Glutathione transferase zeta: Discovery, polymorphic variants, catalysis, inactivation, and properties of Gstz1 -/- mice




Board, Philip
Anders, M W

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Informa Healthcare


Glutathione transferase zeta (GSTZ1) is a member of the GST superfamily of proteins that catalyze the reaction of glutathione with endo- and xenobiotics. GSTZ1-1 was discovered by a bioinformatics strategy that searched the human-expressed sequence-tag database with a sequence that matched a putative plant GST. A sequence that was found was expressed and termed GSTZ1-1. In common with other GSTs, GSTZ1-1 showed some peroxidase activity, but lacked activity with most known GST substrates. GSTZ1-1 was also found to be identical with maleylacetoacetate isomerase, which catalyzes the penultimate step in the tyrosine-degradation pathway. Further studies showed that dichloroacetate (DCA) and a range of αhaloalkanoates and αα, αdihaloalkanoates were substrates. A subsequent search of the human-expressed sequence-tag database showed the presence of four polymorphic alleles: 1a, 1b, 1c, and 1d; GSTZ1c was the most common and was designated as the wild-type gene. DCA was shown to be a kcat inactivator of human, rat, and mouse GSTZ1-1; human GSTZ1-1 was more resistant to inactivation than mouse or rat GSTZ1-1. Proteomic analysis showed that hGSTZ1-1 was inactivated when Cys-16 was modified by glutathione and the carbon skeleton of DCA. The polymorphic variants of hGSTZ1-1 differ in their susceptibility to inactivation, with 1a-1a being more resistant to inactivation than the other variants. The targeted deletion of GSTZ1 yielded mice that were not phenotypically distinctive. Phenylalanine proved, however, to be toxic to Gstz1-/- mice, and these mice showed evidence of organ damage and leucopenia.



Keywords: (alpha chlorocarboxymethyl)glutathione; acetic acid derivative; acetone; alkanoic acid; alpha haloalkanoate derivative; alpha,alpha dihaloalkanoate derivative; carbon; chlorofluoroacetic acid; dichloroacetic acid; enzyme variant; fumarylacetoacetic acid; bioinformatics; dichloroacetate; glutathione transferase zeta; glutathione transferases; maleylacetoacetate isomerase; polymorphic variants; targeted gene deletion



Drug Metabolism Reviews


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