Structures of a constitutively active mutant of human IDH3 reveal new insights into the mechanisms of allosteric activation and the catalytic reaction

Chen, Xingchen; Sun, Pengkai; Liu, Yan; Shen, Senlin; Ma, Tengfei; Ding, Jianping

doi:10.1016/j.jbc.2022.102695

Cited by 6 publications

(3 citation statements)

References 34 publications

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“…These cells -along with non-transduced, D2-HG treated cells -had an increase in protein expression of β-catenin, which is involved in the invasionassociated epithelial-mesenchymal transition [101]. Interestingly, another study utilizing overexpression of IDH1 R132H in U87 and U251 cells demonstrated the opposite effect on cell proliferation and invasion whilst also having a negative effect on β-catenin [102]. This contradictory evidence suggests that IDH mutation, subsequent production of D2-HG, and cell invasion mechanisms are not linear and may have many other factors involved which can be influenced by experimental conditions.…”

Section: The Role Of Idh Mutation In Tumor Invasionmentioning

confidence: 99%

Mutant IDH in Gliomas: Role in Cancer and Treatment Options

Solomou¹,

Finch²,

Asghar³

et al. 2023

Preprint

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Altered metabolism is a common feature of many cancers and in some cases is a consequence of mutation in metabolic genes, such as the ones involved in Krebs cycle. Isocitrate dehydrogenase (IDH) gene is mutated in many gliomas and other cancers. Physiologically IDH converts isocitrate to αketoglutarate (αKG), but when mutated, IDH reduces αKG to D2-hydroxyglutarate (D2-HG). D2-HG accumulates at high levels in IDH mutant cancers, and in the last decade, a massive effort has been done to develop small inhibitors targeting mutant IDH. In this review, we summarize current knowledge about the cellular and molecular consequences of IDH mutations, and the therapeutic approached developed to target IDH mutant tumours, with a focus on gliomas.

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Section: The Role Of Idh Mutation In Tumor Invasionmentioning

confidence: 99%

Mutant IDH in Gliomas: Role in Cancer and Treatment Options

Solomou¹,

Finch²,

Asghar³

et al. 2023

Preprint

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“…Unfortunately, the seizures showed by IDH mutant patients are frequently resistant to first line epilepsy treatment [90]. Nevertheless, recently it has been reported that a patient affected by IDH1 mutant oligodendroglioma showed reduced tumor-associated epilepsy after treatment with the IDH1 mutant inhibitor AG-120 (ivosidenib) [91]. To explain the higher incidence of seizures in IDH mutant patients compared to the IDH wildtype patients, the neuroexcitatory properties of the D2-HG need to be considered.…”

Section: Idh Mutation and Tumour-associated Epilepsymentioning

confidence: 99%

Mutant IDH in Gliomas: Role in Cancer and Treatment Options

Solomou¹,

Finch²,

Asghar³

et al. 2023

Preprint

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“…As such, the cofactor preference of enzymes is crucial for ensuring the proper regulation of metabolism. All IDH3s described so far are regulated allosterically ( Lin and McAlister-Henn 2003 ; Chen et al 2022 ). Conversely, in Escherichia coli , IDH1 and IDH2 are regulated by the phosphorylation of a single Ser in the active site preventing the isocitrate binding ( Dean et al 1989 ), whereas in mammals, the same amino acid interacts with a conserved Asp providing a feedback loop for self-regulation ( Xu et al 2004 ).…”

Section: Introductionmentioning

confidence: 99%

Distribution and Functional Analysis of Isocitrate Dehydrogenases across Kinetoplastids

Chmelová,

Záhonová,

Albanaz

et al. 2024

Genome Biology and Evolution

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Isocitrate dehydrogenase (IDH) is an enzyme converting isocitrate to α-ketoglutarate in the canonical tricarboxylic acid (TCA) cycle. There are three different types of IDH documented in eukaryotes. Our study points out the complex evolutionary history of IDHs across kinetoplastids, where the common ancestor of Trypanosomatidae and Bodonidae was equipped with two isoforms of the IDH enzyme: the NADP+-dependent IDH1 with possibly dual localization in the cytosol and mitochondrion and NADP+-dependent mitochondrial IDH2. In the extant trypanosomatids, IDH1 is present only in a few species suggesting that it was lost upon separation of Trypanosoma spp. and replaced by the mainly NADP+-dependent cytosolic IDH3 of bacterial origin in all the derived lineages. In this study, we experimentally demonstrate that the omnipresent IDH2 has a dual localization in both mitochondrion and cytosol in at least four species that possess only this isoform. The apparent lack of the NAD+-dependent IDH activity in trypanosomatid mitochondrion provides further support to the existence of the non-canonical TCA cycle across trypanosomatids and the bidirectional activity of IDH3 when operating with NADP+ cofactor instead of NAD+. This observation can be extended to all 17 species analyzed in this study, except for Leishmania mexicana which showed only low IDH activity in the cytosol. The variability in isocitrate oxidation capacity among species may reflect the distinct metabolic strategies and needs for reduced cofactors in particular environments.

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Structures of a constitutively active mutant of human IDH3 reveal new insights into the mechanisms of allosteric activation and the catalytic reaction

Cited by 6 publications

References 34 publications

Mutant IDH in Gliomas: Role in Cancer and Treatment Options

Mutant IDH in Gliomas: Role in Cancer and Treatment Options

Mutant IDH in Gliomas: Role in Cancer and Treatment Options

Distribution and Functional Analysis of Isocitrate Dehydrogenases across Kinetoplastids

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