Gamma-Glutamyl Cycle for the biosynthesis and degradation of glutathione, including diseases (Homo sapiens)

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131716177121Gamma-Glutamylcysteine Synthetase DeficiencyGamma-Glutamyl Cycle2, 6, 9Glutathionuria3, 14Glutathione Synthetase DeficiencyOxoprolinuria5, 8, 10, 114, 15GlutamateGGT1GlycineGSSL-Gamma-Glutamyl Amino AcidATPADPADPAmino Acid5-OxoprolinaseCysteineGlutathione5-OxoprolineGamma-GlutamylcysteineATPCysteinylglycineADPGGCTGCLCDipeptidaseATPAmino AcidGlutamate


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 978-3-642-40337-8).

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  1. Ristoff E, Mayatepek E, Larsson A; ''Long-term clinical outcome in patients with glutathione synthetase deficiency.''; J Pediatr, 2001 PubMed Europe PMC
  2. Blau, Nenad, Duran, Marinus, Gibson, K, Michael, Dionisi-Vici, Carlo; ''Physician's Guidee to the Diagnosis, Treatment, and Follow-Up of Inherited Metabolic Diseases'''; ISBN 978-3-64240337-8, 2014
  3. 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 PubMed Europe PMC
  4. 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 PubMed Europe PMC
  5. 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 PubMed Europe PMC
  6. 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 PubMed Europe PMC
  7. 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 PubMed Europe PMC
  8. 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 PubMed Europe PMC
  9. Beutler E, Gelbart T, Kondo T, Matsunaga AT; ''The molecular basis of a case of gamma-glutamylcysteine synthetase deficiency.''; Blood, 1999 PubMed Europe PMC
  10. 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 PubMed Europe PMC
  11. 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 PubMed Europe PMC
  12. Meister A; ''The gamma-glutamyl cycle. Diseases associated with specific enzymedeficiencies.''; Ann Intern Med, 1974 PubMed Europe PMC
  13. Hanigan MH, Ricketts WA; ''Extracellular glutathione is a source of cysteine for cells that express gamma-glutamyl transpeptidase.''; Biochemistry, 1993 PubMed Europe PMC
  14. Beutler E, Moroose R, Kramer L, Gelbart T, Forman L; ''Gamma-glutamylcysteine synthetase deficiency and hemolytic anemia.''; Blood, 1990 PubMed Europe PMC
  15. 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 PubMed Europe PMC
  16. Manning NJ, Davies NP, Olpin SE, Carpenter KH, Smith MF, Pollitt RJ, Duncan SL, Larsson A, Carlsson B; ''Prenatal diagnosis of glutathione synthase deficiency.''; Prenat Diagn, 1994 PubMed Europe PMC
  17. 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 PubMed Europe PMC


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106802view13:28, 17 September 2019MaintBotHMDB identifier normalization
104483view05:23, 29 May 2019EgonwHarmonized the OMIM href URL pattern.
104244view18:23, 11 May 2019EgonwRemoved the RHEA: prefix from the identifier.
104035view17:48, 25 April 2019IreneHemelModified description
103564view09:56, 15 March 2019LobkeM
103385view14:17, 25 February 2019DeSlRemoved weird signs in lit. ref
103319view10:07, 22 February 2019LobkeMChanged CHEBI ID's of ADP, ATP and AA to primary CHEBI ID's
103213view14:03, 17 February 2019DeSlChanged arrows for diseases to graphical interactions.
103183view15:10, 15 February 2019ElineSandersCysteine verplaatst zodat lijnen recht staan
103179view14:55, 15 February 2019LobkeMOntology Term : 'amino acid metabolic pathway' added !
103177view14:51, 15 February 2019LobkeMModified description
103173view14:46, 15 February 2019LobkeMOntology Term : 'metabolic acidosis' added !
103172view14:45, 15 February 2019LobkeMModified description
103171view14:37, 15 February 2019LobkeMOntology Term : 'hemolytic anemia' added !
103168view14:34, 15 February 2019LobkeMModified description
103165view14:32, 15 February 2019LobkeMOntology Term : 'autosomal recessive disease' added !
103164view14:27, 15 February 2019LobkeMadded references to diseases
103157view13:52, 15 February 2019DeSlAdded litrefs from previous version again ;)
103143view09:21, 15 February 2019LobkeMAdded Rhea identifiers
103138view08:54, 15 February 2019LobkeMModified description
103126view17:54, 13 February 2019DeSlOntology Term : 'glutathione metabolic pathway' added !
103125view17:53, 13 February 2019DeSlOntology Term : 'glutathione biosynthetic pathway' added !
103119view16:50, 13 February 2019LobkeMadd references with Rhea and changed layout
103113view13:41, 13 February 2019LobkeMadded literature and changed CHEBI of Glutathione
103106view13:05, 13 February 2019LobkeMModified description
103102view12:54, 13 February 2019LobkeMModified title
103101view12:50, 13 February 2019LobkeMModified description
103100view12:49, 13 February 2019LobkeMNew pathway

External references


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NameTypeDatabase referenceComment
5-OxoprolinaseProteinO14841 (Uniprot-TrEMBL)
5-OxoprolineMetaboliteCHEBI:16010 (ChEBI)
ADPMetaboliteCHEBI:16761 (ChEBI)
ATPMetaboliteCHEBI:15422 (ChEBI)
Amino AcidMetaboliteCHEBI:33704 (ChEBI)
CysteineMetaboliteCHEBI:15356 (ChEBI)
CysteinylglycineMetaboliteHMDB00078 (HMDB)
DipeptidaseProteinA0A140VJI3 (Uniprot-TrEMBL)
GCLCProteinENSG00000001084 (Ensembl)
GGCTProteinENSG00000006625 (Ensembl)
GGT1ProteinENSG00000100031 (Ensembl)
GSSProteinENSG00000100983 (Ensembl)
Gamma-GlutamylcysteineMetaboliteCHEBI:17515 (ChEBI)
GlutamateMetaboliteCHEBI:14321 (ChEBI)
GlutathioneMetaboliteCHEBI:16856 (ChEBI)
GlycineMetaboliteHMDB00123 (HMDB)
L-Gamma-Glutamyl Amino AcidMetaboliteCHEBI:15857 (ChEBI)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
5-OxoprolineGlutamatemim-conversionRHEA:10349 (Rhea)
ADPmim-conversionRHEA:10349 (Rhea)
ADPmim-conversionRHEA:13286 (Rhea)
ADPmim-conversionRHEA:13558 (Rhea)
ATPRHEA:10349 (Rhea)
ATPRHEA:13286 (Rhea)
ATPRHEA:13558 (Rhea)
Amino Acidmim-conversionRHEA:20506 (Rhea)
Amino Acidmim-conversionRHEA:23905 (Rhea)
Cysteinemim-conversionRHEA:13286 (Rhea)
Gamma-GlutamylcysteineGlutathionemim-conversionRHEA:13558 (Rhea)
GlutamateGamma-Glutamylcysteinemim-conversionRHEA:13286 (Rhea)
Glutamatemim-conversionRHEA:28808 (Rhea)
GlutathioneCysteinylglycinemim-conversionRHEA:28808 (Rhea)
GlutathioneL-Gamma-Glutamyl Amino Acidmim-conversionRHEA:23905 (Rhea)
Glycinemim-conversionRHEA:13558 (Rhea)
L-Gamma-Glutamyl Amino Acid5-Oxoprolinemim-conversionRHEA:20506 (Rhea)
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