B Ketterer

The glutathione transferases are recognized as important catalysts in the biotransformation of xenobiotics, including drugs as well as environmental pollutants. Multiple forms exist, and numerous transferases from mammalian tissues, insects, and plants have been isolated and characterized. Enzymatic properties, reactions with antibodies, and structural characteristics have been used for classification of the glutathione transferases. The cytosolic mammalian enzymes could be grouped into three distinct classes--Alpha, Mu, and Pi; the microsomal glutathione transferase differs greatly from all the cytosolic enzymes. Members of each enzyme class have been identified in human, rat, and mouse tissues. Comparison of known primary structures of representatives of each class suggests a divergent evolution of the enzyme proteins from a common precursor. Products of oxidative metabolism such as organic hydroperoxides, epoxides, quinones, and activated alkenes are possible "natural" substrates for the glutathione transferases. Particularly noteworthy are 4-hydroxyalkenals, which are among the best substrates found. Homologous series of substrates give information about the properties of the corresponding binding site. The catalytic mechanism and the active-site topology have been probed also by use of chiral substrates. Steady-state kinetics have provided evidence for a "sequential" mechanism.

In humans, glutathione-dependent conjugation of halomethanes is polymorphic, with 60% of the population classed as conjugators and 40% as non-conjugators. We report the characterization of the genetic polymorphism causing the phenotypic difference. We have isolated a cDNA that encodes a human class Theta GST (GSTT1) and which shares 82% sequence identity with rat class Theta GST5-5. From PCR and Southern blot analyses, it is shown that the GSTT1 gene is absent from 38% of the population. The presence or absence of the GSTT1 gene is coincident with the conjugator (GSST1+) and non-conjugator (GSTT1-) phenotypes respectively. The GSTT1+ phenotype can catalyse the glutathione conjugation of dichloromethane, a metabolic pathway which has been shown to be mutagenic in Salmonella typhimurium mutagenicity tester strains and is believed to be responsible for carcinogenicity of dichloromethane in the mouse. In humans, the enzyme is found in the erythrocyte and this may act as a detoxification sink. Characterization of the GSTT1 polymorphism will thus enable a more accurate assessment of human health risk from synthetic halomethanes and other industrial chemicals.

Glutathione transferases (GSTs) of a novel class, which it is proposed to term Theta, were purified from rat and human liver. Two, named GST 5-5 and GST 12-12, were obtained from the rat, and one, named GST theta, was from the human. Unlike other mammalian GSTs they lack activity towards 1-chloro-2,4-dinitrobenzene and are not retained by GSH affinity matrices. Only GST 5-5 retains full activity during purification, and its activities towards the substrates 1,2-epoxy-3-(p-nitrophenoxy)propane, p-nitrobenzyl chloride, p-nitrophenethyl bromide, cumene hydroperoxide, dichloromethane and DNA hydroperoxide are 185, 86, 67, 42, 11 and 0.03 mumol/min per mg of protein respectively. Earlier preparations of GST 5-5 or GST E were probably a mixture of GST 5-5 and GST 12-12, which was largely inactive, and may also have been contaminated by less than 1% with another GSH peroxidase of far greater activity. Partial analysis of primary structure shows that subunits 5, 12 and theta are related to each other, particularly at the N-terminus, where 25 of 27 residues are identical, but have little relationship to the Alpha, Mu and Pi classes of mammalian GSTs. They do, however, show some relatedness to subunit I of Drosophila melanogaster [Toung, Hsieh & Tu (1990) Proc. Natl. Acad. Sci. U.S.A. 87, 31-35] and the dichloromethane dehalogenase of Methylobacterium DM4 [La Roche & Leisinger (1990) J. Bacteriol, 172, 164-171].

Correspondence| February 15 1992 Nomenclature for human glutathione transferases B Mannervik; B Mannervik Search for other works by this author on: This Site PubMed Google Scholar Y C Awasthi; Y C Awasthi Search for other works by this author on: This Site PubMed Google Scholar P G Board; P G Board Search for other works by this author on: This Site PubMed Google Scholar J D Hayes; J D Hayes Search for other works by this author on: This Site PubMed Google Scholar C Di Ilio; C Di Ilio Search for other works by this author on: This Site PubMed Google Scholar B Ketterer; B Ketterer Search for other works by this author on: This Site PubMed Google Scholar I Listowsky; I Listowsky Search for other works by this author on: This Site PubMed Google Scholar R Morgenstern; R Morgenstern Search for other works by this author on: This Site PubMed Google Scholar M Muramatsu; M Muramatsu Search for other works by this author on: This Site PubMed Google Scholar W R Pearson; W R Pearson Search for other works by this author on: This Site PubMed Google Scholar C B Pickett; C B Pickett Search for other works by this author on: This Site PubMed Google Scholar K Sato; K Sato Search for other works by this author on: This Site PubMed Google Scholar M Widersten; M Widersten Search for other works by this author on: This Site PubMed Google Scholar C R Wolf C R Wolf Search for other works by this author on: This Site PubMed Google Scholar Author and article information Publisher: Portland Press Ltd Online ISSN: 1470-8728 Print ISSN: 0264-6021 © 1992 The Biochemical Society, London1992 Biochem J (1992) 282 (1): 305–306. https://doi.org/10.1042/bj2820305 Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Facebook Twitter LinkedIn Email Cite Icon Cite Get Permissions Citation B Mannervik, Y C Awasthi, P G Board, J D Hayes, C Di Ilio, B Ketterer, I Listowsky, R Morgenstern, M Muramatsu, W R Pearson, C B Pickett, K Sato, M Widersten, C R Wolf; Nomenclature for human glutathione transferases. Biochem J 15 February 1992; 282 (1): 305–306. doi: https://doi.org/10.1042/bj2820305 Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search Dropdown Menu toolbar search search input Search input auto suggest filter your search All ContentAll JournalsBiochemical Journal Search Advanced Search This content is only available as a PDF. © 1992 The Biochemical Society, London1992 Article PDF first page preview Close Modal You do not currently have access to this content.