title: Glutathione transferase zeta: discovery, polymorphic variants, catalysis, inactivation, and properties of Gstz1-/- mice.
abstract: 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 α-haloalkanoates and α,α-dihaloalkanoates 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 k(cat) 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.
authors.affiliation: Molecular Genetics Group, John Curtin School of Medical Research, Australian National University, Canberra, Australia.
authors.forename: Philip G
authors.initials: PG
authors.lastname: Board
authors.forename: M W
authors.initials: MW
authors.lastname: Anders
mesh_terms: D000818:Animals; D002384:Catalysis; D005982:Glutathione Transferase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D015394:Molecular Structure; D010802:Phylogeny; D011110:Polymorphism, Genetic; D013379:Substrate Specificity
chemical_list: C498694:Gstz1 protein, mouse; D005982:Glutathione Transferase