Defective GGT1 does not hydrolyse GSH

Stable Identifier
Reaction [transition]
Homo sapiens
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To be excreted in urine, glutathione conjugates undergo several hydrolysis steps to form mercapturic acids which are readily excreted. The first step is the hydrolysis of a gamma-glutamyl residue from the conjugate catalysed by gamma-glutamyltransferases (GGTs). These are membrane-bound, heterodimeric enzymes composed of light and heavy peptide chains. Extracellular glutathione (GSH) or its conjugates can be hydrolysed to produce cysteinylglycine (CG, or CG conjugates) and free glutamate (L-Glu). Defects in GGT1 can cause glutathionuria (GLUTH; MIM:231950), an autosomal recessive disorder characterised by increased GSH concentration in the plasma and urine. Mutations that cause GLUTH can occur in both chains of the GGT1 dimer. R107H and R107Q in the heavy chain play a significant role in substrate binding rather than catalysis (Ikeda et al. 1993). S451A, S452A, D423A and D423E mutations in the light, catalytic chain of GGT1 completely or almost completely result in loss of function of the enzyme (Ikeda et al. 1995, Ikeda et al. 1995b).

Literature References
PubMed ID Title Journal Year
7759490 Human gamma-glutamyl transpeptidase mutants involving conserved aspartate residues and the unique cysteine residue of the light subunit

Ikeda, Y, Fujii, J, Taniguchi, N, Meister, A

J. Biol. Chem. 1995
7673200 Involvement of Ser-451 and Ser-452 in the catalysis of human gamma-glutamyl transpeptidase

Ikeda, Y, Fujii, J, Anderson, ME, Taniguchi, N, Meister, A

J. Biol. Chem. 1995
8095045 Significance of Arg-107 and Glu-108 in the catalytic mechanism of human gamma-glutamyl transpeptidase. Identification by site-directed mutagenesis

Ikeda, Y, Fujii, J, Taniguchi, N

J. Biol. Chem. 1993
Catalyst Activity

glutathione hydrolase activity of GGT1 mutants [plasma membrane]

Normal reaction
Functional status

Loss of function of GGT1 mutants [plasma membrane]

Name Identifier Synonyms
inherited metabolic disorder DOID:655 Metabolic hereditary disorder, Inborn Errors of Metabolism, inborn metabolism disorder
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