{"uniprot":"P0CG29","gene":"GSTT2","name":"Glutathione S-transferase theta-2","organism":"Homo sapiens (Human)","status":"dark","length":244,"sequence":"MGLELFLDLVSQPSRAVYIFAKKNGIPLELRTVDLVKGQHKSKEFLQINSLGKLPTLKDGDFILTESSAILIYLSCKYQTPDHWYPSDLQARARVHEYLGWHADCIRGTFGIPLWVQVLGPLIGVQVPKEKVERNRTAMDQALQWLEDKFLGDRPFLAGQQVTLADLMALEELMQPVALGYELFEGRPRLAAWRGRVEAFLGAELCQEAHSIILSILEQAAKKTLPTPSPEAYQAMLLRIARIP","function_summary":"A cytosolic theta-class glutathione S-transferase that forms a soluble dimer and uses a glutathione-binding N-terminal thioredoxin-like module coupled to a hydrophobic C-terminal pocket to catalyze glutathione-dependent isomerization and conjugation reactions. This chemistry supports detoxification of electrophiles and reactive carbonyls within the glutathione network of the cytoplasm, with occasional incorporation into extracellular vesicles that can redistribute detoxification capacity.","plain_language":"GSTT2 has barely been studied. The model's best guess: A cytosolic theta-class glutathione S-transferase that forms a soluble dimer and uses a glutathione-binding N-terminal thioredoxin-like module coupled to a hydrophobic C-terminal pocket to catalyze glutathione-dependent isomerization and conjugation reactions. This chemistry supports detoxification of electrophiles and reactive carbonyls within the glutathione network of the cytoplasm, with occasional incorporation into extracellular vesicles that can redistribute detoxification capacity.","uniprot_summary":"Exhibits glutathione-dependent isomerase activity toward 1,2-diphenyl-1,2-propanediol. May be involved in detoxification processes.","go_terms":{"molecular_function":[{"id":"GO:0004364","label":"glutathione transferase activity"}],"biological_process":[{"id":"GO:0006749","label":"glutathione metabolic process"}],"cellular_component":[{"id":"GO:0005829","label":"cytosol"},{"id":"GO:0070062","label":"extracellular exosome"}]},"interpro":[{"id":"IPR036249","name":"Thioredoxin-like superfamily","type":"homologous_superfamily","start":1,"end":86},{"id":"IPR036282","name":"Glutathione S-transferase, C-terminal domain superfamily","type":"homologous_superfamily","start":81,"end":236},{"id":"IPR004045","name":"Glutathione S-transferase, N-terminal","type":"domain","start":1,"end":82},{"id":"IPR040075","name":"Glutathione S-transferase Theta, N-terminal","type":"domain","start":3,"end":78},{"id":"IPR010987","name":"Glutathione S-transferase, C-terminal-like","type":"domain","start":88,"end":224},{"id":"IPR040077","name":"Glutathione S-transferase Theta, C-terminal","type":"domain","start":91,"end":216},{"id":"IPR004046","name":"Glutathione S-transferase, C-terminal","type":"domain","start":128,"end":198},{"id":"IPR051369","name":"Glutathione S-transferase Theta","type":"family","start":1,"end":223},{"id":"IPR040079","name":"Glutathione transferase family","type":"family","start":2,"end":224}],"reasoning":"I begin with the InterPro architecture. The N-terminus (residues 1–86) is covered by IPR036249 (Thioredoxin-like superfamily) and by IPR004045 (Glutathione S-transferase, N-terminal domain, residues 1–82), with theta-class specialization captured by IPR040075 (Glutathione S-transferase Theta, N-terminal, residues 3–78). This thioredoxin-like N-terminal fold forms the canonical G-site that binds reduced glutathione and positions its thiol for nucleophilic attack. The C-terminal half is defined by multiple concordant C-terminal GST signatures—IPR036282 (Glutathione S-transferase, C-terminal domain superfamily, residues 81–236), IPR010987 (Glutathione S-transferase, C-terminal-like, residues 88–224), IPR040077 (Glutathione S-transferase Theta, C-terminal, residues 91–216), and IPR004046 (Glutathione S-transferase, C-terminal, residues 128–198). This helical C-terminal domain forms the hydrophobic H-site that accommodates electrophilic or hydrophobic co-substrates and contributes dimerization surfaces. Family-level assignments IPR051369 (Glutathione S-transferase Theta, residues 1–223) and IPR040079 (Glutathione transferase family, residues 2–224) anchor the enzyme to the theta class, which is known for pronounced glutathione-dependent isomerase and conjugation chemistries.\n\nThis two-domain GST architecture causally dictates the molecular function. The thioredoxin-like N-terminal G-site activates glutathione, while the C-terminal H-site positions diverse hydrophobic electrophiles; together they enable glutathione conjugation chemistry formalized as GO:0004364 glutathione transferase activity. Theta-class active-site geometry also stabilizes an enediolate intermediate, which explains the observed glutathione-dependent isomerization of 1,2-diphenyl-1,2-propanediol and supports a broader role in detoxifying reactive carbonyls and lipid-derived aldehydes.\n\nFrom this chemistry, the biological process follows. By catalyzing glutathione conjugation and isomerization, the enzyme feeds into and modulates the cellular glutathione network, aligning with GO:0006749 glutathione metabolic process. This process-level role integrates detoxification with redox homeostasis, buffering oxidative and electrophilic stress.\n\nCellular localization is inferred from the soluble, dimeric GST fold lacking transmembrane segments or signal peptides, which places the enzyme in the cytosolic compartment consistent with GO:0005829 cytosol and the broader cytoplasmic designation. Its presence in extracellular vesicles is plausible because cytosolic detoxification enzymes are frequently packaged into exosomes; this supports GO:0070062 extracellular exosome as an additional compartment where the enzyme may be exported or sequestered.\n\nMechanistically, the protein likely functions as a cytosolic theta-class GST dimer. The N-terminal thioredoxin-like module binds and activates glutathione; the C-terminal helical bundle shapes a hydrophobic pocket that orients electrophilic substrates for conjugation or channels them toward isomerization. I hypothesize transient assemblies with glutathione-cycle enzymes (glutathione reductase and glutathione synthetase) to maintain substrate flux, and with cytosolic chaperones that stabilize dimer formation. Packaging into exosomes suggests occasional association with vesicle-sorting machinery, enabling extracellular redistribution of detoxification capacity.","category":"dark","control_evaluation":null,"validation_plan":null,"structure":{"source":"AlphaFold DB","pdb":"/structures/AF-P0CG29.pdb","alphafold":"https://alphafold.ebi.ac.uk/entry/P0CG29"},"links":{"uniprot":"https://www.uniprot.org/uniprotkb/P0CG29/entry","atlas":"/p/P0CG29"},"provenance":{"model":"BioReason-Pro (ESM3 esm3-sm-open-v1)","source_list":"Pharos Tdark","note":"AI prediction, not experimentally verified"}}