Growth retardation and cysteine deficiency in gamma-glutamyl transpeptidase-deficient mice.

Abstract

ABSTRACTy-Glutamyl transpeptidase (GGT) is an ectoenzyme that catalyzes the first step in the cleavage of glutathione (GSH) and plays an essential role in the metabolism of GSH and GSH conjugates of carcinogens, toxins, and eicosanoids. To learn more about the role of GGT in metabolism in vivo, we used embryonic stem cell technology to generate GGT-deficient (GGTml/GGTml) mice. GGTdeficient mice appear normal at birth but grow slowly and by 6 weeks are about half the weight of wild-type mice. They are sexually immature, develop cataracts, and have coats with a gray cast. Most die between 10 and 18 weeks. Plasma and urine GSH levels in the GGTml/GGTml mice are elevated 6-fold and 2500-fold, respectively, compared with wild-type mice. Tissue GSH levels are markedly reduced in eye, liver, and pancreas.Plasma cyst(e)ine levels in GGTm'/GGTml mice are reduced to '20% of wild-type mice. Oral administration of Nacetylcysteine to GGTml/GGTml mice results in normal growth rates and partially restores the normal agouti coat color. These findings demonstrate the importance of GGT and the y-glutamyl cycle in cysteine and GSH homeostasis.

Mutations in SLC45A2 Cause Plumage Color Variation in Chicken and Japanese Quail

“…There are also other mutations found to affect pheomelanin production. The gray-lethal (gl) mouse mutation in the GL/ OSTM1 gene results from stalled pheomelanin migration due to clustered pheomelanin granules (Chalhoub et al 2003), and the g-glutamyl transpeptidase (GGT) knockout mice lack cysteine as a result of the nonworking cleavage of glutathione (Lieberman et al 1996). However, if SLC45A2 has an important role for the incorporation of sulfhydryls into pheomelanin it cannot be its sole function since a defect in cystine/cysteine transport should not affect eumelanogenesis, whereas SLC45A2 null mutations almost completely abolish the production of both eumelanin and pheomelanin.…”

Selective fluorescent probes for live-cell monitoring of sulphide

“…The previously mentioned enzymes, CBS and cystathionine γ-lyase, both use cysteine as a substrate for H 2 S production 8,9,[18][19][20] . GSH can be broken down by γ-glutayml transpeptidase and a dipeptidase to give cysteine [21][22][23] , which can then be converted to H 2 S. Therefore, we tested whether a perturbation of the intracellular levels of either cysteine, or GSH could result in an increased cellular concentration of H 2 S. Imaging experiments were carried out with SFP-2, as previously described, and cells were incubated with either 100 µM GSH or cysteine. After 30 min of incubation, addition of both thiol species elicited a significant response rivalling that observed for Na 2 S (Fig.…”

γ-Glutamyl transpeptidase is induced by 4-hydroxynonenal via EpRE/Nrf2 signaling in rat epithelial type II cells

“…γ-Glutamyl transpeptidase (γ-glutamyl transferase, GGT), an enzyme located on the outer surface of the plasma membrane, catalyzes the transfer of the γ-glutamyl moiety from glutathione (GSH), glutathione S-conjugates, or other γ-glutamyl compounds to γ-glutamyl acceptors such as amino acids, dipeptides, or H 2 O. GGT plays key roles in the maintenance of glutathione homeostasis [1][2][3][4][5][6][7] and metabolism of biomolecules such as leukotriene C4 and xenobiotics following their conjugation with GSH [8].…”