrosine, additional GST physiological functions, overview. GSTA3-3 may play an important physiological role as it efficiently catalyzes the isomerization of DELTA5-3-ketosteroids in the synthesis of testosterone and progesterone | Homo sapiens |
| physiological function | all the catalytically active GSTs contribute to the glutathione conjugation or glutathione dependant-biotransformation of xenobiotics and many catalyze glutathione peroxidase or thiol transferase reactions. GSTs also catalyze glutathione dependent isomerization reactions required for the synthesis of several prostaglandins and steroid hormones and the catabolism of tyrosine, additional GST physiological functions, overview. GSTO1 is a determinant of the age at onset of Alzheimer's and Parkinson's diseases | Homo sapiens |
| physiological function | all the catalytically active GSTs contribute to the glutathione conjugation or glutathione dependant-biotransformation of xenobiotics and many catalyze glutathione peroxidase or thiol transferase reactions. GSTs also catalyze glutathione dependent isomerization reactions required for the synthesis of several prostaglandins and steroid hormones and the catabolism of tyrosine, additional GST physiological functions, overview. Interaction between GSTM monomers and ASK1 with regulatory function | Homo sapiens |
| physiological function | all the catalytically active GSTs contribute to the glutathione conjugation or glutathione dependant-biotransformation of xenobiotics and many catalyze glutathione peroxidase or thiol transferase reactions. GSTs also catalyze glutathione dependent isomerization reactions required for the synthesis of several prostaglandins and steroid hormones and the catabolism of tyrosine, additional GST physiological functions, overview. The Pi class GST occurs in a monomer-dimer equilibrium and monomers can bind to and regulate other proteins such as JNK and TRAF | Homo sapiens |
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