GSTT1

Summary

GSTT1 (glutathione S-transferase theta 1, HGNC:4641) is a protein-coding gene on chromosome 22q11.23 alternate reference locus, encoding Glutathione S-transferase theta-1 (P30711). Conjugation of reduced glutathione to a wide number of exogenous and endogenous hydrophobic electrophiles.

The protein encoded by this gene, glutathione S-transferase (GST) theta 1 (GSTT1), is a member of a superfamily of proteins that catalyze the conjugation of reduced glutathione to a variety of electrophilic and hydrophobic compounds. Human GSTs can be divided into five main classes: alpha, mu, pi, theta, and zeta. The theta class includes GSTT1, GSTT2, and GSTT2B. GSTT1 and GSTT2/GSTT2B share 55% amino acid sequence identity and may play a role in human carcinogenesis. The GSTT1 gene is haplotype-specific and is absent from 38% of the population. Alternative splicing of this gene results in multiple transcript variants.

Source: NCBI Gene 2952 — RefSeq curated summary.

At a glance

• GWAS associations: 7
• Clinical variants (ClinVar): 24 total
• Druggable target: yes
• MANE Select transcript: NM_000853

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4641
Approved symbol	GSTT1
Name	glutathione S-transferase theta 1
Location	22q11.23 alternate reference locus
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000277656
OMIM	600436
Entrez	2952

Gene structure

Transcript identifiers

Ensembl transcripts: 0

RefSeq mRNA: 9 — MANE Select: NM_000853 NM_000853, NM_001293807, NM_001293808, NM_001293809, NM_001293810, NM_001293811, NM_001293812, NM_001293813, NM_001293814

Canonical transcript exons

ENST00000612885 — 0 exons

Expression profiles

Bgee: expression breadth ubiquitous, 205 present calls, max score 92.80.

Top tissues by expression

221 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
vena cava	UBERON:0004087	92.80	gold quality
diaphragm	UBERON:0001103	90.98	silver quality
adrenal gland	UBERON:0002369	90.44	gold quality
lateral globus pallidus	UBERON:0002476	89.68	gold quality
jejunal mucosa	UBERON:0000399	88.97	gold quality
heart right ventricle	UBERON:0002080	88.80	gold quality
coronary artery	UBERON:0001621	88.55	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	88.54	gold quality
lateral nuclear group of thalamus	UBERON:0002736	88.26	gold quality
cingulate cortex	UBERON:0003027	88.10	gold quality
anterior cingulate cortex	UBERON:0009835	87.45	gold quality
endometrium epithelium	UBERON:0004811	86.50	gold quality
vastus lateralis	UBERON:0001379	86.27	gold quality
substantia nigra pars compacta	UBERON:0001965	86.14	gold quality
cerebellar vermis	UBERON:0004720	85.82	gold quality
renal medulla	UBERON:0000362	85.45	gold quality
prostate gland	UBERON:0002367	85.45	gold quality
paraflocculus	UBERON:0005351	85.39	gold quality
urethra	UBERON:0000057	85.20	gold quality
gluteal muscle	UBERON:0002000	85.17	gold quality
biceps brachii	UBERON:0001507	84.92	gold quality
seminal vesicle	UBERON:0000998	84.69	gold quality
jejunum	UBERON:0002115	84.58	gold quality
substantia nigra pars reticulata	UBERON:0001966	84.50	gold quality
adult mammalian kidney	UBERON:0000082	84.48	gold quality
mucosa of urinary bladder	UBERON:0001259	84.44	silver quality
quadriceps femoris	UBERON:0001377	84.40	gold quality
adipose tissue	UBERON:0001013	84.26	gold quality
frontal pole	UBERON:0002795	84.18	silver quality
adrenal cortex	UBERON:0001235	84.03	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-GEOD-134144	yes	32.00
E-CURD-11	no	87.54

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 23)

• patients with carcinoma of the breast and inheritance of a combined gene deletion of GSTM1 and GSTT1 might bear an increased risk to develop a secondary therapy-induced hematologic neoplasia (PMID:11792413)
• Genetic determinants of lung cancer short-term survival: the role of glutathione-related genes (PMID:11844594)
• The carcinogenic effects of DCM in humans are caused by the interaction with DNA of a glutathione (GSH) conjugate that is produced by the class theta glutathione S-transferase T1-1 (GST T1-1). (PMID:11884241)
• polymorphism related to chronic lymphocytic leukemia (PMID:12010828)
• Individuals possessing more susceptible non-null GSTT1 genotypes were more likely to reveal p53 overexpression. (PMID:12010862)
• polymorphism of and susceptibility to oral cancer in an Indian population (PMID:12016153)
• effect of genotype on sister chromatid exchange induction by styrene in cultured human lymphocytes (PMID:12016165)
• Childhood acute lymphoblastic leukemia was not associated with the GSTT1-null genotype in blacks or whites, in contrast to previous reports. (PMID:12070010)
• association between polymorphism and survival in colorectal cancer (PMID:12072547)
• Polymorphisms that determine the activity of glutathione transferase GSTT1 appear to significantly influence cutaneous inflammatory reactions after exposure to UV light. (PMID:12083949)
• No association between GSTT1 genotypes and ALL-L1 susceptibility was found in northern Portuguese children. (PMID:12145701)
• certain null GST genotypes may be associated with an elevated risk of breast cancer and the association may be modified by charred meat intake and cigarette smoking (PMID:12150456)
• GSTT1-null genotype is a risk factors for lung adenocarcinoma development (PMID:12163326)
• Relationship between GSTT1 polymorphism and susceptibility to colon cancer (PMID:12210502)
• Women with a GSTT1-null genotype may have an increased risk of breast neoplasms. (PMID:12296511)
• Deletions have a negative prognostic value in adult acute myeloid leukemia (PMID:12351375)
• Women with the GSTT1 null genotype were found to have a significant 3.15-fold increased risk of breast cancer (95% CI = 1.7-5.8), while GSTM1 and NAT2 genotypes were not associated with breast cancer risk. (PMID:12430181)
• detection and characterization of a novel functional polymorphism (PMID:12439221)
• alcohol consumption may increase breast cancer risk among those who carry susceptible GST genotypes. (PMID:12556960)
• Results suggest that women with glutathione S-transferase M1 but not necessarily T1 null polymorphism may have an increased risk of recurrent pregnancy loss. (PMID:12606593)
• Polymorphism is not associated with laryngeal cancer risk in Caucasians. (PMID:12668919)
• polymorphisms in GSTT1 is associated with esophageal tumorigenesis (PMID:12670526)
• genetic polymorphisms of GSTT1 found in head and neck squamous cell carcinoma. (PMID:12748560)

Cross-species orthologs

0 orthologs

Protein

Protein identifiers

Glutathione S-transferase theta-1 — P30711 (reviewed: P30711)

Alternative names: GST class-theta-1, Glutathione transferase T1-1

All UniProt accessions (10): A0A0G2JMS2, A0A0G2JQD2, A0A0G2JQD8, A0A0G2JQM0, A0A0G2JRG0, A0A0G2JRJ5, A0A0G2JRN4, A0A0G2JRQ5, A0A1B0GXB6, P30711

UniProt curated annotations — full annotation on UniProt →

Function. Conjugation of reduced glutathione to a wide number of exogenous and endogenous hydrophobic electrophiles. Acts on 1,2-epoxy-3-(4-nitrophenoxy)propane, phenethylisothiocyanate 4-nitrobenzyl chloride and 4-nitrophenethyl bromide. Displays glutathione peroxidase activity with cumene hydroperoxide.

Subunit / interactions. Homodimer.

Subcellular location. Cytoplasm.

Tissue specificity. Found in erythrocyte. Expressed at low levels in liver. In lung, expressed at low levels in club cells and ciliated cells at the alveolar/bronchiolar junction. Absent from epithelial cells of larger bronchioles.

Polymorphism. The GSTT1 gene is absent from 38% of the population. The presence or absence of the GSTT1 gene is coincident with the conjugator (GSST1+) and non-conjugator (GSTT1-) phenotypes respectively. The GSTT1+ phenotype can catalyze the glutathione conjugation of dichloromethane.

Similarity. Belongs to the GST superfamily. Theta family.

Isoforms (2)

UniProt ID	Names	Canonical?
P30711-1	1	yes
P30711-2	2

RefSeq proteins (9): NP_000844, NP_001280736, NP_001280737, NP_001280738, NP_001280739, NP_001280740, NP_001280741, NP_001280742, NP_001280743 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR004045	Glutathione_S-Trfase_N	Domain
IPR004046	GST_C	Domain
IPR010987	Glutathione-S-Trfase_C-like	Domain
IPR036249	Thioredoxin-like_sf	Homologous_superfamily
IPR036282	Glutathione-S-Trfase_C_sf	Homologous_superfamily
IPR040075	GST_N_Theta	Domain
IPR040077	GST_C_Theta	Domain
IPR040079	Glutathione_S-Trfase	Family
IPR051369	GST_Theta	Family

Pfam: PF00043, PF13417

Enzyme classification (BRENDA):

• EC 2.5.1.18 — glutathione transferase (BRENDA: 178 organisms, 548 substrates, 680 inhibitors, 878 Km, 525 kcat entries)

Substrate kinetics (BRENDA)

79 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
1-CHLORO-2,4-DINITROBENZENE	0.0003–223.6	289
GLUTATHIONE	0.0002–532.43	253
GSH	0.0003–37.4	62
REDUCED GLUTATHIONE	0.017–11.4	24
ETHACRYNIC ACID	0.0001–2.43	19
CUMENE HYDROPEROXIDE	0.038–14.3	10
(+)-2-BROMO-3-(4-NITROPHENYL)PROPANOIC ACID	0.023–0.417	8
MONOCHLOROBIMANE	0.004–0.25	8
4-CHLORO-7-NITROBENZO-2-OXA-1,3-DIAZOLE	0.324–3.866	7
1-IODOHEXANE	0.009–0.059	6
ALACHLOR	0.042–7.23	6
PHENETHYL ISOTHIOCYANATE	0.0065–0.14	6
STYRENE 7,8-OXIDE	0.064–0.365	6
1,2-DICHLORO-4-NITROBENZENE	0.27–1.4	5
1-CHLORO-2,3-DINITROBENZOATE	0.21–20.7	5

Catalyzed reactions (Rhea), 1 shown:

• RX + glutathione = an S-substituted glutathione + a halide anion + H(+) (RHEA:16437)

UniProt features (40 total): helix 17, strand 5, sequence variant 4, sequence conflict 3, binding site 3, mutagenesis site 2, domain 2, initiator methionine 1, chain 1, turn 1, splice variant 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
2C3N	X-RAY DIFFRACTION	1.5
2C3Q	X-RAY DIFFRACTION	1.85
2C3T	X-RAY DIFFRACTION	2.4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P30711-F1	97.82	0.99

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (3): 40; 53–54; 66–67

Mutagenesis-validated functional residues (2):

Position	Phenotype
176	increases activity towards alkylhalogenides, but not hydroperoxides.
234	facilitates binding of substrates and increases catalytic activity.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-156590	Glutathione conjugation
R-HSA-9753281	Paracetamol ADME

MSigDB gene sets: 154 (showing top): GSE45365_CTRL_VS_MCMV_INFECTION_NK_CELL_UP, REACTOME_BIOLOGICAL_OXIDATIONS, YAO_HOXA10_TARGETS_VIA_PROGESTERONE_UP, JAEGER_METASTASIS_DN, GOZGIT_ESR1_TARGETS_DN, DACOSTA_UV_RESPONSE_VIA_ERCC3_UP, SAENZ_DETOX_PATHWAY_AND_CARCINOGENESIS_DN, GOMF_GLUTATHIONE_TRANSFERASE_ACTIVITY, GOLDRATH_ANTIGEN_RESPONSE, GOBP_CELLULAR_RESPONSE_TO_TOXIC_SUBSTANCE, GOBP_AMIDE_METABOLIC_PROCESS, GOBP_DETOXIFICATION, TSENG_IRS1_TARGETS_DN, BROWNE_HCMV_INFECTION_24HR_DN, SANSOM_APC_TARGETS_DN

GO Biological Process (2): glutathione metabolic process (GO:0006749), cellular oxidant detoxification (GO:0098869)

GO Molecular Function (4): glutathione transferase activity (GO:0004364), glutathione peroxidase activity (GO:0004602), protein binding (GO:0005515), transferase activity (GO:0016740)

GO Cellular Component (3): cytoplasm (GO:0005737), cytosol (GO:0005829), extracellular exosome (GO:0070062)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Phase II - Conjugation of compounds	1
Drug ADME	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
modified amino acid metabolic process	1
sulfur compound metabolic process	1
cellular detoxification	1
transferase activity, transferring alkyl or aryl (other than methyl) groups	1
peroxidase activity	1
binding	1
catalytic activity	1
intracellular anatomical structure	1
cytoplasm	1
extracellular vesicle	1

Protein interactions and networks

STRING

0 interactions, top by confidence (×1000):

IntAct

15 interactions, top by confidence:

A	B	Type	Score
EGFR	CTNND1	psi-mi:“MI:0914”(association)	0.750
LRP2BP	GSTT1	psi-mi:“MI:0915”(physical association)	0.590
ACTN2	GSTT1	psi-mi:“MI:0915”(physical association)	0.560
GSTT1	MID1	psi-mi:“MI:0914”(association)	0.530
ZMAT5	DENND4B	psi-mi:“MI:0914”(association)	0.530
GSTT1	CHD4	psi-mi:“MI:0915”(physical association)	0.400
CIDEC	GSTT1	psi-mi:“MI:0915”(physical association)	0.400
RHOF	GSTT1	psi-mi:“MI:0914”(association)	0.350
GSTT1	ENSA	psi-mi:“MI:0914”(association)	0.350

BioGRID (33): GSTT1 (Co-fractionation), GSTT1 (Co-fractionation), GSTT1 (Co-fractionation), GSTT1 (Co-fractionation), GSTT1 (Affinity Capture-MS), GSTT1 (Two-hybrid), MID1 (Affinity Capture-MS), MYLK2 (Affinity Capture-MS), HBB (Affinity Capture-MS), SIRT2 (Affinity Capture-MS), PRSS2 (Affinity Capture-MS), SPRTN (Affinity Capture-MS), GSTT1 (Affinity Capture-MS), HBA2 (Affinity Capture-MS), LURAP1 (Affinity Capture-MS)

ESM2 similar proteins: A0A1W2PR19, A6QPN6, O08914, O09131, O65857, O76483, O77462, O82451, P0CG29, P0CG30, P12653, P20135, P20136, P28342, P30109, P30110, P30568, P30711, P30713, P46409, P46420, P46440, P57108, P78417, P81942, P83006, P97612, Q01579, Q2NL00, Q4V8E6, Q61133, Q64471, Q66LN0, Q6NUM9, Q6QHF9, Q803A8, Q84TK0, Q865R1, Q8BWM0, Q8C0L6

Diamond homologs: A0A1W2PR19, O76483, O77473, P0CG29, P0CG30, P20135, P30711, P30713, P46430, P57108, Q01579, Q03425, Q2NL00, Q4V8E6, Q61133, Q64471, Q8L727, Q94999, Q99L20, Q9D4P7, Q9FHE1, Q9ZRT5, A2XMN2, D2YW48, O04437, O43708, O80662, O86043, P04907, P0ACA3, P0ACA4, P0ACA5, P0ACA6, P25317, P28342, P31784, P32111, P43387, P44521, P45207

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

24 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	17
Likely benign	1
Benign	4

Top pathogenic / likely-pathogenic (0)

SpliceAI

0 predictions. Top by Δscore:

AlphaMissense

0 scored. Top likely-pathogenic:

Disease associations

OMIM: gene MIM:600436 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

7 associations (top):

Study	Trait	p-value
GCST001277_19	Liver enzyme levels (gamma-glutamyl transferase)	2.000000e-09
GCST002481_6	Acne (severe)	6.000000e-07
GCST003483_1	S-phenylmercapturic acid levels in smokers	3.000000e-134
GCST004254_1	Urinary 1,3-butadiene metabolite levels in smokers	3.000000e-09
GCST004254_2	Urinary 1,3-butadiene metabolite levels in smokers	5.000000e-09
GCST004254_3	Urinary 1,3-butadiene metabolite levels in smokers	1.000000e-23
GCST004254_4	Urinary 1,3-butadiene metabolite levels in smokers	1.000000e-14

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004532	serum gamma-glutamyl transferase measurement
EFO:0007651	urinary S-phenylmercapturic acid measurement
EFO:0007957	urinary 1,3-butadiene measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2141 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

PharmGKB clinical annotations

6 annotations.

Variant	Type	Level	Drugs	Phenotypes
GSTT1 non-null, GSTT1 null	Efficacy	3	imatinib	Chronic myelogenous leukemia;BCR-ABL1 positive
GSTT1 non-null, GSTT1 null	Toxicity	3	clozapine
GSTT1 non-null, GSTT1 null	Efficacy	3	cisplatin;doxorubicin;methotrexate	Osteosarcoma
GSTT1 non-null, GSTT1 null	Toxicity	4	cisplatin	Deafness;Neoplasms;Ototoxicity
GSTT1 non-null, GSTT1 null	Toxicity	4	Drugs For Treatment Of Tuberculosis;ethambutol;isoniazid;pyrazinamide;rifampin;streptomycin	Tuberculosis
rs4630	Toxicity	3	thalidomide	Multiple Myeloma

PharmGKB variants

3 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs4630	GSTT1	3	1.50	1	thalidomide
rs1007888	GSTT1		0.00	0
rs2266637	GSTT1		0.00	0

CTD chemical–gene interactions

124 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzene	affects reaction, increases response to substance, affects response to substance, affects metabolic processing, affects abundance (+3 more)	13
Pesticides	increases activity, affects response to substance, increases abundance, increases response to substance	10
Arsenic	affects abundance, affects metabolic processing, affects methylation, affects response to substance	8
Methylene Chloride	affects metabolic processing, affects response to substance, increases metabolic processing	6
diepoxybutane	affects response to substance, increases response to substance, affects metabolic processing, increases activity, affects binding (+2 more)	5
S-phenyl-N-acetylcysteine	affects abundance, affects reaction, affects metabolic processing, affects chemical synthesis	5
Mercury	increases reaction, affects cotreatment, affects response to substance, affects abundance	5
1,2-epoxy-3-(p-nitrophenoxy)propane	decreases reaction, increases glutathionylation, affects metabolic processing	4
Styrene	increases response to substance, affects response to substance, increases reaction	4
Estradiol	decreases expression, affects cotreatment	3
Glutathione	affects metabolic processing, affects cotreatment, affects binding, increases reaction	3
Hydrocarbons, Chlorinated	affects response to substance, increases abundance	3
Lead	increases expression, increases reaction, increases response to substance, affects abundance, decreases expression (+1 more)	3
Tobacco Smoke Pollution	decreases expression, increases expression, increases response to substance	3
Valproic Acid	affects expression, decreases expression	3
Vinyl Chloride	affects cotreatment, increases response to substance, affects mutagenesis, affects reaction	3
Ethylene Dibromide	affects metabolic processing, increases activity, decreases reaction, increases glutathionylation	3
Cyclosporine	decreases expression	3
styrene oxide	affects response to substance, increases response to substance	2
monomethylarsonic acid	affects metabolic processing, affects methylation, affects abundance	2
4-nitrobenzyl chloride	affects metabolic processing, increases glutathionylation	2
methylene bromide	affects metabolic processing, increases activity	2
1,3-butadiene	affects abundance, increases reaction, increases response to substance	2
JP8 aviation fuel	affects response to substance, decreases expression	2
Acetaminophen	increases expression, affects cotreatment, decreases expression	2
Air Pollutants	increases abundance, affects response to substance	2
Asbestos	affects response to substance	2
Cacodylic Acid	affects response to substance, affects abundance, affects metabolic processing	2
Carmustine	affects response to substance, decreases nitrosation	2
Diclofenac	affects expression, affects activity	2

ChEMBL screening assays

2 unique, capped per target: 2 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1743235	ADMET	Substrates for human cytosolic glutathione transferase GSTT1	Casarett and Doull’s Toxicology The Basic Science of Poisons, 7th edition

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.