What is IDH?

Overview

Isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) are enzymes critical for the conversion of isocitrate to α-ketoglutarate (α-KG), a key functional metabolite1. However, the role of IDH goes far beyond simple metabolic catalysis to impact overarching epigenetic regulation.1

Isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) are enzymes critical for the conversion of isocitrate to α-ketoglutarate (α-KG), a key functional metabolite1. However, the role of IDH goes far beyond simple metabolic catalysis to impact overarching epigenetic regulation.1

IDH mutations cause metabolic reprogramming that results
in dysregulation of1:

Icon: Gene expression

Gene expression

Icon: Intracellular trafficking

Intracellular trafficking

Icon: DNA damage repair

DNA damage repair

Icon: Aging

Aging

Icon: Inflammation

Inflammation

Icon: Cell death

Cell death

Differences Between IDH1
and IDH2

Differences Between IDH1 and IDH2

IDH1 is localized in the cytoplasm and IDH2 is localized to the mitochondria.2 Both catalyze important reactions involving isocitrate.2
Understanding the distinct roles of IDH1 and IDH2 is vital, as they may have slight differences in biological impact when mutated.3–5

IDH1 is localized in the cytoplasm and IDH2 is localized to the mitochondria.2 Both catalyze important reactions involving isocitrate.2 Understanding the distinct roles of IDH1 and IDH2 is vital, as they may have slight differences in biological impact when mutated.3–5


Enzymatic reactions catalyzed by wild-type IDH isoforms convert isocitrate to α-KG.2

IDH Enzyme Structure and
Gain-of-Function Mutations

Thumbnail, click for more info: Isocitrate dehydrogenase 1 and 2

IDH enzymes exist as a dimer of two protein chains.6 Heterozygous mutations, e.g., those in one of the two protein chains, create a conformational change favoring a closed conformation, a high affinity for NADPH, and a decreased ability to bind isocitrate.1,6,7
This results in a gain-of-function allowing the mIDH chain to further reduce α-KG, an additional step to the oncometabolite 2-HG.1,6

IDH enzymes exist as a dimer of two protein chains.6 Heterozygous mutations, e.g., those in one of the two protein chains, create a conformational change favoring a closed conformation, a high affinity for NADPH, and a decreased ability to bind isocitrate.1,6,7 This results in a gain-of-function allowing the mIDH chain to further reduce α-KG, an additional step to the oncometabolite 2-HG.1,6

mIDH Impact on Cellular
Differentiation via Epigenetic
Changes

The increased generation of 2-HG by mIDH causes a depletion of α-KG levels.10,11 The inhibitory effect of 2-HG and the depletion of
α-KG affects demethylation enzymes, such as those in the TET and JMJ gene families, as they require α-KG as a cofactor.11,12 Consequently, DNA and histones become hypermethylated, impairing gene transcription and hindering cell differentiation, particularly in blood cell development, thus contributing to the development of cancer.10,13,14

The increased generation of 2-HG by mIDH causes a depletion of α-KG levels.10,11 The inhibitory effect of 2-HG and the depletion of α-KG affects demethylation enzymes, such as those in the TET and JMJ gene families, as they require α-KG as a cofactor.11,12 Consequently, DNA and histones become hypermethylated, impairing gene transcription and hindering cell differentiation, particularly in blood cell development, thus contributing to the development of cancer.10,13,14

Neoplastic activity of mIDH produces high intracellular levels of 2-HG and leads to epigenetic changes that interfere with myeloid differentiation.6,9

mIDH Impact on Immune
System Tumor Response

Additionally, emerging research has unveiled the impact of increased 2-HG levels and its influence on CD8+ T cells in anti-tumor responses.15 2-HG has been found to affect CD8+ T cell function, leading to inhibited proliferation, impaired degranulation, reduced production and release of interferon-ϒ, altered glycolysis, and impaired lactate dehydrogenase (LDH) function within these cells.15 Overall, this impairs the cancer-killing ability of T-cells and allows tumor proliferation.15

IDH mutations are just the tip
of the “iceberg”10–15

Explore video clips on the
function of IDH1 and the
impact of mutation1,2,16–18

Explore video clips on the function of IDH1 and the impact of mutation1,2,16–18

Overview of IDH1 and mutated IDH1 (mIDH1)
https://www.idhlearnmore.com/wp-content/uploads/2023/05/Video-Thumb1@2x.png
What is the normal function of IDH1?
https://www.idhlearnmore.com/wp-content/uploads/2023/05/Video-Thumb2@2x-1.png
What is the impact of mIDH1?
https://www.idhlearnmore.com/wp-content/uploads/2023/05/Video-Thumb3@2x.png

Malignancies Associated with
IDH Mutations

Mutations in IDH1 and IDH2 are seen in a variety of cancers, including acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), IDH-mutant glioma, and cholangiocarcinoma, thus reinforcing the key pathogenetic role of these mutations.1

mIDH is considered an early “driver” mutation in MDS and becomes more frequent as the disease progresses to AML.3,4,6,21 Mutations in IDH1 and IDH2 are present in 6% to 16% and 8% to 19% of patients with newly diagnosed AML, respectively.22

LearnMore about the MDS and AML Spectrum LearnMore about Glioma

Malignancies associated with IDH mutations.1,2,19,20

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References:

1. Pirozzi CJ, Yan H. Nat Rev Clin Oncol. 2021;18(10):645-661. doi:10.1038/s41571-021-00521-0 2. Losman JA, Kaelin WG. Genes Dev. 2013;27(8):836-852. doi:10.1101/gad.217406.113 3. Thol F, Weissinger EM, Krauter J, et al. Haematologica. 2010;95(10):1668-1674. doi:10.3324/haematol.2010.025494 4. Medeiros BC, Fathi AT, DiNardo CD, Pollyea DA, Chan SM, Swords R. Leukemia. 2017;31(2):272-281. doi:10.1038/leu.2016.275 5. Jin J, Hu C, Yu M, et al. PLoS ONE. 2014;9(6):e100206. doi:10.1371/journal.pone.0100206 6. Testa U, Castelli G, Pelosi E. Cancers. 2020;12(9):2427. doi:10.3390/cancers12092427 7. Waitkus MS, Diplas BH, Yan H. Cancer Cell. 2018;34(2):186-195. doi:10.1016/j.ccell.2018.04.011 8. RCSB Protein Data Bank website. https://www.rcsb.org/structure/3MAP. Accessed May 18, 2023. 9. Pan D, Rampal R, Mascarenhas J. Blood Advances. 2020;4(5):970-982. doi:10.1182/bloodadvances.2019001245 10. Wang F, Travins J, DeLaBarre B, et al. Science. 2013;340(6132):622-626. doi:10.1126/science.1234769 11. Kernytsky A, Wang F, Hansen E, et al. Blood. 2015;125(2):296-303. doi:10.1182/blood-2013-10-533604 12. Molenaar RJ, Wilmink JW. J Histochem Cytochem. 2022;70(1):83-97. doi:10.1369/00221554211062499 13. Zhao A, Zhou H, Yang J, Li M, Niu T. Sig Transduct Target Ther. 2023;8(1):71. doi:10.1038/s41392-023-01342-6 14. Schvartzman JM, Reuter VP, Koche RP, Thompson CB. Proc Natl Acad Sci USA. 2019;116(26):12851-12856. doi:10.1073/pnas.1817662116 15. Notarangelo G, Spinelli JB, Perez EM, et al. Science. 2022;377(6614):1519-1529. doi:10.1126/science.abj5104 16. Lu C, Ward PS, Kapoor GS, et al. Nature. 2012;483(7390):474-478. doi:10.1038/nature10860 17. Chowdhury R, Yeoh KK, Tian Y, et al. EMBO Reports. 2011;12(5):463-469. doi:10.1038/embor.2011.43 18. Wu N, Yang M, Gaur U, Xu H, Yao Y, Li D. Biomolecules & Therapeutics. 2016;24(1):1-8. doi:10.4062/biomolther.2015.078 19. Urban DJ, Martinez NJ, Davis MI, et al. Sci Rep. 2017;7(1):12758. doi:10.1038/s41598-017-12630-x 20. Mardis ER, Ding L, Dooling DJ, et al. N Engl J Med. 2009;361(11):1058-1066. doi:10.1056/NEJMoa0903840 21. Makishima H, Yoshizato T, Yoshida K, et al. Nat Genet. 2017;49(2):204-212. doi:10.1038/ng.3742 22. DiNardo CD, Ravandi F, Agresta S, et al. Am J Hematol. 2015;90(8):732-736. doi:10.1002/ajh.24072