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Activity of Four Allelic Forms of Glutathione S-Transferase Hgstp1-1 For Diol Epoxides of Polycyclic Aromatic Hydrocarbons

  1. Author:
    Hu, X.
    Xia, H.
    Srivastava, S. K.
    Herzog, C.
    Awasthi, Y. C.
    Ji, X. H.
    Zimniak, P.
    Singh, S. V.
  2. Author Address

    Singh SV MERCY HOSP PITTSBURGH MERCY CANC INST CANC RES LAB 1400 LOCUST ST PITTSBURGH, PA 15219 USA MERCY HOSP PITTSBURGH MERCY CANC INST CANC RES LAB PITTSBURGH, PA 15219 USA UNIV ARKANSAS MED SCI DEPT MED LITTLE ROCK, AR 72205 USA UNIV ARKANSAS MED SCI DEPT BIOCHEM & MOL BIOL LITTLE ROCK, AR 72205 USA JOHN L MCCLELLAN MEM VET ADM MED CTR LITTLE ROCK, AR 72205 USA UNIV TEXAS MED BRANCH DEPT HUMAN BIOL CHEM & GENET GALVESTON, TX 77555 USA NCI FREDERICK CANC RES & DEV CTR ABL BASIC RES PROGRAM FREDERICK, MD 21702 USA
    1. Year: 1997
  1. Journal: Biochemical and Biophysical Research Communications
    1. 238
    2. 2
    3. Pages: 397-402
  2. Type of Article: Article
  1. Abstract:

    Allelic forms of hGSTP1-1 which differ from each other by their catalytic properties and, structurally, by the amino ac:id(s) in position(s) 104 or (and) 113 are known to exist in human populations. The four possible isoforms of hGSTP1-1 with isoleucine or valine in position 104 and with alanine or valine in position 113 were produced by site-directed mutagenesis of the cDNA followed by bacterial expression and purification of the proteins. Glutathione-conjugating activity was measured with the diol epoxides of benzo(a)pyrene and chrysene, as well as with the model substrate 1-chloro-2,4-dinitrobenzene. Isoenzymes with valine in position 104 were more effective with the diol epoxides of polycyclic aromatic hydrocarbons but less effective with 1-chloro-2,4-dinitrobenzene than the iso forms with isoleucine 104. In addition, the transition A113V in the presence of V104 caused a pronounced increase in catalytic efficiency for the benzo(a)pyrene but not the chrysene diol epoxide. It is proposed that amino acid 113 functions as part of a clamp that lines the mouth of the water channel leading to the active sites of the hGSTP1-1 dimer and controls the access to substrates. Therefore, the hydrophobicity and the size of residue 113 are important in co-determining the substrate specificity of the isoenzymes. The widely different activities of the allelic isoforms toward carcinogenic diol epoxides of polycyclic aromatic hydrocarbons may help to explain the correlation between cancer susceptibility and genotype at the hGSTP1 locus that has been found by others. (C) 1997 Academic Press. [References: 25]

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