The human gamma-glutamyltransferase gene family

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 gamma-glutamyl moieties from glutathione and other gamma-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 gamma-glutamyl transfer is regulated by their, as of yet uncharacterized, enzymatic activities. In view of the widespread clinical use of assays that measure gamma-glutamyl transfer activity, this would appear to be of significant interest.

Human GGT2 Does Not Autocleave into a Functional Enzyme: A Cautionary Tale for Interpretation of Microarray Data on Redox Signaling

“…1) (17,19,32,45). In humans, GGT1 (hGGT1, P19440) is expressed on the apical surfaces of glands and ducts throughout the body (14).…”

“…The GGT2 gene is unique to humans, and it likely arises from a gene duplication event of GGT1 in recent evolutionary history (19). The initial description of a new human gene closely related to hGGT1 was first reported in 1988, but the gene was not officially named GGT2 until 2008 (18,19,40,41).…”

Donor substrate specificity of bovine kidney gamma-glutamyltransferase

“…Furthermore, human genomic analysis has identified multiple members of the human GGT family, 6 of the 13 members may be functional proteins (Heisterkamp et al, 2008). Since few have been enzymatically characterized, it would beneficial to study the donor substrate specificity of human GGTs.…”

“…Mammalian GGT is a membrane-bound heterodimeric glycoprotein; the heavy subunit of GGT anchors the protein to the membrane and the light subunit contains the catalytic site of the enzyme (Castonguay et al, 2007). GGT acts in the metabolism of xenobiotics and endogenous GSH conjugates, in GSH homeostasis, in cysteine recovery, and it is often used as a biomarker of liver damage (Lieberman et al, 1996;Ikeda and Taniguchi, 2005;Castonguay et al, 2007;Heisterkamp et al, 2008;Wickham et al, 2011). GGT-knock-out mice had elevated levels of GSH in the urine (15 mM) and plasma (175 μM); GSH levels of WT mice in the urine and plasma were 6 μM and 28 μM, respectively (Lieberman et al, 1996).…”

“…Serum GGT is "mainly derived from the liver" (Okada et al, 2006). Elevated levels of serum GGT usually indicates hepatic damage, allowing for the use of GGT as a biomarker of liver damage (Okada et al, 2006;Heisterkamp et al, 2008). GGT exhibits an αββα fold (Okada et al, 2006), as shown in Figure 3.…”