Isocitrate dehydrogenase 1

{{Short description|Protein-coding gene in the species Homo sapiens}} {{Use dmy dates|date=August 2024}} {{cs1 config |name-list-style=vanc |display-authors=6}} {{Infobox gene}} '''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]<ref name="entrez">{{cite web| title = Entrez Gene: Isocitrate dehydrogenase 1 (NADP+), soluble| url = https://www.ncbi.nlm.nih.gov/gene?db=gene&cmd=retrieve&list_uids=3417| access-date = 30 December 2011 | archive-date = 8 August 2024| archive-url = https://web.archive.org/web/20240808061335/https://www.ncbi.nlm.nih.gov/gene?cmd=retrieve&list_uids=3417| url-status = live}}</ref>

== 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''.<ref name=pmid25678837>{{cite journal | vauthors = Dimitrov L, Hong CS, Yang C, Zhuang Z, Heiss JD | title = New developments in the pathogenesis and therapeutic targeting of the IDH1 mutation in glioma | journal = International Journal of Medical Sciences | volume = 12 | issue = 3 | pages = 201–213 | date = 2015 | pmid = 25678837 | pmc = 4323358 | doi = 10.7150/ijms.11047 }}</ref>

IDH1 forms an asymmetric homodimer in the cytoplasm and carries out its function through two hydrophilic active sites formed by both protein subunits.<ref name=pmid24880135>{{cite journal | vauthors = Molenaar RJ, Radivoyevitch T, Maciejewski JP, van Noorden CJ, Bleeker FE | title = The driver and passenger effects of isocitrate dehydrogenase 1 and 2 mutations in oncogenesis and survival prolongation | journal = Biochimica et Biophysica Acta (BBA) - Reviews on Cancer | volume = 1846 | issue = 2 | pages = 326–341 | date = December 2014 | pmid = 24880135 | doi = 10.1016/j.bbcan.2014.05.004 }}</ref><ref name=pmid26508549>{{cite journal | vauthors = Kim HJ, Fei X, Cho SC, Choi BY, Ahn HC, Lee K, Seo SY, Keum YS | title = Discovery of α-mangostin as a novel competitive inhibitor against mutant isocitrate dehydrogenase-1 | journal = Bioorganic & Medicinal Chemistry Letters | volume = 25 | issue = 23 | pages = 5625–5631 | date = December 2015 | pmid = 26508549 | doi = 10.1016/j.bmcl.2015.10.034 }}</ref><ref name=pmid21079649>{{cite journal | vauthors = Zhao S, Guan KL | title = IDH1 mutant structures reveal a mechanism of dominant inhibition | journal = Cell Research | volume = 20 | issue = 12 | pages = 1279–1281 | date = December 2010 | pmid = 21079649 | doi = 10.1038/cr.2010.160 | s2cid = 41199424 | doi-access = free }}</ref><ref name=pmid22002076>{{cite journal | vauthors = Guo C, Pirozzi CJ, Lopez GY, Yan H | title = Isocitrate dehydrogenase mutations in gliomas: mechanisms, biomarkers and therapeutic target | journal = Current Opinion in Neurology | volume = 24 | issue = 6 | pages = 648–652 | date = December 2011 | pmid = 22002076 | pmc = 3640434 | doi = 10.1097/WCO.0b013e32834cd415 }}</ref><ref name=pmid15173171>{{cite journal | vauthors = Xu X, Zhao J, Xu Z, Peng B, Huang Q, Arnold E, Ding J | title = Structures of human cytosolic NADP-dependent isocitrate dehydrogenase reveal a novel self-regulatory mechanism of activity | journal = The Journal of Biological Chemistry | volume = 279 | issue = 32 | pages = 33946–33957 | date = August 2004 | pmid = 15173171 | doi = 10.1074/jbc.M404298200 | s2cid = 7513167 | doi-access = free }}</ref> 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.<ref name=pmid15173171/>

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.<ref name=pmid21079649/><ref name=pmid15173171/> This conformation enables isocitrate to bind the active site, inducing a closed conformation that also activates IDH1.<ref name=pmid21079649/> 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.<ref name=pmid15173171/>

There is also a type 1 peroxisomal targeting sequence at its C-terminal that targets the protein to the peroxisome.<ref name=pmid15173171/>

== 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.<ref name=pmid25678837/><ref name=pmid24880135/><ref name=pmid26508549/><ref name=pmid22002076/><ref name=pmid15173171/><ref>{{cite journal | vauthors = Reitman ZJ, Yan H | title = Isocitrate dehydrogenase 1 and 2 mutations in cancer: alterations at a crossroads of cellular metabolism | journal = Journal of the National Cancer Institute | volume = 102 | issue = 13 | pages = 932–941 | date = July 2010 | pmid = 20513808 | doi = 10.1093/jnci/djq187 | pmc = 2897878 }}</ref> 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).<ref name=pmid24880135/><ref name=pmid26508549/><ref name=pmid22002076/> Since NADPH and α-KG function in cellular detoxification processes in response to oxidative stress, IDH1 also indirectly participates in mitigating oxidative damage.<ref name=pmid25678837/><ref name=pmid24880135/><ref name=pmid15173171/><ref name=pmid20510884>{{cite journal | vauthors = Fu Y, Huang R, Du J, Yang R, An N, Liang A | title = Glioma-derived mutations in IDH: from mechanism to potential therapy | journal = Biochemical and Biophysical Research Communications | volume = 397 | issue = 2 | pages = 127–130 | date = June 2010 | pmid = 20510884 | doi = 10.1016/j.bbrc.2010.05.115 | bibcode = 2010BBRC..397..127F }}</ref> In addition, IDH1 is key to β-oxidation of unsaturated fatty acids in the peroxisomes of liver cells.<ref name=pmid15173171/> IDH1 also participates in the regulation of glucose-induced insulin secretion.<ref name=pmid25678837/> Notably, IDH1 is the primary producer of NADPH in most tissues, especially in brain.<ref name=pmid24880135/> Within cells, IDH1 has been observed to localize to the cytoplasm, peroxisome, and endoplasmic reticulum.<ref name=pmid22002076/><ref name="pmid20510884"/>

Under hypoxic conditions, IDH1 catalyzes the reverse reaction of α-KG to isocitrate, which contributes to citrate production via glutaminolysis.<ref name=pmid25678837/><ref name=pmid24880135/> Isocitrate can also be converted into acetyl-CoA for lipid metabolism.<ref name=pmid25678837/>

=== Mutation ===

''IDH1'' mutations are heterozygous, typically involving an amino acid substitution in the active site of the enzyme in codon 132.<ref>{{cite web | publisher = National Library of Medicine (US) |title=IDH1 gene | work = MedlinePlus Genetics |url=https://medlineplus.gov/genetics/gene/idh1/ |access-date=10 November 2024 |language=en}}</ref> These mutations are somatic, meaning they primarily occur in cells that can become cancerous, such as those in brain and bone tumors.<ref name=IDH1-JAMA>{{cite journal | vauthors = Turkalp Z, Karamchandani J, Das S | title = IDH mutation in glioma: new insights and promises for the future | journal = JAMA Neurology | volume = 71 | issue = 10 | pages = 1319–1325 | date = October 2014 | pmid = 25155243 | doi = 10.1001/jamaneurol.2014.1205 }}</ref><ref name=IDH1-HH>{{cite journal | vauthors = Liu X, Ling ZQ | title = Role of isocitrate dehydrogenase 1/2 (IDH 1/2) gene mutations in human tumors | journal = Histology and Histopathology | volume = 30 | issue = 10 | pages = 1155–1160 | date = October 2015 | pmid = 26147657 | doi = 10.14670/HH-11-643 }}</ref> The mutation results in a loss of normal enzymatic function and the abnormal production of 2-hydroxyglutarate (2-HG).<ref name=IDH1-JAMA/> It has been considered to take place due to a change in the binding site of the enzyme.<ref>{{Cite bioRxiv| vauthors = Bascur JP, Alegría-Arcos M, Araya-Durán I, Juritz EI, González-Nilo FD, Almonacid DE |date=20 October 2018|title=IDH1 and IDH2 mutants identified in cancer lose inhibition by isocitrate because of a change in their binding sites |language=en|biorxiv=10.1101/425025}}</ref> 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.<ref name=IDH1-HH/><ref>{{cite journal | vauthors = Wang YP, Lei QY | title = Metabolic recoding of epigenetics in cancer | journal = Cancer Communications | volume = 38 | issue = 1 | date = May 2018 | page = 25 | pmid = 29784032 | pmc = 5993135 | doi = 10.1186/s40880-018-0302-3 | doi-access = free }}</ref>

== Clinical significance ==

Mutations in this gene have been shown to cause metaphyseal chondromatosis with aciduria.<ref name="pmid22025298">{{cite journal | vauthors = 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 | title = Whole-exome sequencing detects somatic mutations of IDH1 in metaphyseal chondromatosis with D-2-hydroxyglutaric aciduria (MC-HGA) | journal = American Journal of Medical Genetics. Part A | volume = 155A | issue = 11 | pages = 2609–2616 | date = November 2011 | pmid = 22025298 | doi = 10.1002/ajmg.a.34325 | s2cid = 33345097 }}</ref>

Mutations in ''IDH1'' are also implicated in cancer. Originally, mutations in ''IDH1'' were detected in an integrated genomic analysis of human glioblastoma multiforme.<ref name="pmid18772396">{{cite journal | vauthors = 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 | title = An integrated genomic analysis of human glioblastoma multiforme | journal = Science | volume = 321 | issue = 5897 | pages = 1807–1812 | date = September 2008 | pmid = 18772396 | pmc = 2820389 | doi = 10.1126/science.1164382 | bibcode = 2008Sci...321.1807P }}</ref> 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.<ref name="pmid19228619">{{cite journal | vauthors = 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 | title = IDH1 and IDH2 mutations in gliomas | journal = The New England Journal of Medicine | volume = 360 | issue = 8 | pages = 765–773 | date = February 2009 | pmid = 19228619 | pmc = 2820383 | doi = 10.1056/NEJMoa0808710 }}</ref> 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.<ref name="pmid19246647">{{cite journal | vauthors = Watanabe T, Nobusawa S, Kleihues P, Ohgaki H | title = IDH1 mutations are early events in the development of astrocytomas and oligodendrogliomas | journal = The American Journal of Pathology | volume = 174 | issue = 4 | pages = 1149–1153 | date = April 2009 | pmid = 19246647 | pmc = 2671348 | doi = 10.2353/ajpath.2009.080958 }}</ref><ref>{{cite journal | vauthors = Bleeker FE, Molenaar RJ, Leenstra S | title = Recent advances in the molecular understanding of glioblastoma | journal = Journal of Neuro-Oncology | volume = 108 | issue = 1 | pages = 11–27 | date = May 2012 | pmid = 22270850 | pmc = 3337398 | doi = 10.1007/s11060-011-0793-0 }}</ref><ref>{{cite journal | vauthors = Bai H, Harmancı AS, Erson-Omay EZ, Li J, Coşkun S, Simon M, Krischek B, Özduman K, Omay SB, Sorensen EA, Turcan Ş, Bakırcığlu M, Carrión-Grant G, Murray PB, Clark VE, Ercan-Sencicek AG, Knight J, Sencar L, Altınok S, Kaulen LD, Gülez B, Timmer M, Schramm J, Mishra-Gorur K, Henegariu O, Moliterno J, Louvi A, Chan TA, Tannheimer SL, Pamir MN, Vortmeyer AO, Bilguvar K, Yasuno K, Günel M | title = Integrated genomic characterization of IDH1-mutant glioma malignant progression | journal = Nature Genetics | volume = 48 | issue = 1 | pages = 59–66 | date = January 2016 | pmid = 26618343 | pmc = 4829945 | doi = 10.1038/ng.3457 }}</ref> 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.<ref>{{cite journal | vauthors = 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 | title = The combination of IDH1 mutations and MGMT methylation status predicts survival in glioblastoma better than either IDH1 or MGMT alone | journal = Neuro-Oncology | volume = 16 | issue = 9 | pages = 1263–1273 | date = September 2014 | pmid = 24510240 | pmc = 4136888 | doi = 10.1093/neuonc/nou005 }}</ref> Tumors of various tissue types with ''IDH1/2'' mutations show improved responses to radiation and chemotherapy.<ref>{{cite journal | vauthors = Molenaar RJ, Maciejewski JP, Wilmink JW, van Noorden CJ | title = Wild-type and mutated IDH1/2 enzymes and therapy responses | journal = Oncogene | volume = 37 | issue = 15 | pages = 1949–1960 | date = April 2018 | pmid = 29367755 | pmc = 5895605 | doi = 10.1038/s41388-017-0077-z }}</ref><ref>{{cite journal | vauthors = Miyata S, Tominaga K, Sakashita E, Urabe M, Onuki Y, Gomi A, Yamaguchi T, Mieno M, Mizukami H, Kume A, Ozawa K, Watanabe E, Kawai K, Endo H | title = Comprehensive Metabolomic Analysis of IDH1R132H Clinical Glioma Samples Reveals Suppression of β-oxidation Due to Carnitine Deficiency | journal = Scientific Reports | volume = 9 | issue = 1 | page = 9787 | date = July 2019 | pmid = 31278288 | pmc = 6611790 | doi = 10.1038/s41598-019-46217-5 | bibcode = 2019NatSR...9.9787M }}</ref> The best-studied mutation in ''IDH1'' is R132H, which has been shown to act as a tumor suppressor.<ref>{{cite journal | vauthors = Núñez FJ, Mendez FM, Kadiyala P, Alghamri MS, Savelieff MG, Garcia-Fabiani MB, Haase S, Koschmann C, Calinescu AA, Kamran N, Saxena M, Patel R, Carney S, Guo MZ, Edwards M, Ljungman M, Qin T, Sartor MA, Tagett R, Venneti S, Brosnan-Cashman J, Meeker A, Gorbunova V, Zhao L, Kremer DM, Zhang L, Lyssiotis CA, Jones L, Herting CJ, Ross JL, Hambardzumyan D, Hervey-Jumper S, Figueroa ME, Lowenstein PR, Castro MG | title = IDH1-R132H acts as a tumor suppressor in glioma via epigenetic up-regulation of the DNA damage response | journal = Science Translational Medicine | volume = 11 | issue = 479 | article-number = eaaq1427 | date = February 2019 | pmid = 30760578 | pmc = 6400220 | doi = 10.1126/scitranslmed.aaq1427 }}</ref>

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.<ref>{{cite journal | vauthors = Dekker LJ, Verheul C, Wensveen N, Leenders W, Lamfers ML, Leenstra S, Luider TM | title = Effects of the IDH1 R132H Mutation on the Energy Metabolism: A Comparison between Tissue and Corresponding Primary Glioma Cell Cultures | journal = ACS Omega | volume = 7 | issue = 4 | pages = 3568–3578 | date = February 2022 | pmid = 35128264 | doi = 10.1021/acsomega.1c06121 | doi-access = free| pmc = 8811756 | hdl = 2066/248779 | hdl-access = free }}</ref> 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.<ref>{{cite journal | vauthors = Pennanen M, Tynninen O, Kytölä S, Ellonen P, Mustonen H, Heiskanen I, Haglund C, Arola J | title = IDH1 Expression via the R132H Mutation-Specific Antibody in Adrenocortical Neoplasias-Prognostic Impact in Carcinomas | journal = Journal of the Endocrine Society | volume = 4 | issue = 4 | article-number = bvaa018 | date = April 2020 | doi = 10.1210/jendso/bvaa018 | doi-access = free | pmid = 32190803 | pmc = 7069839 }}</ref> 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.<ref name="pmid19657110">{{cite journal | vauthors = 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 | title = Recurring mutations found by sequencing an acute myeloid leukemia genome | journal = The New England Journal of Medicine | volume = 361 | issue = 11 | pages = 1058–1066 | date = September 2009 | pmid = 19657110 | pmc = 3201812 | doi = 10.1056/NEJMoa0903840 }}</ref><ref name="pmid22898539">{{cite journal | vauthors = Shih AH, Abdel-Wahab O, Patel JP, Levine RL | title = The role of mutations in epigenetic regulators in myeloid malignancies | journal = Nature Reviews. Cancer | volume = 12 | issue = 9 | pages = 599–612 | date = September 2012 | pmid = 22898539 | doi = 10.1038/nrc3343 | s2cid = 20214444 }}</ref>

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.<ref name="Schumacher_2014">{{cite journal | vauthors = Schumacher T, Bunse L, Pusch S, Sahm F, Wiestler B, Quandt J, Menn O, Osswald M, Oezen I, Ott M, Keil M, Balß J, Rauschenbach K, Grabowska AK, Vogler I, Diekmann J, Trautwein N, Eichmüller SB, Okun J, Stevanović S, Riemer AB, Sahin U, Friese MA, Beckhove P, von Deimling A, Wick W, Platten M | title = A vaccine targeting mutant IDH1 induces antitumour immunity | journal = Nature | volume = 512 | issue = 7514 | pages = 324–327 | date = August 2014 | pmid = 25043048 | doi = 10.1038/nature13387 | s2cid = 4468160 | bibcode = 2014Natur.512..324S }}</ref> 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.<ref name="Schumacher_2014" />

===As a drug target=== Mutated and normal forms of IDH1 had been studied for drug inhibition both ''in silico'' and ''in vitro''.<ref>{{cite journal | vauthors = Juritz EI, Bascur JP, Almonacid DE, González-Nilo FD | title = Novel Insights for Inhibiting Mutant Heterodimer IDH1wt-R132H in Cancer: An In-Silico Approach | journal = Molecular Diagnosis & Therapy | volume = 22 | issue = 3 | pages = 369–380 | date = June 2018 | pmid = 29651790 | doi = 10.1007/s40291-018-0331-2 | s2cid = 4798363 }}</ref><ref>{{cite journal | vauthors = Jakob CG, Upadhyay AK, Donner PL, Nicholl E, Addo SN, Qiu W, Ling C, Gopalakrishnan SM, Torrent M, Cepa SP, Shanley J, Shoemaker AR, Sun CC, Vasudevan A, Woller KR, Shotwell JB, Shaw B, Bian Z, Hutti JE | title = Novel Modes of Inhibition of Wild-Type Isocitrate Dehydrogenase 1 (IDH1): Direct Covalent Modification of His315 | journal = Journal of Medicinal Chemistry | volume = 61 | issue = 15 | pages = 6647–6657 | date = August 2018 | pmid = 30004704 | doi = 10.1021/acs.jmedchem.8b00305 | osti = 1471640 | s2cid = 51625776 }}</ref><ref>{{cite journal | vauthors = Xie X, Baird D, Bowen K, Capka V, Chen J, Chenail G, Cho Y, Dooley J, Farsidjani A, Fortin P, Kohls D, Kulathila R, Lin F, McKay D, Rodrigues L, Sage D, Touré BB, van der Plas S, Wright K, Xu M, Yin H, Levell J, Pagliarini RA | title = Allosteric Mutant IDH1 Inhibitors Reveal Mechanisms for IDH1 Mutant and Isoform Selectivity | journal = Structure | volume = 25 | issue = 3 | pages = 506–513 | date = March 2017 | pmid = 28132785 | doi = 10.1016/j.str.2016.12.017 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Jones S, Ahmet J, Ayton K, Ball M, Cockerill M, Fairweather E, Hamilton N, Harper P, Hitchin J, Jordan A, Levy C, Lopez R, McKenzie E, Packer M, Plant D, Simpson I, Simpson P, Sinclair I, Somervaille TC, Small H, Spencer GJ, Thomson G, Tonge M, Waddell I, Walsh J, Waszkowycz B, Wigglesworth M, Wiseman DH, Ogilvie D | title = Discovery and Optimization of Allosteric Inhibitors of Mutant Isocitrate Dehydrogenase 1 (R132H IDH1) Displaying Activity in Human Acute Myeloid Leukemia Cells | journal = Journal of Medicinal Chemistry | volume = 59 | issue = 24 | pages = 11120–11137 | date = December 2016 | pmid = 28002956 | doi = 10.1021/acs.jmedchem.6b01320 | doi-access = free }}</ref> 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.<ref>{{Cite press release |url=https://www.fda.gov/news-events/press-announcements/fda-approves-first-targeted-treatment-patients-relapsed-or-refractory-acute-myeloid-leukemia-who |title=FDA approves first targeted treatment for patients with relapsed or refractory acute myeloid leukemia who have a certain genetic mutation |website=U.S. Food and Drug Administration (FDA) |date=20 July 2018 |access-date=11 January 2019 |archive-date=11 December 2019 |archive-url=https://web.archive.org/web/20191211204726/https://www.fda.gov/news-events/press-announcements/fda-approves-first-targeted-treatment-patients-relapsed-or-refractory-acute-myeloid-leukemia-who }}</ref> Ivosidenib (AG-120) has exhibited potent anti-wtIDH1 properties in melanoma under low magnesium and nutrient levels, reflective of the tumor microenvironment in natura.<ref>{{cite journal | vauthors = Zarei M, Hajihassani O, Hue JJ, Graor HJ, Loftus AW, Rathore M, Vaziri-Gohar A, Asara JM, Winter JM, Rothermel LD | title = Wild-type IDH1 inhibition enhances chemotherapy response in melanoma | journal = Journal of Experimental & Clinical Cancer Research | volume = 41 | issue = 1 | article-number = 283 | date = September 2022 | pmid = 36153582 | doi = 10.1186/s13046-022-02489-w | pmc = 9509573 | doi-access = free }}</ref> Vorasidenib was approved for medical use in the United States in August 2024.<ref name="FDA 20240806">{{cite web | title=FDA approves vorasidenib for Grade 2 astrocytoma or oligodendroglioma with a susceptible IDH1 or IDH2 mutation | website=U.S. Food and Drug Administration (FDA) | date=6 August 2024 | url=https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-vorasidenib-grade-2-astrocytoma-or-oligodendroglioma-susceptible-idh1-or-idh2-mutation | access-date=7 August 2024 | archive-date=7 August 2024 | archive-url=https://web.archive.org/web/20240807035511/https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-vorasidenib-grade-2-astrocytoma-or-oligodendroglioma-susceptible-idh1-or-idh2-mutation }} {{PD-notice}}</ref><ref>{{cite press release | title=Servier's Voranigo (vorasidenib) Tablets Receives FDA Approval as First Targeted Therapy for Grade 2 IDH-mutant Glioma | publisher=Servier Pharmaceuticals | via=PR Newswire | date=6 August 2024 | url=https://www.prnewswire.com/news-releases/serviers-voranigo-vorasidenib-tablets-receives-fda-approval-as-first-targeted-therapy-for-grade-2-idh-mutant-glioma-302215991.html | access-date=7 August 2024 | archive-date=7 August 2024 | archive-url=https://web.archive.org/web/20240807072643/https://www.prnewswire.com/news-releases/serviers-voranigo-vorasidenib-tablets-receives-fda-approval-as-first-targeted-therapy-for-grade-2-idh-mutant-glioma-302215991.html | url-status=live }}</ref> 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.<ref name="FDA 20240806" />

Ivosidenib is a highly selective, small-molecule inhibitor designed to target the mutant IDH1 enzyme.<ref>{{cite journal | vauthors = Lavacchi D, Caliman E, Rossi G, Buttitta E, Botteri C, Fancelli S, Pellegrini E, Roviello G, Pillozzi S, Antonuzzo L | title = Ivosidenib in IDH1-mutated cholangiocarcinoma: Clinical evaluation and future directions | journal = Pharmacology & Therapeutics | volume = 237 | article-number = 108170 | date = September 2022 | pmid = 35296436 | doi = 10.1016/j.pharmthera.2022.108170 | hdl = 2158/1286728 | hdl-access = free }}</ref> 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.<ref>{{cite journal | vauthors = Merchant SL, Culos K, Wyatt H | title = Ivosidenib: IDH1 Inhibitor for the Treatment of Acute Myeloid Leukemia | journal = Journal of the Advanced Practitioner in Oncology | volume = 10 | issue = 5 | pages = 494–500 | date = July 2019 | doi = 10.6004/jadpro.2019.10.5.7 | pmid = 33457062 | pmc = 7779565 }}</ref>

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.<ref>{{cite journal | vauthors = Mellinghoff IK, Lu M, Wen PY, Taylor JW, Maher EA, Arrillaga-Romany I, Peters KB, Ellingson BM, Rosenblum MK, Chun S, Le K, Tassinari A, Choe S, Toubouti Y, Schoenfeld S, Pandya SS, Hassan I, Steelman L, Clarke JL, Cloughesy TF | title = Vorasidenib and ivosidenib in IDH1-mutant low-grade glioma: a randomized, perioperative phase 1 trial | journal = Nature Medicine | volume = 29 | issue = 3 | pages = 615–622 | date = March 2023 | pmid = 36823302 | doi = 10.1038/s41591-022-02141-2 | pmc = 10313524 }}</ref>

== References == {{reflist}}

==Further reading == {{refbegin|30em}} * {{cite journal | vauthors = Geisbrecht BV, Gould SJ | title = The human PICD gene encodes a cytoplasmic and peroxisomal NADP(+)-dependent isocitrate dehydrogenase | journal = The Journal of Biological Chemistry | volume = 274 | issue = 43 | pages = 30527–30533 | date = October 1999 | pmid = 10521434 | doi = 10.1074/jbc.274.43.30527 | s2cid = 42785832 | doi-access = free }} * {{cite journal | vauthors = Shechter I, Dai P, Huo L, Guan G | title = 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 = Journal of Lipid Research | volume = 44 | issue = 11 | pages = 2169–2180 | date = November 2003 | pmid = 12923220 | doi = 10.1194/jlr.M300285-JLR200 |doi-access=free | s2cid = 219228278 }} * {{cite journal | vauthors = Xu X, Zhao J, Xu Z, Peng B, Huang Q, Arnold E, Ding J | title = Structures of human cytosolic NADP-dependent isocitrate dehydrogenase reveal a novel self-regulatory mechanism of activity | journal = The Journal of Biological Chemistry | volume = 279 | issue = 32 | pages = 33946–33957 | date = August 2004 | pmid = 15173171 | doi = 10.1074/jbc.M404298200 | s2cid = 7513167 | doi-access = free }} * {{cite journal | vauthors = Memon AA, Chang JW, Oh BR, Yoo YJ | title = Identification of differentially expressed proteins during human urinary bladder cancer progression | journal = Cancer Detection and Prevention | volume = 29 | issue = 3 | pages = 249–255 | year = 2005 | pmid = 15936593 | doi = 10.1016/j.cdp.2005.01.002 }} * {{cite journal | vauthors = Guo D, Han J, Adam BL, Colburn NH, Wang MH, Dong Z, Eizirik DL, She JX, Wang CY | title = Proteomic analysis of SUMO4 substrates in HEK293 cells under serum starvation-induced stress | journal = Biochemical and Biophysical Research Communications | volume = 337 | issue = 4 | pages = 1308–1318 | date = December 2005 | pmid = 16236267 | doi = 10.1016/j.bbrc.2005.09.191 | bibcode = 2005BBRC..337.1308G }} * {{cite journal | vauthors = Kullberg M, Nilsson MA, Arnason U, Harley EH, Janke A | title = Housekeeping genes for phylogenetic analysis of eutherian relationships | journal = Molecular Biology and Evolution | volume = 23 | issue = 8 | pages = 1493–1503 | date = August 2006 | pmid = 16751257 | doi = 10.1093/molbev/msl027 }} * {{cite journal | vauthors = Wanders RJ, Waterham HR | title = Biochemistry of mammalian peroxisomes revisited | journal = Annual Review of Biochemistry | volume = 75 | pages = 295–332 | year = 2006 | issue = 1 | pmid = 16756494 | doi = 10.1146/annurev.biochem.74.082803.133329 | bibcode = 2006ARBio..75..295W }} * {{cite journal | vauthors = Balss J, Meyer J, Mueller W, Korshunov A, Hartmann C, von Deimling A | title = Analysis of the IDH1 codon 132 mutation in brain tumors | journal = Acta Neuropathologica | volume = 116 | issue = 6 | pages = 597–602 | date = December 2008 | pmid = 18985363 | doi = 10.1007/s00401-008-0455-2 | s2cid = 9530236 }} * {{cite journal | vauthors = 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 | title = IDH1 mutations at residue p.R132 (IDH1(R132)) occur frequently in high-grade gliomas but not in other solid tumors | journal = Human Mutation | volume = 30 | issue = 1 | pages = 7–11 | date = January 2009 | pmid = 19117336 | doi = 10.1002/humu.20937 | s2cid = 7742965 | doi-access = free }} {{refend}}

Category:EC 1.1.1