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The human gamma-glutamyltransferase gene family

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Abstract

Assays for gamma-glutamyl transferase (GGT1, EC 2.3.2.2) activity in blood are widely used in a clinical setting to measure tissue damage. The well-characterized GGT1 is an extracellular enzyme that is anchored to the plasma membrane of cells. There, it hydrolyzes and transfers γ-glutamyl moieties from glutathione and other γ-glutamyl compounds to acceptors. As such, it has a critical function in the metabolism of glutathione and in the conversion of the leukotriene LTC4 to LTD4. GGT deficiency in man is rare and for the few patients reported to date, mutations in GGT1 have not been described. These patients do secrete glutathione in urine and fail to metabolize LTC4. Earlier pre-genome investigations had indicated that besides GGT1, the human genome contains additional related genes or sequences. These sequences were given multiple different names, leading to inconsistencies and confusion. Here we systematically evaluated all human sequences related to GGT1 using genomic and cDNA database searches and identified thirteen genes belonging to the extended GGT family, of which at least six appear to be active. In collaboration with the HUGO Gene Nomenclature Committee (HGNC) we have designated possible active genes with nucleotide or amino acid sequence similarity to GGT1, as GGT5 (formerly GGL, GGTLA1/GGT-rel), GGT6 (formerly rat ggt6 homologue) and GGT7 (formerly GGTL3, GGT4). Two loci have the potential to encode only the light chain portion of GGT and have now been designated GGTLC1 (formerly GGTL6, GGTLA4) and GGTLC2. Of the five full-length genes, three lack of significant nucleotide sequence homology but have significant (GGT5, GGT7) or very limited (GGT6) amino acid similarity to GGT1 and belong to separate families. GGT6 and GGT7 have not yet been described, raising the possibility that leukotriene synthesis, glutathione metabolism or γ-glutamyl transfer is regulated by their, as of yet uncharacterized, enzymatic activities. In view of the widespread clinical use of assays that measure γ-glutamyl transfer activity, this would appear to be of significant interest.

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Acknowledgments

The literature on GGT in human and other species is very extensive and we apologize to those authors of whom the work could not be cited. This work was supported by PHS grants HL071945 and HL060231, NHGRI grant P41 HG 003345, the UK Medical Research Council and the Wellcome Trust.

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Authors and Affiliations

  1. Division of Hematology/Oncology, The Saban Research Institute of Childrens Hospital, Los Angeles, CA, 90027, USA

    Nora Heisterkamp & John Groffen

  2. Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA

    Nora Heisterkamp & John Groffen

  3. Developmental Biology Program and Department of Surgery, The Saban Research Institute of Childrens Hospital, Los Angeles, CA, 90027, USA

    David Warburton

  4. HUGO Gene Nomenclature Committee (HGNC), Department of Biology, University College London, London, NW1 2HE, UK

    Tam P. Sneddon

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  1. Nora Heisterkamp
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  2. John Groffen
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  4. Tam P. Sneddon
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Correspondence to Nora Heisterkamp.

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Heisterkamp, N., Groffen, J., Warburton, D. et al. The human gamma-glutamyltransferase gene family. Hum Genet 123, 321–332 (2008). https://doi.org/10.1007/s00439-008-0487-7

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