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

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)).
last edited

Authors

LobkeM, DeSl, ElineSanders, IreneHemel, Egonw, MaintBot, Fehrhart, Eweitz, and Finterly

Cited In

Organism

Homo sapiens

Communities

Inborn Errors of Metabolism (IEM) Pathways Rare Diseases

Annotations

Pathway Ontology: disease pathway glutathione biosynthetic pathway amino acid metabolic pathway glutathione metabolic pathway

Disease Ontology: hemolytic anemia metabolic acidosis autosomal recessive disease

Participants

Label Type Compact Identifier
Glutamate Metabolite chebi:14321
GGT1 Protein ensembl:ENSG00000100031
Glycine Metabolite hmdb:HMDB0000123
GSS Protein ensembl:ENSG00000100983
L-Gamma-Glutamyl Amino Acid Metabolite chebi:15857
ATP Metabolite chebi:15422
ADP Metabolite chebi:16761
ADP Metabolite chebi:16761
Amino Acid Metabolite chebi:33704
5-Oxoprolinase Protein uniprot:O14841
Cysteine Metabolite chebi:15356
Glutathione Metabolite chebi:16856
5-Oxoproline Metabolite chebi:16010
Gamma-Glutamylcysteine Metabolite chebi:17515
ATP Metabolite chebi:15422
Cysteinylglycine Metabolite hmdb:HMDB0000078
ADP Metabolite chebi:16761
GGCT Protein ensembl:ENSG00000006625
GCLC Protein ensembl:ENSG00000001084
Dipeptidase Protein uniprot:A0A140VJI3
ATP Metabolite chebi:15422
Amino Acid Metabolite chebi:33704
Glutamate Metabolite chebi:14321

References

  1. Schulman JD, Goodman SI, Mace JW, Patrick AD, Tietze F, Butler EJ. Glutathionuria: inborn error of metabolism due to tissue deficiency of gamma-glutamyl transpeptidase. Biochem Biophys Res Commun. 1975 Jul 8;65(1):68–74. PubMed Europe PMC Scholia
  2. Beutler E, Moroose R, Kramer L, Gelbart T, Forman L. Gamma-glutamylcysteine synthetase deficiency and hemolytic anemia. Blood. 1990 Jan 1;75(1):271–3. PubMed Europe PMC Scholia
  3. Wellner VP, Sekura R, Meister A, Larsson A. Glutathione synthetase deficiency, an inborn error of metabolism involving the gamma-glutamyl cycle in patients with 5-oxoprolinuria (pyroglutamic aciduria). Proc Natl Acad Sci U S A. 1974 Jun;71(6):2505–9. PubMed Europe PMC Scholia
  4. Meister A. The gamma-glutamyl cycle. Diseases associated with specific enzyme deficiencies. Ann Intern Med. 1974 Aug;81(2):247–53. PubMed Europe PMC Scholia
  5. Van der Werf P, Orlowski M, Meister A. Enzymatic conversion of 5-oxo-L-proline (L-pyrrolidone carboxylate) to L-glutamate coupled with cleavage of adenosine triphosphate to adenosine diphosphate, a reaction in the -glutamyl cycle. Proc Natl Acad Sci U S A. 1971 Dec;68(12):2982–5. PubMed Europe PMC Scholia
  6. Larsson A, Mattsson B, Wauters EA, van Gool JD, Duran M, Wadman SK. 5-oxoprolinuria due to hereditary 5-oxoprolinase deficiency in two brothers--a new inborn error of the gamma-glutamyl cycle. Acta Paediatr Scand. 1981;70(3):301–8. PubMed Europe PMC Scholia
  7. Manning NJ, Davies NP, Olpin SE, Carpenter KH, Smith MF, Pollitt RJ, et al. Prenatal diagnosis of glutathione synthase deficiency. Prenat Diagn. 1994 Jun;14(6):475–8. PubMed Europe PMC Scholia
  8. Hanigan MH, Ricketts WA. Extracellular glutathione is a source of cysteine for cells that express gamma-glutamyl transpeptidase. Biochemistry. 1993 Jun 22;32(24):6302–6. PubMed Europe PMC Scholia
  9. Henderson MJ, Larsson A, Carlsson B, Dear PR. 5-Oxoprolinuria associated with 5-oxoprolinase deficiency; further evidence that this is a benign disorder. J Inherit Metab Dis. 1993;16(6):1051–2. PubMed Europe PMC Scholia
  10. Hara T, Kato H, Katsube Y, Oda J. 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. Biochemistry. 1996 Sep 17;35(37):11967–74. PubMed Europe PMC Scholia
  11. Beutler E, Gelbart T, Kondo T, Matsunaga AT. The molecular basis of a case of gamma-glutamylcysteine synthetase deficiency. Blood. 1999 Oct 15;94(8):2890–4. PubMed Europe PMC Scholia
  12. Ristoff E, Mayatepek E, Larsson A. Long-term clinical outcome in patients with glutathione synthetase deficiency. J Pediatr. 2001 Jul;139(1):79–84. PubMed Europe PMC Scholia
  13. Njålsson R, Ristoff E, Carlsson K, Winkler A, Larsson A, Norgren S. Genotype, enzyme activity, glutathione level, and clinical phenotype in patients with glutathione synthetase deficiency. Hum Genet. 2005 Apr;116(5):384–9. PubMed Europe PMC Scholia
  14. Okada T, Suzuki H, Wada K, Kumagai H, Fukuyama K. Crystal structures of gamma-glutamyltranspeptidase from Escherichia coli, a key enzyme in glutathione metabolism, and its reaction intermediate. Proc Natl Acad Sci U S A. 2006 Apr 25;103(17):6471–6. PubMed Europe PMC Scholia
  15. Oakley AJ, Yamada T, Liu D, Coggan M, Clark AG, Board PG. The identification and structural characterization of C7orf24 as gamma-glutamyl cyclotransferase. An essential enzyme in the gamma-glutamyl cycle. J Biol Chem. 2008 Aug 8;283(32):22031–42. PubMed Europe PMC Scholia
  16. Darin N, Leckström K, Sikora P, Lindgren J, Almén G, Asin-Cayuela J. γ-glutamyl transpeptidase deficiency caused by a large homozygous intragenic deletion in GGT1. Eur J Hum Genet. 2018 Jun;26(6):808–17. PubMed Europe PMC Scholia
  17. PubMed Europe PMC Scholia