Affinage

GSTM2

Glutathione S-transferase Mu 2 · UniProt P28161

Length
218 aa
Mass
25.7 kDa
Annotated
2026-06-10
32 papers in source corpus 20 papers cited in narrative 20 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

GSTM2 is a dimeric class-mu glutathione S-transferase that conjugates glutathione to electrophilic substrates and, beyond detoxification, acts as a regulator of intracellular Ca2+ handling and redox-coupled signaling (PMID:8182750, PMID:2034681, PMID:18308613). Crystallographic and kinetic analyses established its catalytic core: the active site binds glutathione first and releases chloride first in a steady-state ordered bi-bi mechanism, with a hydrophobic substrate pocket distinct from rodent orthologs (PMID:8182750, PMID:2034681). In cardiac muscle GSTM2 localizes to the sarcoplasmic reticulum lumen, where it binds the luminal domain of the ryanodine receptor and modulates channel activity; its C-terminal helix 6 region, and specifically residues F157 and Y160, are necessary and sufficient to inhibit RyR2-mediated Ca2+ release and suppress cardiomyocyte contractility and Ca2+ transients independently of GSH binding (PMID:18308613, PMID:19168034, PMID:27612301). GSTM2 transcription is controlled by Nrf2, which is required for both constitutive and inducible expression (PMID:11991805). GSTM2 protein abundance is set by competing modifications at Cys174: SMURF1-mediated K48-linked ubiquitination at this residue drives proteasomal degradation, while Cys174 sulfenylation blocks that ubiquitination and stabilizes the protein, linking redox state to protein turnover (PMID:40772306, PMID:41637880). Through these activities GSTM2 limits oxidative and DNA-damage-associated stress in multiple settings—suppressing STAT3 phosphorylation and Drp1-driven mitochondrial fission via direct STAT3 binding in astrocytes (PMID:41916017), and protecting against high-glucose-induced endothelial senescence (PMID:41637880)—and its elevation confers cytoprotective, therapy-resistant phenotypes in cancer, including AhR-driven, p38 MAPK-mediated resistance to androgen receptor inhibitors in prostate cancer (PMID:36038661).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 1991 High

    Defining the catalytic mechanism of the muscle class-mu enzyme established GSTM2 as a glutathione transferase with a defined substrate-ordering, the foundation for all later functional inference.

    Evidence recombinant expression in E. coli with product-inhibition enzyme kinetics

    PMID:2034681

    Open questions at the time
    • Physiological electrophilic substrates in vivo not enumerated
    • Does not address non-catalytic functions
  2. 1994 High

    Solving the human GSTM2-2 crystal structure resolved the active-site architecture and showed divergence from the rodent ortholog, anchoring substrate-binding interpretation to human enzyme.

    Evidence X-ray crystallography in three independent crystal forms at 1.85–3.5 Å

    PMID:8182750

    Open questions at the time
    • Dinitrobenzene/electrophile portion not resolved in density
    • No structure of RyR-bound or C-terminal regulatory state
  3. 2002 High

    Identifying Nrf2 as required for constitutive and inducible GSTM2 expression placed the gene within the antioxidant transcriptional response.

    Evidence Nrf2 knockout mouse with enzyme assay, Western blot, and real-time PCR

    PMID:11991805

    Open questions at the time
    • Direct ARE element in GSTM2 promoter not mapped
    • Mouse model; human regulation not directly tested
  4. 2009 High

    Mapping RyR inhibition to the GSH-independent C-terminal helix 6 separated GSTM2's Ca2+-channel regulatory function from its enzymatic activity and identified the structural element responsible.

    Evidence truncation mutants in SR Ca2+ release assays, single-channel electrophysiology, cross-linking, and circular dichroism (extending the 2008 luminal-localization finding)

    PMID:18308613 PMID:19168034

    Open questions at the time
    • Atomic structure of the GSTM2-RyR interface unresolved
    • Differential effect on RyR1 vs RyR2 mechanistically incomplete
  5. 2016 High

    Showing that the C-terminal fragment internalizes into cardiomyocytes and that F157/Y160 are required for activity demonstrated functional RyR2 inhibition in intact cells and pinpointed essential residues.

    Evidence tagged GSTM2C internalization, contractility and Ca2+ transient imaging, site-directed mutagenesis in neonatal cardiomyocytes

    PMID:27612301

    Open questions at the time
    • Endogenous full-length protein contribution vs fragment not distinguished
    • In vivo cardiac role not tested here
  6. 2022 Medium

    Linking AhR-driven GSTM2 elevation to androgen-receptor-inhibitor resistance via oxidative-stress protection and p38 MAPK gave GSTM2 a defined role in cancer therapy resistance.

    Evidence gain/loss-of-function in prostate cancer lines with AhR inhibition and p38 MAPK pathway readouts

    PMID:36038661

    Open questions at the time
    • Direct AhR binding to GSTM2 regulatory region not shown
    • Whether catalytic activity is required for resistance unclear
  7. 2023 Medium

    GSTM2 overexpression attenuating cardiac hypertrophy by reducing DNA damage and eccDNA-driven interferon inflammation extended its cardiac role to a protective anti-inflammatory function.

    Evidence GSTM2 overexpression in TAC heart failure mouse with proteomics, transcriptomics, and eccDNA detection

    PMID:38037116

    Open questions at the time
    • Mechanism linking GSTM2 to reduced DNA damage not defined
    • Relationship to RyR2 regulation in same model untested
  8. 2025 Medium

    Identifying SMURF1 as the E3 ligase that ubiquitinates GSTM2 for degradation revealed the post-translational control of GSTM2 protein abundance.

    Evidence co-IP, ubiquitination assay, cycloheximide chase, SMURF1 overexpression/knockdown, and xenograft in gastric cancer

    PMID:40772306

    Open questions at the time
    • Ubiquitination site not specified in this study
    • Whether SMURF1-GSTM2 regulation operates outside gastric cancer unknown
  9. 2026 Medium

    Showing that Cys174 sulfenylation blocks K48 ubiquitination at the same residue established a redox switch governing GSTM2 stability and a route to pharmacological stabilization.

    Evidence site-specific sulfenylation detection, K48-linkage ubiquitination assays, HCY-NBD treatment in cells and db/db mice

    PMID:41637880

    Open questions at the time
    • Endogenous oxidant generating Cys174 sulfenylation not identified
    • Whether SMURF1 is the ligase acting at Cys174 not directly connected
  10. 2026 Medium

    Demonstrating direct GSTM2-STAT3 binding that suppresses STAT3 phosphorylation and Drp1-mediated fission defined a non-enzymatic signaling function controlling mitochondrial dynamics.

    Evidence IP-mass spectrometry and surface plasmon resonance with astrocyte-specific overexpression/knockout in db/db mice

    PMID:41916017

    Open questions at the time
    • GSTM2 domain mediating STAT3 binding not mapped
    • Generalizability beyond astrocytes untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • How GSTM2's enzymatic, Ca2+-channel-regulatory, and protein-protein scaffolding functions are coordinated within a single cell, and which domains govern each, remains unresolved.
  • No structure of any GSTM2 regulatory complex (RyR, STAT3)
  • Tissue-specific partitioning of catalytic vs non-catalytic roles unknown
  • Whether redox-controlled stability gates the signaling functions untested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 4 GO:0016740 transferase activity 2 GO:0016787 hydrolase activity 1
Localization
GO:0005783 endoplasmic reticulum 1 GO:0005829 cytosol 1
Pathway
R-HSA-392499 Metabolism of proteins 2 R-HSA-8953897 Cellular responses to stimuli 2 R-HSA-1643685 Disease 1
Partners
RYR1RYR2SMURF1STAT3

Evidence

Reading pass · 20 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1994 Crystal structure of human GSTM2-2 was determined in three crystal forms at resolutions of 1.85–3.5 Å. The active site that binds hydrophobic substrates differs significantly from the rat class mu GST3-3 ortholog, with a 2 Å shift in a helix C-terminus and heterogeneity in the last 15 residues of the carboxy terminus. Electron density confirmed glutathione (but not the dinitrobenzene portion of the ligand) binds in the active site. X-ray crystallography (molecular replacement + anomalous scattering from single isomorphous derivative), three independent crystal forms Journal of molecular biology High 8182750
1991 GSTM2 (product of the GST4 locus) encodes a class-mu glutathione S-transferase expressed in human muscle. Kinetic product-inhibition studies established a steady-state ordered bi-bi reaction mechanism: glutathione is the first substrate bound, and chloride ion is the first product released. Chloride ion also acts as an inhibitor of the muscle enzyme. Recombinant expression in E. coli, enzyme kinetics with product inhibition studies Proceedings of the National Academy of Sciences of the United States of America High 2034681
2002 Nrf2 transcription factor is required for constitutive and inducible hepatic expression of GSTM2. Nrf2 knockout mice showed constitutive GSTM2 protein and mRNA reduced to 3–60% of wild-type levels, and BHA-induced upregulation of GSTM2 was attenuated in knockouts. Nrf2 knockout mouse model, enzyme assay, Western blotting, TaqMan real-time PCR The Biochemical journal High 11991805
2008 GSTM2-2 protein is localized to the lumen of the sarcoplasmic reticulum (SR) in cardiac muscle (but not skeletal muscle), where it modifies ryanodine receptor (RyR) activity by binding to the luminal domain of the RyR channel complex. Luminal GSTM2-2 activates both cardiac RyR2 and skeletal RyR1 by increasing open probability and conductance in a manner independent of luminal Ca2+ concentration. Immunofluorescence with anti-GSTM2-2 antibody in cardiac SR fractions, single-channel electrophysiology, comparison with calsequestrin effects The international journal of biochemistry & cell biology Medium 18308613
2009 The C-terminal half of GSTM2-2 (lacking the GSH binding site) is sufficient for inhibition of cardiac RyR2 but not activation of skeletal RyR1. The C-terminal helix 6 sequence is the critical structural element: fragments containing helix 6 inhibited Ca2+ release from cardiac SR, while fragments containing helices 5–8 cross-linked to RyR2 but not RyR1. Helical structure in the helix 6 region is required for efficacy. Truncation mutants expressed and tested in SR vesicle Ca2+ release assays, single-channel electrophysiology, chemical cross-linking, circular dichroism Biochemical pharmacology High 19168034
2016 The C-terminal domain of GSTM2 (GSTM2C) enters neonatal rat ventricular cardiomyocytes, reduces spontaneous contraction frequency, decreases myocyte shortening, reduces Ca2+ transient amplitude, and prolongs Ca2+ transient rise time. Mutations F157A and Y160A within GSTM2C abolished these effects, demonstrating that these residues are required for RyR2 inhibitory activity in intact cardiomyocytes. Oregon green-tagged GSTM2C internalization into cultured cardiomyocytes, contractility measurements, Ca2+ transient imaging, site-directed mutagenesis PloS one High 27612301
2001 The murine GSTM2 gene consists of 8 exons. The transcription start site is 40 bp upstream of the initiating AUG. Maximal promoter activity resides in a 170 bp 5'-flanking region; deletion analysis revealed repressor elements between −170 and −402 bp. An SP1 site at −38 is essential for promoter activity (deletion abolished activity). The promoter contains eight putative Myb responsive elements and is transcriptionally activated by t-Myb but not c-Myb. Genomic cloning, primer extension, promoter deletion analysis in transfection assays, Myb overexpression Gene Medium 11404019
2013 GSTM2 can functionally compensate for absent GSTM1 activity in GSTM1-null individuals. GSTM2 shows maximum structural homology to GSTM1 in silico; total plasma GST activity is similar regardless of GSTM1 genotype; and transient knockdown of GSTM1 in HeLa cells leads to upregulation of GSTM2 protein, which is confirmed by GSTM2 overexpression rescue experiments. In silico structural homology analysis, plasma GST activity assay, Western blotting, RT-PCR, siRNA knockdown and overexpression in HeLa cells Scientific reports Medium 24048194
2022 GSTM2 mediates resistance to second-generation androgen receptor inhibitors (enzalutamide, apalutamide, darolutamide) in prostate cancer. Elevated GSTM2 in enzalutamide-resistant cells is driven by the upstream transcription factor aryl hydrocarbon receptor (AhR). Mechanistically, GSTM2 protects cells from oxidative stress-associated damage and activates the p38 MAPK pathway to antagonize enzalutamide effects. Overexpression of GSTM2 in sensitive cells converted them to a resistant phenotype. GSTM2 overexpression/knockdown in prostate cancer cell lines, AhR inhibition, p38 MAPK pathway analysis, drug sensitivity assays Oncogene Medium 36038661
2023 GSTM2 overexpression in a TAC-induced heart failure mouse model reduced cardiac hypertrophy progression. GSTM2 attenuated DNA damage and extrachromosomal circular DNA (eccDNA) production in cardiomyocytes, thereby reducing interferon-I-stimulated macrophage inflammation in heart tissue. GSTM2 overexpression in TAC mouse model, proteomics, transcriptomics, DNA damage assays, eccDNA detection Cell & bioscience Medium 38037116
2024 GSTM2 delivered via fibroblast-derived extracellular vesicles to aging skin alleviates oxidative stress in dermal fibroblasts by modulating mitochondrial oxidative phosphorylation, and promotes fibroblasts to secrete NACA (Nascent Polypeptide-Associated Complex Alpha subunit) by paracrine signaling, which in turn regulates epidermal cell turnover through the ROS-ERK-ETS-Cyclin D pathway. EVs-mediated Gstm2 mRNA delivery to aged mouse skin, aged mouse wound healing model, mitochondrial oxidative phosphorylation assays, paracrine secretion analysis, pathway inhibition experiments Journal of nanobiotechnology Medium 38825668
2025 SMURF1 acts as an E3 ubiquitin ligase that targets GSTM2 for ubiquitin-mediated proteasomal degradation in gastric cancer cells. SMURF1 overexpression suppressed GSTM2 protein levels and enhanced cell proliferation, migration, and invasion, while SMURF1 silencing reduced GSTM2 ubiquitination and stabilized GSTM2 protein. Co-immunoprecipitation, ubiquitination assay (Western blot + IP), cycloheximide chase, SMURF1 overexpression/knockdown, xenograft mouse model Histology and histopathology Medium 40772306
2026 GSTM2 protein is stabilized by sulfenylation at Cys174, which inhibits K48-linked ubiquitination at the same residue and prevents proteasomal degradation. The small molecule HCY-NBD promotes this Cys174 sulfenylation, thereby stabilizing GSTM2 and protecting vascular endothelial cells from high-glucose-induced senescence and calcification in vitro and in db/db mice in vivo. Site-specific sulfenylation detection, ubiquitination assays (K48-linkage), HCY-NBD treatment in cell and mouse models, db/db in vivo experiments Redox biology Medium 41637880
2026 GSTM2 directly interacts with STAT3 in astrocytes, suppressing STAT3 phosphorylation and thereby downregulating Drp1 signaling, which protects against mitochondrial fragmentation and oxidative stress in diabetes-associated cognitive dysfunction. Identified by immunoprecipitation-mass spectrometry and validated by surface plasmon resonance. Immunoprecipitation-mass spectrometry, surface plasmon resonance, astrocyte-specific GSTM2 overexpression/knockout in db/db mice, STAT3 and Drp1 pathway analysis Redox biology Medium 41916017
2025 YTHDF1 (an m6A reader protein) regulates GSTM2 mRNA and protein levels in malignant rhabdoid tumor cells. YTHDF1 knockout reduced both GSTM2 mRNA and protein, increased susceptibility to ferroptosis, and impaired the glutathione-related signaling pathway. GSTM2 overexpression in YTHDF1 KO cells partially restored the oncogenic phenotype. CRISPR/Cas9 YTHDF1 KO, 4D-label-free quantitative proteomics, Western blot, qRT-PCR, GSTM2 overexpression rescue, ferroptosis assays Cell biology and toxicology Medium 40481948
2020 GSTM2 expression is induced by gemcitabine treatment in pancreatic cancer cell lines. siRNA-mediated knockdown of GSTM2 increased apoptosis and decreased viability of gemcitabine-treated pancreatic cancer cells. shRNA-induced GSTM2 downregulation enhanced gemcitabine sensitivity in an orthotopic pancreatic tumor mouse model. siRNA knockdown, shRNA in vivo orthotopic mouse model, cell viability assay, apoptosis assay Pancreatology Medium 33341341
2000 EGCG (epigallocatechin gallate) specifically induces GSTM2 subunit expression in rat liver in a dose- and time-dependent manner (~2-fold at protein and mRNA levels), without substantially affecting GSTA1/2 or GSTM1 subunits at the same doses. The induction originates near hepatic veins and spreads outward over time. Portal vein perfusion of EGCG in rats, GST activity assay, Western blotting, immunohistochemistry, RT-PCR Biochemical pharmacology Low 10927022
2003 Butyrate specifically induces GSTM2 protein and mRNA expression in human colon cancer HT29 cells (GSTM2 undetectable in controls, induced ~14-fold at mRNA level after 24 h) and in colon fibroblasts (1.7-fold protein induction). GSTM1 and GSTT1 were not induced by butyrate in the same cells. Western blotting, RT-PCR, GST activity assay in HT29 cells and primary colon fibroblasts treated with butyrate Carcinogenesis Low 12896903
2016 GSTM2 knockdown in swine testis cells suppresses phosphorylation of STAT1 (consistent with GSTM2 binding to STAT1), which in turn regulates expression of uterus receptivity-related genes (CCLs, IRF9, IFITs, MXs, OAS). GSTM2 was also found to affect SRC, OPN, and SLC expression. siRNA knockdown of GSTM2, RNA-seq transcriptome profiling, Western blot for STAT1 phosphorylation Scientific reports Low 27905550
2025 GSTM2-targeted small molecules (NBDHEX analogues) selectively inhibit GSTM2 enzymatic activity in vitro, activate the JNK pathway, and induce apoptosis in breast cancer and pancreatic cancer cell lines. Compound 5b combined with gemcitabine significantly reduced tumor growth in vivo in an NSG mouse model, overcoming gemcitabine resistance. In vitro enzyme inhibition assays, cancer cell line cytotoxicity, JNK pathway analysis, NSG mouse xenograft bioRxivpreprint Low bio_10.1101_2025.10.20.683468

Source papers

Stage 0 corpus · 32 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 Loss of the Nrf2 transcription factor causes a marked reduction in constitutive and inducible expression of the glutathione S-transferase Gsta1, Gsta2, Gstm1, Gstm2, Gstm3 and Gstm4 genes in the livers of male and female mice. The Biochemical journal 378 11991805
1994 Crystal structure of human class mu glutathione transferase GSTM2-2. Effects of lattice packing on conformational heterogeneity. Journal of molecular biology 109 8182750
2003 Expression of glutathione S-transferases (GSTs) in human colon cells and inducibility of GSTM2 by butyrate. Carcinogenesis 87 12896903
1991 Cloning, expression, and characterization of a class-mu glutathione transferase from human muscle, the product of the GST4 locus. Proceedings of the National Academy of Sciences of the United States of America 83 2034681
2013 Functional compensation of glutathione S-transferase M1 (GSTM1) null by another GST superfamily member, GSTM2. Scientific reports 59 24048194
2016 SKN-1-independent transcriptional activation of glutathione S-transferase 4 (GST-4) by EGF signaling. Worm 48 28090393
2000 Specific induction of glutathione S-transferase GSTM2 subunit expression by epigallocatechin gallate in rat liver. Biochemical pharmacology 43 10927022
2017 Diosgenin a phytosterol substitute for cholesterol, prolongs the lifespan and mitigates glucose toxicity via DAF-16/FOXO and GST-4 in Caenorhabditis elegans. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 34 28954389
2009 No evidence for glutathione S-transferases GSTA2, GSTM2, GSTO1, GSTO2, and GSTZ1 in breast cancer risk. Breast cancer research and treatment 29 19859803
2007 Reduced expression of GSTM2 and increased oxidative stress in spontaneously hypertensive rat. Molecular and cellular biochemistry 27 18008142
2009 Genetic variants in GSTM3 gene within GSTM4-GSTM2-GSTM1-GSTM5-GSTM3 cluster influence breast cancer susceptibility depending on GSTM1. Breast cancer research and treatment 25 19856098
2009 Dissection of the inhibition of cardiac ryanodine receptors by human glutathione transferase GSTM2-2. Biochemical pharmacology 14 19168034
2024 Improving dermal fibroblast-to-epidermis communications and aging wound repair through extracellular vesicle-mediated delivery of Gstm2 mRNA. Journal of nanobiotechnology 13 38825668
2020 Downregulation of GSTM2 enhances gemcitabine chemosensitivity of pancreatic cancer in vitro and in vivo. Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.] 13 33341341
2001 Genomic organization and characterization of the promoter region of murine GSTM2 gene. Gene 13 11404019
2022 GSTM2 is a key molecular determinant of resistance to SG-ARIs. Oncogene 11 36038661
2013 Effect of GSTM2-5 polymorphisms in relation to tobacco smoke exposures on lung function growth: a birth cohort study. BMC pulmonary medicine 11 24004509
2008 Muscle-specific GSTM2-2 on the luminal side of the sarcoplasmic reticulum modifies RyR ion channel activity. The international journal of biochemistry & cell biology 11 18308613
2016 The GSTM2 C-Terminal Domain Depresses Contractility and Ca2+ Transients in Neonatal Rat Ventricular Cardiomyocytes. PloS one 10 27612301
2016 Deep sequencing of transcriptome profiling of GSTM2 knock-down in swine testis cells. Scientific reports 8 27905550
2023 GSTM2 alleviates heart failure by inhibiting DNA damage in cardiomyocytes. Cell & bioscience 6 38037116
2022 Integrated computer analysis and a self-built Chinese cohort study identified GSTM2 as one survival-relevant gene in human colon cancer potentially regulating immune microenvironment. Frontiers in oncology 5 36263204
2024 β-asarone protects against age-related motor decline via activation of SKN-1/Nrf2 and subsequent induction of GST-4. Pharmacological research 4 39366648
2007 Cloning, sequence analysis and identification of a nonsense mutation-mediated mRNA decay of porcine GSTM2 gene. Acta biochimica et biophysica Sinica 3 17687490
2024 Transcriptome and proteome analyses reveal that upregulation of GSTM2 by allisartan improves cardiac remodeling and dysfunction in hypertensive rats. Experimental and therapeutic medicine 2 38590561
2025 Loss of YTHDF1 suppresses the progression of malignant rhabdoid tumor of the kidney by regulating Glutathione S-transferase Mu 2 (GSTM2). Cell biology and toxicology 1 40481948
2025 Suppressing SMURF1 to preserve GSTM2: An approach to reducing gastric cancer aggressiveness in vitro and in vivo. Histology and histopathology 1 40772306
2026 Pseudogene-Derived Long Noncoding RNAs GSTM3P1/Gstm2-ps1 Exacerbate Sepsis-Associated Acute Kidney Injury by Suppressing Their Parent Gene Translation. The American journal of pathology 0 41633446
2026 Small molecule HCY-NBD stabilizes GSTM2 via cys174 sulfenylation to attenuate high glucose induced endothelial cell senescence and calcification. Redox biology 0 41637880
2026 Astrocytic GSTM2-STAT3 interaction ameliorates the diabetes associated cognitive dysfunction via targeting mitochondrial defects and oxidative stress. Redox biology 0 41916017
2026 GSTM2 as the molecular linking of depression-driven colon cancer progression and chemoresistance: Reversal by Sinisan. Phytomedicine : international journal of phytotherapy and phytopharmacology 0 41962265
2025 Inhibition of acn-1 , an ACE ortholog, reduces intestinal GST-4 expression in Caenorhabditis elegans. microPublication biology 0 41142193

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