title: Quantitative differences in the active-site hydrophobicity of five human glutathione S-transferase isoenzymes: water-soluble carcinogen-selective properties of the neoplastic GSTP1-1 species.
abstract: The active-site (the H-site) hydrophobicity of five human glutathione S-transferases (GSTs) was analyzed by application of linear free energy relationships (LFERs) with a series of S-alkylated glutathione inhibitors, GS(CH2)n - 1CH3 (n = 1-14). Distinct linear reltionships were observed in the plots of log Ki (inhibition constant) vs n for the five forms, whereby the Kis varied by three to four orders of magnitude. Mean free enthalpy changes per methylene group (-Delta DeltaG degreess), a measure of H-site hydrophobicity, were in the order M1-1 (4.6 kJ/mol) > A1-1 (3. 9 kJ/mol) > A1-2 (3.8 kJ/mol) > A2-2 (2.8 kJ/mol) > P1-1 (1.6 kJ/mol). The quantitative differences may in part account for the extraordinary broad and overlapping substrate specificities of the Alpha-, Mu-, and Pi-class isoenzymes. In contrast to the Alpha and Mu classes being selective for strongly electrophilic compounds, the neoplastic P1-1 species was indicated to be selective for weakly electrophilic and water-soluble carcinogens such as acrolein and hydroxyalkenals.
authors.affiliation: Second Department of Biochemistry, Hirosaki University, School of Medicine, Hirosaki, 036, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Satoh
authors.forename: R
authors.initials: R
authors.lastname: Sato
authors.forename: T
authors.initials: T
authors.lastname: Takahata
authors.forename: S
authors.initials: S
authors.lastname: Suzuki
authors.forename: M
authors.initials: M
authors.lastname: Hayakari
authors.forename: S
authors.initials: S
authors.lastname: Tsuchida
authors.forename: I
authors.initials: I
authors.lastname: Hatayama
mesh_terms: D001665:Binding Sites; D002273:Carcinogens / Q000737:chemistry* / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005978:Glutathione / Q000378:metabolism; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D012995:Solubility; D013816:Thermodynamics; D014867:Water / Q000378:metabolism*
chemical_list: D002273:Carcinogens; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D009363:Neoplasm Proteins; D014867:Water; C496556:GSTP1 protein, human; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase; D005978:Glutathione