Glutathionuria: Inborn error of metabolism due to tissue deficiency of gamma-glutamyl transpeptidase

Schulman, Joseph D.; Goodman, Stephen I.; Mace, John; Patrick, A. D.; Tietze, Frank; Butler, E.J.

doi:10.1016/s0006-291x(75)80062-3

Cited by 141 publications

(45 citation statements)

References 14 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…DISCUSSION These findings illuminate an aspect of glutathione metabolism not previously examined (i.e., the flow of intracellular glutathione in the kidney to the membrane-bound enzyme). Such a translocation of glutathione was suggested previously (1), and is consistent with findings on a patient with an inborn deficiency of y-glutamyl transpeptidase (18). Glutathionuria induced by administration of transpeptidase inhibitors therefore provides [as noted previously (1) Bartoli and Sies (22), who found a substantial efflux of glutathione in this system to non-hemoglobin-containing perfusate.…”

Section: Resultssupporting

confidence: 90%

Translocation of intracellular glutathione to membrane-bound γ-glutamyl transpeptidase as a discrete step in the γ-glutamyl cycle: Glutathionuria after inhibition of transpeptidase

Griffith

Meister

1979

Proc. Natl. Acad. Sci. U.S.A.

226

View full text Add to dashboard Cite

Several inhibitors of 'y-glutamyl transpeptidase in vitro [L-serine plus borate, 6-diazo-5-oxo-L-norleucine, and L-and Dy-glutamyl-(o-carboxy)phenylhydrazidel are active in vivo, as indicated by their effect in decreasing the conversion of administered D"-glutamyl-L-a-amino[14Cbutyrate to respiratory 14CO2 in mice. The hydrazides (both L and D isomers) are the most ptent inhibitors in vitro and in vivo. Inhibition of y-glutamyl transpeptidase in vivo by the hydrazides is accompanied by extensive glutathionuria. The evidence suggests that a substantial fraction of the urinary glutathione arises from the kidney. The findings support the view that renal intracellular glutathione is normally tra-slocated to the membrane-bound 'y-glutamyl transpeptidase as a separate step in the -utamyl cycle. Studies on in vivo inhibition of glutathione synthesis and of 'y-glutamyl transpeptidase provide direct evidence that glutathione is normally translocated from tissues to the blood plasma and that the turnover of plasma glutathione is relativelyMigh. The data suggest that the low but significant steady-state level of glutathione in the plasma reflects synthesis of glutathione (predominantly in the liver) and its utilization by -y-glutamyl transpeptidase (predominantly in the kidney). Thus, glutathione synthesized in cells that have transpeptidase may be translocated to and used by the membrane-bound enzyme, whereas glutathione synthesized in cells that lack the transtidase may be transported via the plasma to transpeptidase ocated on the membranes of other cells. Previous studies in this laboratory provided evidence that the 'y-glutamyl cycle functions in the kidney by using intracellular glutathione and that the steady-state level of glutathione in the kidney reflects a balance between glutathione synthesis and glutathione utilization (1). Thus, administration of prothionine sulfoximine, an inhibitor of y-glutamyl-cysteine synthetase (and therefore of glutathione synthesis), was followed by a rapid decline in the glutathione level (2). Administration of large doses of amino acids also decreased kidney levels of glutathione, an effect ascribed to increased utilization of glutathione by 'yglutamyl transpeptidase. Inhibition of 'y-glutamyl transpeptidase by administration of L-serine plus borate decreased the rate of glutathione disappearance that occurs after inhibition of glutathione synthesis and also decreased the extent of glutathione disappearance that follows administration of amino acids. [A similar result was observed after inhibition of -y-glutamyl transpeptidase in vivo by administration of 6-diazo-5-oxo-L-norleucine (data cited in ref. 1).]Glutathione occurs predominantly intracellularly, whereas most of the y-glutamyl transpeptidase activity present in tissues is bound to cell membranes, and there is evidence that a substantial fraction of the enzyme is bound to the outer surface of the membrane (3-8). Previous studies indicated that intracellular glutathione must be accessible to the transpeptidase to acc...

show abstract

Section: Resultssupporting

confidence: 90%

Translocation of intracellular glutathione to membrane-bound γ-glutamyl transpeptidase as a discrete step in the γ-glutamyl cycle: Glutathionuria after inhibition of transpeptidase

Griffith

Meister

1979

Proc. Natl. Acad. Sci. U.S.A.

226

View full text Add to dashboard Cite

show abstract

“…Inborn deficiency of GGT1 causes glutathionuria (Schulman et al 1975;Wright et al 1980). TGM1, also known as transglutaminase, is expressed during terminal differentiation of keratinocytes (Candi et al 1995); this enzyme synthesizes the cornified envelope by a cross-linking reaction (Melino et al 2000).…”

Section: Introductionmentioning

confidence: 99%

Catalog of 680 variations among eight cytochrome P450 (CYP) genes, nine esterase genes, and two other genes in the Japanese population

et al. 2003

View full text Add to dashboard Cite

We screened DNAs from 48 Japanese individuals for single-nucleotide polymorphisms (SNPs) in eight cytochrome P450 (CYP) genes, nine esterase genes, and two other genes by directly sequencing the relevant genomic regions in their entirety except for repetitive elements. This approach identified 607 SNPs and 73 insertion/deletion polymorphisms among the 19 genes examined. Of the 607 SNPs, 284 were identified in CYP genes, 302 in esterase genes, and 21 in the other two genes (GGT1, and TGM1); overall, 37 SNPs were located in 5' flanking regions, 496 in introns, 55 in exons, and 19 in 3' flanking regions. These variants should contribute to studies designed to investigate possible correlations between genotypes and phenotypes of disease susceptibility or responsiveness to drug therapy.Keywords Single-nucleotide polymorphism (SNP) AE Cytochrome P450 (CYP) AE Esterase AE GGT1 AE TGM1

show abstract

“…In mammals, GGT is involved in the conversion of leukotriene C 4 to D 4 , although GGT is not the only enzyme that catalyzes this reaction (6,7). GGT is a key enzyme in glutathione metabolism, and genetic diseases of GGT deficiency, including glutathionemia and glutathionuria, are associated with mental retardation (8,9).…”

mentioning

confidence: 99%

Crystal structures of γ-glutamyltranspeptidase from Escherichia coli , a key enzyme in glutathione metabolism, and its reaction intermediate

Okada

Suzuki

Wada

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

159

211

View full text Add to dashboard Cite

␥-Glutamyltranspeptidase (GGT) is a heterodimic enzyme that is generated from the precursor protein through posttranslational processing and catalyzes the hydrolysis of ␥-glutamyl bonds in ␥-glutamyl compounds such as glutathione and͞or the transfer of the ␥-glutamyl group to other amino acids and peptides. We have determined the crystal structure of GGT from Escherichia coli K-12 at 1.95 Å resolution. GGT has a stacked ␣␤␤␣ fold comprising the large and small subunits, similar to the folds seen in members of the N-terminal nucleophile hydrolase superfamily. The active site Thr-391, the N-terminal residue of the small subunit, is located in the groove, from which the pocket for ␥-glutamyl moiety binding follows. We have further determined the structure of the ␥-glutamyl

show abstract

Glutathionuria: Inborn error of metabolism due to tissue deficiency of gamma-glutamyl transpeptidase

Cited by 141 publications

References 14 publications

Translocation of intracellular glutathione to membrane-bound γ-glutamyl transpeptidase as a discrete step in the γ-glutamyl cycle: Glutathionuria after inhibition of transpeptidase

Translocation of intracellular glutathione to membrane-bound γ-glutamyl transpeptidase as a discrete step in the γ-glutamyl cycle: Glutathionuria after inhibition of transpeptidase

Catalog of 680 variations among eight cytochrome P450 (CYP) genes, nine esterase genes, and two other genes in the Japanese population

Crystal structures of γ-glutamyltranspeptidase from Escherichia coli , a key enzyme in glutathione metabolism, and its reaction intermediate

Contact Info

Product

Resources

About