IDH1
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| Location (UCSC) | Chr 2: 208.24 – 208.27 Mb | Chr 1: 65.2 – 65.23 Mb | |||||||
| PubMed search | [3] | [4] | |||||||
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Isocitrate dehydrogenase 1 (NADP+), soluble is an
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
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.
There is also a type 1 peroxisomal
Function
As an isocitrate dehydrogenase, IDH1 catalyzes the reversible oxidative decarboxylation of isocitrate to yield α-ketoglutarate (α-KG) as part of the
Under
Mutation
IDH1 mutations are heterozygous, typically involving an amino acid substitution in the active site of the enzyme in codon 132.
Clinical significance
Mutations in this gene have been shown to cause
Mutations in IDH1 are also implicated in cancer. Originally, mutations in IDH1 were detected in an integrated genomic analysis of human
In addition to being mutated in diffuse gliomas, IDH1 has also been shown to harbor mutations in human acute myeloid leukemia.[27][28]
The IDH1 mutation is considered a driver alteration and occurs early during tumorigenesis, in specific in glioma and glioblastoma multiforme, its possible use as a new tumour-specific antigen to induce antitumor immunity for the cancer treatment has recently been prompted.[29] A tumour vaccine can stimulate the body's immune system, upon exposure to a tumour-specific peptide antigen, by activation or amplification of a humoral and cytotoxic immune response targeted at the specific cancer cells.
The study of Schumacher et al. has been shown that this attractive target (the mutation in the isocitrate dehydrogenase 1) from an immunological perspective represents a potential tumour-specific neoantigen with high uniformity and penetrance and could be exploited by immunotherapy through vaccination. Accordingly, some patients with IDH1-mutated gliomas demonstrated spontaneous peripheral CD4+ T-cell responses against the mutated IDH1 region with generation B-cell producing antibodies. Vaccination of MHC-humanized transgenic mice with mutant IDH1 peptide induced an IFN-γ CD4+ T-helper 1 cell response, indicating an endogenous processing through MHC class II, and production of antibodies targeting mutant IDH1. Tumour vaccination, both prophylactic and therapeutic, resulted in growth suppression of transplanted IDH1-expressing sarcomas in MHC-humanized mice. This in vivo data shows a specific and potent immunologic response in both transplanted and existing tumours.[29]
As a drug target
Mutated and normal forms of IDH1 had been studied for drug inhibition both in silico and in vitro,[30][31][32][33] and some drugs are being developed (e.g. Ivosidenib and Vorasidenib). Ivosidenib was approved by the FDA in July 2018 for relapsed or refractory acute myeloid leukemia (AML) with an IDH1 mutation.[34] Ivosidenib (AG-120) has exhibited potent anti-wtIDH1 properties in melanoma under low magnesium and nutrient levels, reflective of the tumor microenvironment in natura.[35]
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000138413 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000025950 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Entrez Gene: Isocitrate dehydrogenase 1 (NADP+), soluble". Retrieved 2011-12-30.
- ^ PMID 25678837.
- ^ PMID 24880135.
- ^ PMID 26508549.
- ^ S2CID 41199424.
- ^ PMID 22002076.
- ^ S2CID 7513167.
- ^ PMID 20510884.
- ^ PMID 25155243.
- ^ PMID 26147657.
- S2CID 91257424.
- PMID 29784032.
- S2CID 33345097.
- PMID 18772396.
- PMID 19228619.
- PMID 19246647.
- PMID 22270850.
- PMID 26618343.
- PMID 24510240.
- PMID 29367755.
- PMID 31278288.
- PMID 30760578.
- PMID 19657110.
- S2CID 20214444.
- ^ S2CID 4468160.
- S2CID 4798363.
- S2CID 51625776.
- PMID 28132785.
- PMID 28002956.
- ^ Commissioner, Office of the. "Press Announcements - FDA approves first targeted treatment for patients with relapsed or refractory acute myeloid leukemia who have a certain genetic mutation". www.fda.gov. Retrieved 2019-01-11.
- PMID 36153582.
Further reading
- Geisbrecht BV, Gould SJ (October 1999). "The human PICD gene encodes a cytoplasmic and peroxisomal NADP(+)-dependent isocitrate dehydrogenase". The Journal of Biological Chemistry. 274 (43): 30527–30533. S2CID 42785832.
- Shechter I, Dai P, Huo L, Guan G (November 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): 2169–2180. S2CID 219228278.
- Xu X, Zhao J, Xu Z, Peng B, Huang Q, Arnold E, Ding J (August 2004). "Structures of human cytosolic NADP-dependent isocitrate dehydrogenase reveal a novel self-regulatory mechanism of activity". The Journal of Biological Chemistry. 279 (32): 33946–33957. S2CID 7513167.
- 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. PMID 15936593.
- Guo D, Han J, Adam BL, Colburn NH, Wang MH, Dong Z, et al. (December 2005). "Proteomic analysis of SUMO4 substrates in HEK293 cells under serum starvation-induced stress". Biochemical and Biophysical Research Communications. 337 (4): 1308–1318. PMID 16236267.
- Kullberg M, Nilsson MA, Arnason U, Harley EH, Janke A (August 2006). "Housekeeping genes for phylogenetic analysis of eutherian relationships". Molecular Biology and Evolution. 23 (8): 1493–1503. PMID 16751257.
- Wanders RJ, Waterham HR (2006). "Biochemistry of mammalian peroxisomes revisited". Annual Review of Biochemistry. 75: 295–332. PMID 16756494.
- Balss J, Meyer J, Mueller W, Korshunov A, Hartmann C, von Deimling A (December 2008). "Analysis of the IDH1 codon 132 mutation in brain tumors". Acta Neuropathologica. 116 (6): 597–602. S2CID 9530236.
- Bleeker FE, Lamba S, Leenstra S, Troost D, Hulsebos T, Vandertop WP, et al. (January 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. S2CID 7742965.
This article incorporates text from the United States National Library of Medicine, which is in the public domain.
