Gamma-glutamyl cycle for the biosynthesis and degradation of glutathione, including diseases (WP4518)

Homo sapiens

This pathway shows diseases related to the biosynthesis and degradation of glutathione. Diseases resulting from an enzyme deficiency are highlighted in pink. The four genetic defects, causing the diseases, are all inherited as autosomal recessive traits. All patients with gamma-glutamylcysteine synthetase deficiency are diagnosed with hemolytic anemia. Glutathione synthetase deficiency is classified in mild, moderate and severe. Patient diagnosed with mild glutathione synthetase deficiency suffer from hemolytic anemia only, while patient with the moderate and severe form show neurological symptoms, metabolic acidosis and bacterial infections as well. This pathway was inspired by Chapter 42 of the book of Blau (ISBN 3642403360 (978-3642403361)).

Authors

Lobke Meels , Denise Slenter , Eline Sanders , Irene Hemel , Egon Willighagen , Friederike Ehrhart , Eric Weitz , and Finterly Hu

Activity

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Cited In

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Organisms

Homo sapiens

Communities

Inherited Metabolic Disorders (IMD) Pathways Rare Diseases

Annotations

Pathway Ontology

glutathione metabolic pathway amino acid metabolic pathway disease pathway glutathione biosynthetic pathway glutathionuria disease pathway

Disease Ontology

hemolytic anemia gamma-glutamyl transpeptidase deficiency autosomal recessive disease metabolic acidosis

Participants

Label Type Compact URI Comment
Glutamate Metabolite chebi:14321
Glycine Metabolite chebi:15428
L-gamma-glutamyl amino acid Metabolite chebi:15857
ATP Metabolite chebi:15422
ADP Metabolite chebi:16761
Amino acid Metabolite chebi:33704
Cysteine Metabolite chebi:15356
Glutathione Metabolite chebi:16856
5-Oxoproline Metabolite chebi:16010
Gamma-glutamylcysteine Metabolite chebi:17515
Cysteinylglycine Metabolite chebi:4047
GGT1 Protein uniprot:P19440
GSS Protein uniprot:P48637
5-Oxoprolinase Protein uniprot:O14841
GGCT Protein uniprot:O75223
GCLC Protein uniprot:P48506
Dipeptidase Protein uniprot:P16444 DPEP1

References

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  2. Gamma-glutamylcysteine synthetase deficiency and hemolytic anemia. Beutler E, Moroose R, Kramer L, Gelbart T, Forman L. Blood. 1990 Jan 1;75(1):271–3. PubMed Europe PMC Scholia
  3. Glutathione synthetase deficiency, an inborn error of metabolism involving the gamma-glutamyl cycle in patients with 5-oxoprolinuria (pyroglutamic aciduria). Wellner VP, Sekura R, Meister A, Larsson A. Proc Natl Acad Sci U S A. 1974 Jun;71(6):2505–9. PubMed Europe PMC Scholia
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  9. 5-Oxoprolinuria associated with 5-oxoprolinase deficiency; further evidence that this is a benign disorder. Henderson MJ, Larsson A, Carlsson B, Dear PR. J Inherit Metab Dis. 1993;16(6):1051–2. PubMed Europe PMC Scholia
  10. A pseudo-michaelis quaternary complex in the reverse reaction of a ligase: structure of Escherichia coli B glutathione synthetase complexed with ADP, glutathione, and sulfate at 2.0 A resolution. Hara T, Kato H, Katsube Y, Oda J. Biochemistry. 1996 Sep 17;35(37):11967–74. PubMed Europe PMC Scholia
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  12. Long-term clinical outcome in patients with glutathione synthetase deficiency. Ristoff E, Mayatepek E, Larsson A. J Pediatr. 2001 Jul;139(1):79–84. PubMed Europe PMC Scholia
  13. Genotype, enzyme activity, glutathione level, and clinical phenotype in patients with glutathione synthetase deficiency. Njålsson R, Ristoff E, Carlsson K, Winkler A, Larsson A, Norgren S. Hum Genet. 2005 Apr;116(5):384–9. PubMed Europe PMC Scholia
  14. Crystal structures of gamma-glutamyltranspeptidase from Escherichia coli, a key enzyme in glutathione metabolism, and its reaction intermediate. Okada T, Suzuki H, Wada K, Kumagai H, Fukuyama K. Proc Natl Acad Sci U S A. 2006 Apr 25;103(17):6471–6. PubMed Europe PMC Scholia
  15. The identification and structural characterization of C7orf24 as gamma-glutamyl cyclotransferase. An essential enzyme in the gamma-glutamyl cycle. Oakley AJ, Yamada T, Liu D, Coggan M, Clark AG, Board PG. J Biol Chem. 2008 Aug 8;283(32):22031–42. PubMed Europe PMC Scholia
  16. γ-glutamyl transpeptidase deficiency caused by a large homozygous intragenic deletion in GGT1. Darin N, Leckström K, Sikora P, Lindgren J, Almén G, Asin-Cayuela J. Eur J Hum Genet. 2018 Jun;26(6):808–17. PubMed Europe PMC Scholia
  17. Pubmed: 9783642403361