Jump to content

IDH1

From Wikipedia, the free encyclopedia

This is an old revision of this page, as edited by Headbomb (talk | contribs) at 01:06, 9 July 2016 (→Clinical Significance: clean up, replaced: American Journal of Medical Genetics. Part A → American Journal of Medical Genetics Part A using AWB). The present address (URL) is a permanent link to this revision, which may differ significantly from the current revision.

IDH1
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesIDH1, HEL-216, HEL-S-26, IDCD, IDH, IDP, IDPC, PICD, isocitrate dehydrogenase (NADP(+)) 1, cytosolic, isocitrate dehydrogenase (NADP(+)) 1
External IDsOMIM: 147700; MGI: 96413; HomoloGene: 21195; GeneCards: IDH1; OMA:IDH1 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

3417

15926

Ensembl

ENSG00000138413

ENSMUSG00000025950

UniProt

O75874

O88844

RefSeq (mRNA)

NM_005896
NM_001282386
NM_001282387

NM_001111320
NM_010497

RefSeq (protein)

NP_001269315
NP_001269316
NP_005887

NP_001104790
NP_034627

Location (UCSC)Chr 2: 208.24 – 208.27 MbChr 1: 65.2 – 65.23 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Isocitrate dehydrogenase 1 (NADP+), soluble is an enzyme that in humans is encoded by the IDH1 gene on chromosome 2. 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. Alternatively spliced transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Sep 2013][5]

Structure

IDH1 is one of three isocitrate dehydrogenase isozymes, the other two being IDH2 and IDH3, and encoded by one of five isocitrate dehydrogenase genes, which are IDH1, IDH2, IDH3A, IDH3B, and IDH3G.[6]

IDH1 forms an asymmetric homodimer in the cytoplasm and carries out its function through two hydrophilic active sites formed by both protein subunits.[7][8][9][10][11] Each subunit or monomer is composed of three domains: a large domain (residues 1–103 and 286–414), a small domain (residues 104–136 and 186–285), and a clasp domain (residues 137 to 185). The large domain contains a Rossmann fold, while the small domain forms an α/β sandwich structure, and the clasp domain folds as two stacked double-stranded anti-parallel β-sheets. A β-sheet joins the large and small domains and is flanked by two clefts on opposite sides. The deep cleft, also known as the active site, is formed by the large and small domains of one subunit and a small domain of the other subunit. This active site includes the NADP-binding site and the isocitrate-metal ion-binding site. The shallow cleft, also referred to as the back cleft, is formed by both domains of one subunit and participates in the conformational changes of homodimeric IDH1. Finally, the clasp domains of both subunits intertwine to form a double layer of four-stranded anti-parallel β-sheets linking together the two subunits and the two active sites.[11]

Furthermore, conformational changes to the subunits and a conserved structure at the active site affect the activity of the enzyme. In its open, inactive form, the active site structure forms a loop while one subunit adopts an asymmetric open conformation and the other adopts a quasi-open conformation.[9][11] This conformation enables isocitrate to bind the active site, inducing a closed conformation that also activates IDH1.[9] In its closed, inactive form, the active site structure becomes an α-helix that can chelate metal ions. An intermediate, semi-open form features this active site structure as a partially unraveled α-helix.[11]

There is also a type 1 peroxisomal targeting sequence at its C-terminal that targets the protein to the peroxisome.[11]

Function

As an isocitrate dehydrogenase, IDH1 catalyzes the reversible oxidative decarboxylation of isocitrate to yield α-ketoglutarate (α-KG) as part of the TCA cycle in glucose metabolism.[6][7][8][10][11] This step also allows for the concomitant reduction of nicotinamide adenine dinucleotide phosphate (NADP+) to reduced nicotinamide adenine dinucleotide phosphate (NADPH).[7][8][10] Since NADPH and α-KG function in cellular detoxification processes in response to oxidative stress, IDH1 also indirectly participates in mitigating oxidative damage.[6][7][11][12] In addition, IDH1 is key to β-oxidation of unsaturated fatty acids in the peroxisomes of liver cells.[11] IDH1 also participates in the regulation of glucose-induced insulin secretion.[6] Notably, IDH1 is the primary producer of NADPH in most tissues, especially in brain.[7] Within cells, IDH1 has been observed to localize to the cytoplasm, peroxisome, and endoplasmic reticulum.[10][12]

Under hypoxic conditions, IDH1 catalyzes the reverse reaction of α-KG to isocitrate, which contributes to citrate production via glutaminolysis.[6][7] Isocitrate can also be converted into acetyl-CoA for lipid metabolism.[6]

Mutation

IDH1 mutations are heterozygous, typically involving an amino acid substitution in the active site of the enzyme in codon 132.[13][14] The mutation results in a loss of normal enzymatic function and the abnormal production of 2-hydroxyglutarate (2-HG).[13] 2-HG has been found to inhibit enzymatic function of many alpha-ketoglutarate dependent dioxygenases, including histone and DNA demethylases, causing widespread changes in histone and DNA methylation and potentially promoting tumorigenesis.[14]

Clinical Significance

Mutations in this gene have been shown to cause metaphyseal chondromatosis with aciduria.[15]

Mutations in IDH1 are also implicated in cancer. Originally, mutations in IDH1 were detected in an integrated genomic analysis of human glioblastoma multiforme.[16] 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.[17] 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.[18][19][20] 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.[21]

In addition to being mutated in diffuse gliomas, IDH1 has also been shown to harbor mutations in human acute myeloid leukemia.[22][23]

References

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000138413 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000025950 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ "Entrez Gene: Isocitrate dehydrogenase 1 (NADP+), soluble". Retrieved 2011-12-30.
  6. ^ a b c d e f Dimitrov L, Hong CS, Yang C, Zhuang Z, Heiss JD (2015). "New developments in the pathogenesis and therapeutic targeting of the IDH1 mutation in glioma". International Journal of Medical Sciences. 12 (3): 201–13. doi:10.7150/ijms.11047. PMID 25678837.
  7. ^ a b c d e f Molenaar RJ, Radivoyevitch T, Maciejewski JP, van Noorden CJ, Bleeker FE (Dec 2014). "The driver and passenger effects of isocitrate dehydrogenase 1 and 2 mutations in oncogenesis and survival prolongation". Biochimica et Biophysica Acta. 1846 (2): 326–41. doi:10.1016/j.bbcan.2014.05.004. PMID 24880135.
  8. ^ a b c Kim HJ, Fei X, Cho SC, Choi BY, Ahn HC, Lee K, Seo SY, Keum YS (Dec 2015). "Discovery of α-mangostin as a novel competitive inhibitor against mutant isocitrate dehydrogenase-1". Bioorganic & Medicinal Chemistry Letters. 25 (23): 5625–31. doi:10.1016/j.bmcl.2015.10.034. PMID 26508549.
  9. ^ a b c Zhao S, Guan KL (Dec 2010). "IDH1 mutant structures reveal a mechanism of dominant inhibition". Cell Research. 20 (12): 1279–81. doi:10.1038/cr.2010.160. PMID 21079649.
  10. ^ a b c d Guo C, Pirozzi CJ, Lopez GY, Yan H (Dec 2011). "Isocitrate dehydrogenase mutations in gliomas: mechanisms, biomarkers and therapeutic target". Current Opinion in Neurology. 24 (6): 648–52. doi:10.1097/WCO.0b013e32834cd415. PMID 22002076.
  11. ^ a b c d e f g h Xu X, Zhao J, Xu Z, Peng B, Huang Q, Arnold E, Ding J (Aug 2004). "Structures of human cytosolic NADP-dependent isocitrate dehydrogenase reveal a novel self-regulatory mechanism of activity". The Journal of Biological Chemistry. 279 (32): 33946–57. doi:10.1074/jbc.M404298200. PMID 15173171.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  12. ^ a b Fu Y, Huang R, Du J, Yang R, An N, Liang A (Jun 2010). "Glioma-derived mutations in IDH: from mechanism to potential therapy". Biochemical and Biophysical Research Communications. 397 (2): 127–30. doi:10.1016/j.bbrc.2010.05.115. PMID 20510884.
  13. ^ a b Turkalp Z, Karamchandani J, Das S (Oct 2014). "IDH mutation in glioma: new insights and promises for the future". JAMA Neurology. 71 (10): 1319–25. doi:10.1001/jamaneurol.2014.1205. PMID 25155243.
  14. ^ a b Liu X, Ling ZQ (Oct 2015). "Role of isocitrate dehydrogenase 1/2 (IDH 1/2) gene mutations in human tumors". Histology and Histopathology. 30 (10): 1155–60. doi:10.14670/HH-11-643. PMID 26147657.
  15. ^ Vissers LE, Fano V, Martinelli D, Campos-Xavier B, Barbuti D, Cho TJ, et al. (Nov 2011). "Whole-exome sequencing detects somatic mutations of IDH1 in metaphyseal chondromatosis with D-2-hydroxyglutaric aciduria (MC-HGA)". American Journal of Medical Genetics Part A. 155A (11): 2609–16. doi:10.1002/ajmg.a.34325. PMID 22025298.
  16. ^ Parsons DW, Jones S, Zhang X, Lin JC, Leary RJ, Angenendt P, et al. (Sep 2008). "An integrated genomic analysis of human glioblastoma multiforme". Science. 321 (5897): 1807–12. doi:10.1126/science.1164382. PMC 2820389. PMID 18772396.
  17. ^ Yan H, Parsons DW, Jin G, McLendon R, Rasheed BA, Yuan W, et al. (Feb 2009). "IDH1 and IDH2 mutations in gliomas". The New England Journal of Medicine. 360 (8): 765–73. doi:10.1056/NEJMoa0808710. PMC 2820383. PMID 19228619.
  18. ^ Watanabe T, Nobusawa S, Kleihues P, Ohgaki H (Apr 2009). "IDH1 mutations are early events in the development of astrocytomas and oligodendrogliomas". The American Journal of Pathology. 174 (4): 1149–53. doi:10.2353/ajpath.2009.080958. PMC 2671348. PMID 19246647.
  19. ^ Bleeker FE, Molenaar RJ, Leenstra S (May 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.
  20. ^ Bai H, Harmancı AS, Erson-Omay AZ, Li J, Coșkun S, Simon M, et al. (Nov 2015). "Integrated genomic characterization of IDH1-mutant glioma malignant progression". Nature Genetics. doi:10.1038/ng.3457.
  21. ^ Molenaar RJ, Verbaan D, Lamba S, Zanon C, Jeuken JW, Boots-Sprenger SH, et al. (Sep 2014). "The combination of IDH1 mutations and MGMT methylation status predicts survival in glioblastoma better than either IDH1 or MGMT alone". Neuro-Oncology. 16 (9): 1263–73. doi:10.1093/neuonc/nou005. PMC 4136888. PMID 24510240.
  22. ^ Mardis ER, Ding L, Dooling DJ, Larson DE, McLellan MD, Chen K, et al. (Sep 2009). "Recurring mutations found by sequencing an acute myeloid leukemia genome". The New England Journal of Medicine. 361 (11): 1058–66. doi:10.1056/NEJMoa0903840. PMC 3201812. PMID 19657110.
  23. ^ Shih AH, Abdel-Wahab O, Patel JP, Levine RL (Sep 2012). "The role of mutations in epigenetic regulators in myeloid malignancies". Nature Reviews. Cancer. 12 (9): 599–612. doi:10.1038/nrc3343. PMID 22898539.

Further reading

  • Geisbrecht BV, Gould SJ (Oct 1999). "The human PICD gene encodes a cytoplasmic and peroxisomal NADP(+)-dependent isocitrate dehydrogenase". The Journal of Biological Chemistry. 274 (43): 30527–33. doi:10.1074/jbc.274.43.30527. PMID 10521434.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  • Shechter I, Dai P, Huo L, Guan G (Nov 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". Journal of Lipid Research. 44 (11): 2169–80. doi:10.1194/jlr.M300285-JLR200. PMID 12923220.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  • Xu X, Zhao J, Xu Z, Peng B, Huang Q, Arnold E, Ding J (Aug 2004). "Structures of human cytosolic NADP-dependent isocitrate dehydrogenase reveal a novel self-regulatory mechanism of activity". The Journal of Biological Chemistry. 279 (32): 33946–57. doi:10.1074/jbc.M404298200. PMID 15173171.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  • 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): 249–55. 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 (Dec 2005). "Proteomic analysis of SUMO4 substrates in HEK293 cells under serum starvation-induced stress". Biochemical and Biophysical Research Communications. 337 (4): 1308–18. doi:10.1016/j.bbrc.2005.09.191. PMID 16236267.
  • Kullberg M, Nilsson MA, Arnason U, Harley EH, Janke A (Aug 2006). "Housekeeping genes for phylogenetic analysis of eutherian relationships". Molecular Biology and Evolution. 23 (8): 1493–503. 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.
  • Balss J, Meyer J, Mueller W, Korshunov A, Hartmann C, von Deimling A (Dec 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 (Jan 2009). "IDH1 mutations at residue p.R132 (IDH1(R132)) 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.


Retrieved from "https://en.wikipedia.org/w/index.php?title=IDH1&oldid=728984074"