IDH1

Isocitrate dehydrogenase 1 (NADP+), soluble
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
SymbolsIDH1 ; IDCD; IDH; IDP; IDPC; PICD
External IDsOMIM: 147700 MGI: 96413 HomoloGene: 21195 GeneCards: IDH1 Gene
EC number1.1.1.42
Orthologs
SpeciesHumanMouse
Entrez341715926
EnsemblENSG00000138413ENSMUSG00000025950
UniProtO75874O88844
RefSeq (mRNA)NM_005896NM_001111320
RefSeq (protein)NP_005887NP_001104790
Location (UCSC)Chr 2:
209.1 – 209.13 Mb		Chr 1:
65.16 – 65.19 Mb
PubMed search

Isocitrate dehydrogenase 1 (NADP+), soluble is an enzyme that in humans is encoded by the IDH1 gene.[1]

Function

Isocitrate dehydrogenases catalyze the oxidative decarboxylation of isocitrate to 2-oxoglutarate. These enzymes belong to two distinct subclasses, one of which uses NAD+ as the electron acceptor and the other NADP+. Five isocitrate dehydrogenases have been reported: three NAD+-dependent isocitrate dehydrogenases, which localize to the mitochondrial matrix, and two NADP+-dependent isocitrate dehydrogenases, one of which is mitochondrial and the other predominantly cytosolic. Each NADP+-dependent isozyme is a homodimer. The protein encoded by this gene is the NADP+-dependent isocitrate dehydrogenase found in the cytoplasm and peroxisomes. It contains the PTS-1 peroxisomal targeting signal sequence. The presence of this enzyme in peroxisomes suggests roles in the regeneration of NADPH for intraperoxisomal reductions, such as the conversion of 2,4-dienoyl-CoAs to 3-enoyl-CoAs, as well as in peroxisomal reactions that consume 2-oxoglutarate, namely the alpha-hydroxylation of phytanic acid. The cytoplasmic enzyme serves a significant role in cytoplasmic NADPH production.[1]

Clinical relevance

Mutations in this gene have been shown to cause metaphyseal chondromatosis with aciduria.[2]

Mutations in IDH1 are also implicated in cancer. Originally, mutations in IDH1 were detected in an integrated genomic analysis of human glioblastoma multiforme.[3] Since then it has become clear that mutations in IDH1 and its homologue IDH2 are among the most frequent mutations in diffuse gliomas, including diffuse astrocytoma, anaplastic astrocytoma, oligodendroglioma, anaplastic oligodendroglioma, oligoastrocytoma, anaplastic oligoastrocytoma, and secondary glioblastoma.[4] Watanabe and coworkers could show that mutations in IDH1 are often the first hit in the development of diffuse gliomas, suggesting ‘’IDH1’’ mutations as key events in the formation of these brain tumors.[5][6] IDH1 mutations are associated with a prolonged survival. Glioblastomas with a wild-type IDH1 gene have a median overall survival of only 1 year, whereas IDH1-mutated glioblastoma patients have a median overall survival of over 2 years.[7]

In addition to being mutated in diffuse gliomas, IDH1 has also been shown to harbor mutations in human acute myeloid leukemia.[8][9]

References

  1. ↑ 1.0 1.1 "Entrez Gene: Isocitrate dehydrogenase 1 (NADP+), soluble". Retrieved 2011-12-30.
  2. ↑ Vissers LE, Fano V, Martinelli D, Campos-Xavier B, Barbuti D, Cho TJ, Dursun A, Kim OH, Lee SH, Timpani G, Nishimura G, Unger S, Sass JO, Veltman JA, Brunner HG, Bonafé L, Dionisi-Vici C, Superti-Furga A (November 2011). "Whole-exome sequencing detects somatic mutations of IDH1 in metaphyseal chondromatosis with D-2-hydroxyglutaric aciduria (MC-HGA)". Am. J. Med. Genet. A 155A (11): 2609–16. doi:10.1002/ajmg.a.34325. PMID 22025298.
  3. ↑ 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 (September 2008). "An integrated genomic analysis of human glioblastoma multiforme.". Science 321 (5897): 1807–12. doi:10.1126/science.1164382. PMC 2820389. PMID 18772396.
  4. ↑ Yan H, Parsons DW, Jin G, McLendon R, Rasheed BA, Yuan W, Kos I, Batinic-Haberle I, Jones S, Riggins GJ, Friedman H, Friedman A, Reardon D, Herndon J, Kinzler KW, Velculescu VE, Vogelstein B, Bigner DD (February 2009). "IDH1 and IDH2 mutations in gliomas.". N Engl J Med 360 (8): 765–73. doi:10.1056/NEJMoa0808710. PMC 2820383. PMID 19228619.
  5. ↑ Watanabe T, Nobusawa S, Kleihues P, Ohgaki H (April 2009). "IDH1 mutations are early events in the development of astrocytomas and oligodendrogliomas.". Am J Pathol. 174 issue = 4 (4): 1149–53. doi:10.2353/ajpath.2009.080958. PMC 2671348. PMID 19246647.
  6. ↑ Bleeker FE, Molenaar RJ, Leenstra S (2012). "Recent advances in the molecular understanding of glioblastoma". Journal of Neuro-Oncology 108 (1): 11–27. doi:10.1007/s11060-011-0793-0. PMC 3337398. PMID 22270850.
  7. ↑ Molenaar RJ, Verbaan D, Lamba S, Zanon C, Jeuken JW, Boots-Sprenger SH, Wesseling P, Hulsebos TJ, Troost D, van Tilborg AA, Leenstra S, Vandertop WP, Bardelli A, van Noorden CJ, Bleeker FE (2014). "The combination of IDH1 mutations and MGMT methylation status predicts survival in glioblastoma better than either IDH1 or MGMT alone". Neuro-Oncology 16: 1263–1273. doi:10.1093/neuonc/nou005. PMID 24510240.
  8. ↑ Mardis ER, Ding L, Dooling DJ, Larson DE, McLellan MD, Chen K, Koboldt DC, Fulton RS, Delehaunty KD, McGrath SD, Fulton LA, Locke DP, Magrini VJ, Abbott RM, Vickery TL, Reed JS, Robinson JS, Wylie T, Smith SM, Carmichael L, Eldred JM, Harris CC, Walker J, Peck JB, Du F, Dukes AF, Sanderson GE, Brummett AM, Clark E, McMichael JF, Meyer RJ, Schindler JK, Pohl CS, Wallis JW, Shi X, Lin L, Schmidt H, Tang Y, Haipek C, Wiechert ME, Ivy JV, Kalicki J, Elliott G, Ries RE, Payton JE, Westervelt P, Tomasson MH, Watson MA, Baty J, Heath S, Shannon WD, Nagarajan R, Link DC, Walter MJ, Graubert TA, DiPersio JF, Wilson RK, Ley TJ (2009). "Recurring mutations found by sequencing an acute myeloid leukemia genome". N. Engl. J. Med. 361 (11): 1058–66. doi:10.1056/NEJMoa0903840. PMC 3201812. PMID 19657110.
  9. ↑ Shih AH, Abdel-Wahab O, Patel JP, Levine RL (September 2012). "The role of mutations in epigenetic regulators in myeloid malignancies.". Nat Rev Cancer. 12 (9): 599–612. doi:10.1038/nrc3343. PMID 22898539.

Further reading

  • Geisbrecht BV, Gould SJ (1999). "The human PICD gene encodes a cytoplasmic and peroxisomal NADP(+)-dependent isocitrate dehydrogenase". The Journal of Biological Chemistry 274 (43): 30527–30533. doi:10.1074/jbc.274.43.30527. PMID 10521434.
  • Shechter I, Dai P, Huo L, Guan G (2003). "IDH1 gene transcription is sterol regulated and activated by SREBP-1a and SREBP-2 in human hepatoma HepG2 cells: Evidence that IDH1 may regulate lipogenesis in hepatic cells". The Journal of Lipid Research 44 (11): 2169–2180. doi:10.1194/jlr.M300285-JLR200. PMID 12923220.
  • Xu X, Zhao J, Xu Z, Peng B, Huang Q, Arnold E, Ding J (2004). "Structures of Human Cytosolic NADP-dependent Isocitrate Dehydrogenase Reveal a Novel Self-regulatory Mechanism of Activity". Journal of Biological Chemistry 279 (32): 33946–33957. doi:10.1074/jbc.M404298200. PMID 15173171.
  • Memon AA, Chang JW, Oh BR, Yoo YJ (2005). "Identification of differentially expressed proteins during human urinary bladder cancer progression". Cancer Detection and Prevention 29 (3): 249–255. doi:10.1016/j.cdp.2005.01.002. PMID 15936593.
  • Guo D, Han J, Adam BL, Colburn NH, Wang MH, Dong Z, Eizirik DL, She JX, Wang CY (2005). "Proteomic analysis of SUMO4 substrates in HEK293 cells under serum starvation-induced stress". Biochemical and Biophysical Research Communications 337 (4): 1308–1318. doi:10.1016/j.bbrc.2005.09.191. PMID 16236267.
  • Kullberg M, Nilsson MA, Arnason U, Harley EH, Janke A (2006). "Housekeeping Genes for Phylogenetic Analysis of Eutherian Relationships". Molecular Biology and Evolution 23 (8): 1493–1503. doi:10.1093/molbev/msl027. PMID 16751257.
  • Wanders RJ, Waterham HR (2006). "Biochemistry of Mammalian Peroxisomes Revisited". Annual Review of Biochemistry 75: 295–332. doi:10.1146/annurev.biochem.74.082803.133329. PMID 16756494.
  • 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 (2008). "An Integrated Genomic Analysis of Human Glioblastoma Multiforme". Science 321 (5897): 1807–1812. doi:10.1126/science.1164382. PMC 2820389. PMID 18772396.
  • Balss J, Meyer J, Mueller W, Korshunov A, Hartmann C, von Deimling A (2008). "Analysis of the IDH1 codon 132 mutation in brain tumors". Acta Neuropathologica 116 (6): 597–602. doi:10.1007/s00401-008-0455-2. PMID 18985363.
  • Bleeker FE, Lamba S, Leenstra S, Troost D, Hulsebos T, Vandertop WP, Frattini M, Molinari F, Knowles M, Cerrato A, Rodolfo M, Scarpa A, Felicioni L, Buttitta F, Malatesta S, Marchetti A, Bardelli A (2009). "IDH1mutations at residue p.R132 (IDH1R132) occur frequently in high-grade gliomas but not in other solid tumors". Human Mutation 30 (1): 7–11. doi:10.1002/humu.20937. PMID 19117336.

This article incorporates text from the United States National Library of Medicine, which is in the public domain.