Biology:Isocitrate dehydrogenase 1

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Short description: Protein-coding gene in the species Homo sapiens

A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

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][1]

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.[2]

IDH1 forms an asymmetric homodimer in the cytoplasm and carries out its function through two hydrophilic active sites formed by both protein subunits.[3][4][5][6][7] 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.[7]

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.[5][7] This conformation enables isocitrate to bind the active site, inducing a closed conformation that also activates IDH1.[5] 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.[7]

There is also a type 1 peroxisomal targeting sequence at its C-terminal that targets the protein to the peroxisome.[7]

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.[2][3][4][6][7][8] IDH1 interacts with isocitrate and a divalent metal ion cofactor, typically Mg2+ or Mn2+, which plays a crucial role in stabilizing the negatively charged intermediates formed during the enzymatic reaction. It undergoes oxidation at the hydroxyl group on the C2 carbon, a reaction that removes electrons and produces oxalosuccinate. During this step, NAD(P)+ acts as an electron acceptor, transforming into NAD(P)H by gaining these electrons. Subsequently, oxalosuccinate undergoes decarboxylation, meaning it loses a carbon dioxide molecule, resulting in the formation of α-ketoglutarate. This step also allows for the concomitant reduction of nicotinamide adenine dinucleotide phosphate (NADP+) to reduced nicotinamide adenine dinucleotide phosphate (NADPH).[3][4][6] Since NADPH and α-KG function in cellular detoxification processes in response to oxidative stress, IDH1 also indirectly participates in mitigating oxidative damage.[2][3][7][9] In addition, IDH1 is key to β-oxidation of unsaturated fatty acids in the peroxisomes of liver cells.[7] IDH1 also participates in the regulation of glucose-induced insulin secretion.[2] Notably, IDH1 is the primary producer of NADPH in most tissues, especially in brain.[3] Within cells, IDH1 has been observed to localize to the cytoplasm, peroxisome, and endoplasmic reticulum.[6][9]

Under hypoxic conditions, IDH1 catalyzes the reverse reaction of α-KG to isocitrate, which contributes to citrate production via glutaminolysis.[2][3] Isocitrate can also be converted into acetyl-CoA for lipid metabolism.[2]

Mutation

IDH1 mutations are heterozygous, typically involving an amino acid substitution in the active site of the enzyme in codon 132.[10] These mutations are somatic, meaning they primarily occur in cells that can become cancerous, such as those in brain and bone tumors.[11][12] The mutation results in a loss of normal enzymatic function and the abnormal production of 2-hydroxyglutarate (2-HG).[11] It has been considered to take place due to a change in the binding site of the enzyme.[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.[12][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] Tumors of various tissue types with IDH1/2 mutations show improved responses to radiation and chemotherapy.[22][23] The best-studied mutation in IDH1 is R132H, which has been shown to act as a tumor suppressor.[24]

The IDH1 R132H mutation is a crucial prognostic indicator in glioma, frequently arising in the early stages of tumor development. It is predominantly found in low-grade gliomas (WHO Grades II and III) and secondary glioblastomas, which originate from the progression of lower-grade gliomas.[25] Its presence is commonly linked to improved survival rates compared to IDH wild-type gliomas.

In its wild-type form, the IDH1 enzyme is active in the cytoplasm and peroxisomes, where it catalyzes the conversion of isocitrate into α-ketoglutarate (α-KG) as part of the citric acid cycle. This process generates NADPH, a vital molecule that supports antioxidant defenses and biosynthetic processes.

When mutated, IDH1 undergoes a neomorphic transformation, shifting its function. The altered enzyme converts α-KG into D-2-hydroxyglutarate (D-2HG), an oncometabolite. Elevated D-2HG levels disrupt normal cellular processes by inhibiting α-KG–dependent dioxygenases, leading to epigenetic changes, DNA hypermethylation, and impaired differentiation.[26] Moreover, the mutation redirects NADPH consumption, increasing oxidative stress, which further drives tumor development.

The accumulation of D-2HG and elevated oxidative stress play a critical role in reshaping the tumor microenvironment, positioning the R132H mutation as a prime target for IDH inhibitors. These therapies aim to restore regular metabolic functions and reduce tumor aggressiveness, offering a promising avenue for glioma treatment.

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] Ivosidenib was approved by the US Food and Drug Administration (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] Vorasidenib was approved for medical use in the United States in August 2024.[36][37] Vorasidenib is the first approval by the FDA of a systemic therapy for people with grade 2 astrocytoma or oligodendroglioma with a susceptible isocitrate dehydrogenase-1 or isocitrate dehydrogenase-2 mutation.[36]

Ivosidenib is a highly selective, small-molecule inhibitor designed to target the mutant IDH1 enzyme.[38] It works by reversibly inhibiting the mutated enzyme, effectively reducing the production of the oncometabolite D-2-hydroxyglutarate (D-2HG). By lowering D-2HG levels, ivosidenib helps restore normal cellular differentiation that is often disrupted in IDH1-mutant cancers, such as acute myeloid leukemia (AML) and cholangiocarcinoma.[39]

This therapeutic approach is based on the idea that altering the D-2HG concentration interferes with both cellular metabolism and epigenetic regulation, processes that are key to the cancerous transformation driven by IDH1 mutations. Specifically, ivosidenib targets IDH1 mutations at the R132 residue, particularly the R132H and R132C variants, which are among the most common in human cancers.

In in vitro studies, ivosidenib has been shown to inhibit mutant IDH1 at significantly lower concentrations than it does the wild-type enzyme. This high level of specificity minimizes the impact on normal metabolic processes, enhancing its therapeutic efficacy while reducing off-target effects. The drug's targeted action offers promise for personalized cancer treatment by addressing the underlying metabolic disruptions caused by IDH1 mutations.

Clinical trials have demonstrated that ivosidenib is effective in improving outcomes for patients with IDH1-mutant cancers, and its ability to reduce D-2HG levels is a critical component of its mechanism of action.[40]

References

  1. ↑ "Entrez Gene: Isocitrate dehydrogenase 1 (NADP+), soluble". https://www.ncbi.nlm.nih.gov/gene?db=gene&cmd=retrieve&list_uids=3417. 
  2. ↑ 2.0 2.1 2.2 2.3 2.4 2.5 "New developments in the pathogenesis and therapeutic targeting of the IDH1 mutation in glioma". International Journal of Medical Sciences 12 (3): 201–213. 2015. doi:10.7150/ijms.11047. PMID 25678837. 
  3. ↑ 3.0 3.1 3.2 3.3 3.4 3.5 "The driver and passenger effects of isocitrate dehydrogenase 1 and 2 mutations in oncogenesis and survival prolongation". Biochimica et Biophysica Acta (BBA) - Reviews on Cancer 1846 (2): 326–341. December 2014. doi:10.1016/j.bbcan.2014.05.004. PMID 24880135. 
  4. ↑ 4.0 4.1 4.2 "Discovery of α-mangostin as a novel competitive inhibitor against mutant isocitrate dehydrogenase-1". Bioorganic & Medicinal Chemistry Letters 25 (23): 5625–5631. December 2015. doi:10.1016/j.bmcl.2015.10.034. PMID 26508549. 
  5. ↑ 5.0 5.1 5.2 "IDH1 mutant structures reveal a mechanism of dominant inhibition". Cell Research 20 (12): 1279–1281. December 2010. doi:10.1038/cr.2010.160. PMID 21079649. 
  6. ↑ 6.0 6.1 6.2 6.3 "Isocitrate dehydrogenase mutations in gliomas: mechanisms, biomarkers and therapeutic target". Current Opinion in Neurology 24 (6): 648–652. December 2011. doi:10.1097/WCO.0b013e32834cd415. PMID 22002076. 
  7. ↑ 7.0 7.1 7.2 7.3 7.4 7.5 7.6 7.7 "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. August 2004. doi:10.1074/jbc.M404298200. PMID 15173171. 
  8. ↑ "Isocitrate dehydrogenase 1 and 2 mutations in cancer: alterations at a crossroads of cellular metabolism". Journal of the National Cancer Institute 102 (13): 932–941. July 2010. doi:10.1093/jnci/djq187. PMID 20513808. 
  9. ↑ 9.0 9.1 "Glioma-derived mutations in IDH: from mechanism to potential therapy". Biochemical and Biophysical Research Communications 397 (2): 127–130. June 2010. doi:10.1016/j.bbrc.2010.05.115. PMID 20510884. Bibcode: 2010BBRC..397..127F. 
  10. ↑ "IDH1 gene" (in en). MedlinePlus Genetics. National Library of Medicine (US). https://medlineplus.gov/genetics/gene/idh1/. 
  11. ↑ 11.0 11.1 "IDH mutation in glioma: new insights and promises for the future". JAMA Neurology 71 (10): 1319–1325. October 2014. doi:10.1001/jamaneurol.2014.1205. PMID 25155243. 
  12. ↑ 12.0 12.1 "Role of isocitrate dehydrogenase 1/2 (IDH 1/2) gene mutations in human tumors". Histology and Histopathology 30 (10): 1155–1160. October 2015. doi:10.14670/HH-11-643. PMID 26147657. 
  13. ↑ "IDH1 and IDH2 mutants identified in cancer lose inhibition by isocitrate because of a change in their binding sites" (in en). bioRxiv. 20 October 2018. doi:10.1101/425025. 
  14. ↑ "Metabolic recoding of epigenetics in cancer". Cancer Communications 38 (1): 25. May 2018. doi:10.1186/s40880-018-0302-3. PMID 29784032. 
  15. ↑ "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): 2609–2616. November 2011. doi:10.1002/ajmg.a.34325. PMID 22025298. 
  16. ↑ "An integrated genomic analysis of human glioblastoma multiforme". Science 321 (5897): 1807–1812. September 2008. doi:10.1126/science.1164382. PMID 18772396. Bibcode: 2008Sci...321.1807P. 
  17. ↑ "IDH1 and IDH2 mutations in gliomas". The New England Journal of Medicine 360 (8): 765–773. February 2009. doi:10.1056/NEJMoa0808710. PMID 19228619. 
  18. ↑ "IDH1 mutations are early events in the development of astrocytomas and oligodendrogliomas". The American Journal of Pathology 174 (4): 1149–1153. April 2009. doi:10.2353/ajpath.2009.080958. PMID 19246647. 
  19. ↑ "Recent advances in the molecular understanding of glioblastoma". Journal of Neuro-Oncology 108 (1): 11–27. May 2012. doi:10.1007/s11060-011-0793-0. PMID 22270850. 
  20. ↑ "Integrated genomic characterization of IDH1-mutant glioma malignant progression". Nature Genetics 48 (1): 59–66. January 2016. doi:10.1038/ng.3457. PMID 26618343. 
  21. ↑ "The combination of IDH1 mutations and MGMT methylation status predicts survival in glioblastoma better than either IDH1 or MGMT alone". Neuro-Oncology 16 (9): 1263–1273. September 2014. doi:10.1093/neuonc/nou005. PMID 24510240. 
  22. ↑ "Wild-type and mutated IDH1/2 enzymes and therapy responses". Oncogene 37 (15): 1949–1960. April 2018. doi:10.1038/s41388-017-0077-z. PMID 29367755. 
  23. ↑ "Comprehensive Metabolomic Analysis of IDH1R132H Clinical Glioma Samples Reveals Suppression of β-oxidation Due to Carnitine Deficiency". Scientific Reports 9 (1): 9787. July 2019. doi:10.1038/s41598-019-46217-5. PMID 31278288. Bibcode: 2019NatSR...9.9787M. 
  24. ↑ "IDH1-R132H acts as a tumor suppressor in glioma via epigenetic up-regulation of the DNA damage response". Science Translational Medicine 11 (479). February 2019. doi:10.1126/scitranslmed.aaq1427. PMID 30760578. 
  25. ↑ "Effects of the IDH1 R132H Mutation on the Energy Metabolism: A Comparison between Tissue and Corresponding Primary Glioma Cell Cultures". ACS Omega 7 (4): 3568–3578. February 2022. doi:10.1021/acsomega.1c06121. PMID 35128264. 
  26. ↑ "IDH1 Expression via the R132H Mutation-Specific Antibody in Adrenocortical Neoplasias-Prognostic Impact in Carcinomas". Journal of the Endocrine Society 4 (4). April 2020. doi:10.1210/jendso/bvaa018. PMID 32190803. 
  27. ↑ "Recurring mutations found by sequencing an acute myeloid leukemia genome". The New England Journal of Medicine 361 (11): 1058–1066. September 2009. doi:10.1056/NEJMoa0903840. PMID 19657110. 
  28. ↑ "The role of mutations in epigenetic regulators in myeloid malignancies". Nature Reviews. Cancer 12 (9): 599–612. September 2012. doi:10.1038/nrc3343. PMID 22898539. 
  29. ↑ 29.0 29.1 "A vaccine targeting mutant IDH1 induces antitumour immunity". Nature 512 (7514): 324–327. August 2014. doi:10.1038/nature13387. PMID 25043048. Bibcode: 2014Natur.512..324S. 
  30. ↑ "Novel Insights for Inhibiting Mutant Heterodimer IDH1wt-R132H in Cancer: An In-Silico Approach". Molecular Diagnosis & Therapy 22 (3): 369–380. June 2018. doi:10.1007/s40291-018-0331-2. PMID 29651790. 
  31. ↑ "Novel Modes of Inhibition of Wild-Type Isocitrate Dehydrogenase 1 (IDH1): Direct Covalent Modification of His315". Journal of Medicinal Chemistry 61 (15): 6647–6657. August 2018. doi:10.1021/acs.jmedchem.8b00305. PMID 30004704. 
  32. ↑ "Allosteric Mutant IDH1 Inhibitors Reveal Mechanisms for IDH1 Mutant and Isoform Selectivity". Structure 25 (3): 506–513. March 2017. doi:10.1016/j.str.2016.12.017. PMID 28132785. 
  33. ↑ "Discovery and Optimization of Allosteric Inhibitors of Mutant Isocitrate Dehydrogenase 1 (R132H IDH1) Displaying Activity in Human Acute Myeloid Leukemia Cells". Journal of Medicinal Chemistry 59 (24): 11120–11137. December 2016. doi:10.1021/acs.jmedchem.6b01320. PMID 28002956. 
  34. ↑ "FDA approves first targeted treatment for patients with relapsed or refractory acute myeloid leukemia who have a certain genetic mutation". U.S. Food and Drug Administration (FDA) (Press release). 20 July 2018. Archived from the original on 11 December 2019. Retrieved 11 January 2019.
  35. ↑ "Wild-type IDH1 inhibition enhances chemotherapy response in melanoma". Journal of Experimental & Clinical Cancer Research 41 (1). September 2022. doi:10.1186/s13046-022-02489-w. PMID 36153582. 
  36. ↑ 36.0 36.1 "FDA approves vorasidenib for Grade 2 astrocytoma or oligodendroglioma with a susceptible IDH1 or IDH2 mutation". 6 August 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-vorasidenib-grade-2-astrocytoma-or-oligodendroglioma-susceptible-idh1-or-idh2-mutation.  Public Domain This article incorporates text from this source, which is in the public domain.
  37. ↑ "Servier's Voranigo (vorasidenib) Tablets Receives FDA Approval as First Targeted Therapy for Grade 2 IDH-mutant Glioma" (Press release). Servier Pharmaceuticals. 6 August 2024. Archived from the original on 7 August 2024. Retrieved 7 August 2024 – via PR Newswire.
  38. ↑ "Ivosidenib in IDH1-mutated cholangiocarcinoma: Clinical evaluation and future directions". Pharmacology & Therapeutics 237. September 2022. doi:10.1016/j.pharmthera.2022.108170. PMID 35296436. 
  39. ↑ "Ivosidenib: IDH1 Inhibitor for the Treatment of Acute Myeloid Leukemia". Journal of the Advanced Practitioner in Oncology 10 (5): 494–500. July 2019. doi:10.6004/jadpro.2019.10.5.7. PMID 33457062. 
  40. ↑ "Vorasidenib and ivosidenib in IDH1-mutant low-grade glioma: a randomized, perioperative phase 1 trial". Nature Medicine 29 (3): 615–622. March 2023. doi:10.1038/s41591-022-02141-2. PMID 36823302. 

Further reading

  • "The human PICD gene encodes a cytoplasmic and peroxisomal NADP(+)-dependent isocitrate dehydrogenase". The Journal of Biological Chemistry 274 (43): 30527–30533. October 1999. doi:10.1074/jbc.274.43.30527. PMID 10521434. 
  • "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. November 2003. doi:10.1194/jlr.M300285-JLR200. PMID 12923220. 
  • "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. August 2004. doi:10.1074/jbc.M404298200. PMID 15173171. 
  • "Identification of differentially expressed proteins during human urinary bladder cancer progression". Cancer Detection and Prevention 29 (3): 249–255. 2005. doi:10.1016/j.cdp.2005.01.002. PMID 15936593. 
  • "Proteomic analysis of SUMO4 substrates in HEK293 cells under serum starvation-induced stress". Biochemical and Biophysical Research Communications 337 (4): 1308–1318. December 2005. doi:10.1016/j.bbrc.2005.09.191. PMID 16236267. Bibcode: 2005BBRC..337.1308G. 
  • "Housekeeping genes for phylogenetic analysis of eutherian relationships". Molecular Biology and Evolution 23 (8): 1493–1503. August 2006. doi:10.1093/molbev/msl027. PMID 16751257. 
  • "Biochemistry of mammalian peroxisomes revisited". Annual Review of Biochemistry 75: 295–332. 2006. doi:10.1146/annurev.biochem.74.082803.133329. PMID 16756494. 
  • "Analysis of the IDH1 codon 132 mutation in brain tumors". Acta Neuropathologica 116 (6): 597–602. December 2008. doi:10.1007/s00401-008-0455-2. PMID 18985363. 
  • "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. January 2009. 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.




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