Abnormal conversion of 2-oxoglutarate to 2-hydroxyglutarate (Homo sapiens)

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1, 21cytosol2OGIDH1 R132H mutant IDH1 R132S mutant IDH1 R132L mutant IDH1 R132mutantdimersNADPHH+NADP+2HGIDH1 R132C mutant


Description

Somatic mutations affecting arginine residue 132 of IDH1 (isocitrate dehydrogenase 1, a cytosolic enzyme that normally catalyzes the NADP+-dependent conversion of isocitrate to 2-oxoglutarate), are very commonly found in human glioblastomas (Parsons et al. 2008). These mutant proteins efficiently catalyze the NADPH-dependent reduction of 2-oxoglutarate to form 2-hydroxyglutarate. Cells expressing the mutant protein accumulate elevated levels of 2-hydroxyglutarate, probably in the cytosol as IDH1 is a cytosolic enzyme. The fate of the 2-hydroxyglutarate is unclear, but the high frequency with which the mutation is found in surveys of primary tumors is consistent with the possibility that it is advantageous to the tumor cells (Dang et al 2009). View original pathway at:Reactome.

Comments

Reactome-Converter 
Pathway is converted from Reactome ID: 2978092
Reactome-version 
Reactome version: 66
Reactome Author 
Reactome Author: D'Eustachio, Peter

Quality Tags

Ontology Terms

 

Bibliography

  1. Dang L, White DW, Gross S, Bennett BD, Bittinger MA, Driggers EM, Fantin VR, Jang HG, Jin S, Keenan MC, Marks KM, Prins RM, Ward PS, Yen KE, Liau LM, Rabinowitz JD, Cantley LC, Thompson CB, Vander Heiden MG, Su SM.; ''Cancer-associated IDH1 mutations produce 2-hydroxyglutarate.''; PubMed Europe PMC
  2. Parsons DW, Jones S, Zhang X, Lin JC, Leary RJ, Angenendt P, Mankoo P, Carter H, Siu IM, Gallia GL, Olivi A, McLendon R, Rasheed BA, Keir S, Nikolskaya T, Nikolsky Y, Busam DA, Tekleab H, Diaz LA, Hartigan J, Smith DR, Strausberg RL, Marie SK, Shinjo SM, Yan H, Riggins GJ, Bigner DD, Karchin R, Papadopoulos N, Parmigiani G, Vogelstein B, Velculescu VE, Kinzler KW.; ''An integrated genomic analysis of human glioblastoma multiforme.''; PubMed Europe PMC

History

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CompareRevisionActionTimeUserComment
101628view11:49, 1 November 2018ReactomeTeamreactome version 66
101164view21:35, 31 October 2018ReactomeTeamreactome version 65
100690view20:08, 31 October 2018ReactomeTeamreactome version 64
100240view16:54, 31 October 2018ReactomeTeamreactome version 63
99792view15:19, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99343view12:48, 31 October 2018ReactomeTeamreactome version 62
94002view13:50, 16 August 2017ReactomeTeamreactome version 61
93613view11:28, 9 August 2017ReactomeTeamreactome version 61
87074view14:19, 18 July 2016MkutmonOntology Term : 'metabolic disease pathway' added !
86721view09:24, 11 July 2016ReactomeTeamreactome version 56
83298view10:40, 18 November 2015ReactomeTeamVersion54
82423view13:11, 29 September 2015ReactomeTeamNew pathway

External references

DataNodes

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NameTypeDatabase referenceComment
2HGMetaboliteCHEBI:32796 (ChEBI)
2OGMetaboliteCHEBI:30915 (ChEBI)
H+MetaboliteCHEBI:15378 (ChEBI)
IDH1 R132C mutant ProteinO75874 (Uniprot-TrEMBL)
IDH1 R132H mutant ProteinO75874 (Uniprot-TrEMBL)
IDH1 R132L mutant ProteinO75874 (Uniprot-TrEMBL)
IDH1 R132S mutant ProteinO75874 (Uniprot-TrEMBL)
IDH1 R132mutant dimersComplexR-HSA-880004 (Reactome)
NADP+MetaboliteCHEBI:18009 (ChEBI)
NADPHMetaboliteCHEBI:16474 (ChEBI)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
2HGArrowR-HSA-880053 (Reactome)
2OGR-HSA-880053 (Reactome)
H+R-HSA-880053 (Reactome)
IDH1 R132mutant dimersmim-catalysisR-HSA-880053 (Reactome)
NADP+ArrowR-HSA-880053 (Reactome)
NADPHR-HSA-880053 (Reactome)
R-HSA-880053 (Reactome) Mutant forms of IDH1 in which the arginine residue at position 132 has been replaced by histidine, cystine, leucine, or serine catalyze the reaction of 2-oxoglutarate and NADPH + H+ to form (R)-2-hydroxyglutarate and NADP+. Like normal IDH1, the mutant enzyme forms a dimer located in the cytosol (Dang et al. 2009).

Such mutations occur frequently as a somatic event in human glioblastomas (Parsons et al. 2008). Cells expressing the mutant protein accumulate elevated levels of 2-hydroxyglutarate, probably in the cytosol as IDH1 is a cytosolic enzyme. The fate of the 2-hydroxyglutarate is unclear, but the high frequency with which the mutation is found in surveys of primary tumors is consistent with the possibility that it is advantageous to the tumor cells (Dang et al. 2009).

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