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Results for “Isocitrate dehydrogenase 2 (IDH2)”

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PubMed1983

Gene mapping and linkage analysis in Chinese hamster: assignment of the genes for APRT, LDHA, IDH2, and GAA to chromosome 3.

Interspecific somatic cell hybrids were generated by fusion of Chinese hamster spleen cells or primary fibroblasts with cells from an adenine phosphoribosyltransferase (APRT)-deficient mouse subline derived from LMTK- Cl.1D. Subclones which had been selected for either retention or loss of APRT were subjected to combined isozyme and chromosome segregation analysis. Concordant expression or segregation of Chinese hamster APRT, lactate dehydrogenase A (LDHA), isocitrate dehydrogenase 2 (IDH2), and alpha-glucosidase (GAA) with Chinese hamster chromosome 3 allowed provisional assignment of all four loci to that chromosome. Exceptional subclones, in which coordinate segregation of these syntenic markers was disrupted by chromosome breakage or deletions, allowed further localization of these genes to specific regions of the 3 chromosome.

Adenine Phosphoribosyltransferase↗

PubMed1998

[Chromosomal localization of nine genes in common shrew (Sorex araneus)].

Syntheny and localization of the following genes in common shrew Sorex araneus were determined: isocitrate dehydrogenase 2 (IDH2), acid phosphatase 2 (ACP2), glutamine--pyruvate--oxo-acid transaminase (GPT), and inorganic pyrophosphatase (PP) on chromosome ik; adenylate kinases 1 and 3 (AK1 and AK3) on chromosome af; and enolase 1 (ENO1) on chromosome jl. Two genes were assigned to definite arms: aminoacylase 1 (ACY1) to arm p of chromosome mp and glutamic-oxaloacetic transaminase 1 (GOT1) to arm q of chromosome qr. Thus, 26 genes marking eight out of ten chromosomes are present now on the cytogenetic map of common shrew. These include previously described localizations.

Acid Phosphatase↗

PubMed2003

Two phenotypically compensating isocitrate dehydrogenases in Ralstonia eutropha.

The tricarboxylic acid (TCA) cycle enzyme isocitrate dehydrogenase (IDH) and the glyoxylate bypass enzyme isocitrate lyase are involved in catabolism of isocitrate and play a key role in controlling the metabolic flux between the TCA cycle and the glyoxylate shunt. Two IDH genes icd1 and icd2 of Ralstonia eutropha HF39, encoding isocitrate dehydrogenase 1 (IDH1) and isocitrate dehydrogenase 2 (IDH2), were identified and characterized. Icd1 was functionally expressed in Escherichia coli, whereas icd2 was expressed in E. coli but no activity was obtained. Interposon-mutants of icd1 (HF39Deltaicd1) and icd2 (HF39Deltaicd2) of R. eutropha HF39 were constructed and their phenotypes were investigated. HF39Deltaicd1 retained 43% of IDH activity, which was not induced by acetate, and HF39Deltaicd2 expressed 74% of acetate-induced IDH activity. Both HF39Deltaicd1and HF39Deltaicd2 kept the same growth rate on acetate as the wild-type. These data suggested that IDH1 is induced by acetate. The interposon-mutants HF39Deltaicd1 and HF39Deltaicd2 accumulated the same amount of poly(3-hydroxybutyric acid) as the wild-type.

Amino Acid Sequence↗

PubMed1997

Chromosome location of sixteen genes in the common shrew, Sorex araneus L. (Mammalia, Insectivora).

This report extends the genetic map of the common shrew (Sorex araneus) by use of a clone panel of shrew-Chinese hamster and shrew-mouse hybrid cells (Pack et al., 1995; Matyakhina et al., 1996). This set of hybrid clones made it possible to assign the shrew genes for isocitrate dehydrogenase 2 (IDH2), inorganic pyrophosphatase (PP), glutamicpyruvate transaminase (GPT), adenosine kinase (ADK), glucuronidase 2 (GUSB) and acid phosphatase 2 (ACP2) to chromosome ik; the genes for adenylate kinases 1 and 3 (AK1 and AK3) to chromosome af; the genes for glutamate-oxaloacetate transaminase 2 (GOT2), peptidase D (PEPD) and growth hormone (GH) to chromosome hn; the gene for phosphoglucomutase 2 (PGM2) to chromosome go, the gene for enolase 1 (ENO1) to chromosome ji, the gene for ornithine carbamoyl-transferase (OTC) to chromosome de, the gene for aminoacylase 1 (ACY1) to arm m (chromosome mp), the gene for glutamate-oxaloacetate transaminase 1 (GOT1) to arm q (chromosome qr). Thus, the genetic map of the common shrew now contains 33 genes and it is possible to compare the syntenic associations with other species.

Animals↗

PubMed2025

Targeting IDH2 promotes antitumor immunity through epigenetic activation of cGAS-STING pathway.

Reductive carboxylation is critical for the proliferation of cancer cells and the differentiation of T cells. However, the role of this reaction in cancer cell-mediated tumor immunity remains unclear. Analysis of TCGA database showed a negative correlation between IDH2 expression and the presence of CD8+ T cells in lung and breast cancers, whereas IDH1 expression didn't show such a correlation. Further GSEA analysis revealed a significant enrichment of immune-related genes within IDH2-associated genes, specifically those in the type Ⅰ interferon pathway. In lung cancer cells, the depletion of IDH2 expression indeed could induce the activation of the immune-related and specially type Ⅰ interferon pathway. Targeting IDH2 with shRNA or its inhibitor AGI-6780 caused an increase in intracellular α-ketoglutarate concentration and a decrease in ATP and SAM levels, leading to a reduction in the methylation of STING promoter and elevated levels expression of STING. The increase of STING expression underlies the activation of type I interferon pathway observed in IDH2 compromised tumor cells and increased defense responses in the tumors in mice. These results identify IDH2 as a potential target to enhance cancer immune therapy.

Humans↗

PubMed1991

NAD(+)-dependent isocitrate dehydrogenase. Cloning, nucleotide sequence, and disruption of the IDH2 gene from Saccharomyces cerevisiae.

NAD(+)-dependent isocitrate dehydrogenase from Saccharomyces cerevisiae is composed of two nonidentical subunits, designated IDH1 (Mr approximately 40,000) and IDH2 (Mr approximately 39,000). We have isolated and characterized a yeast genomic clone containing the IDH2 gene. The amino acid sequence deduced from the gene indicates that IDH2 is synthesized as a precursor of 369 amino acids (Mr 39,694) and is processed upon mitochondrial import to yield a mature protein of 354 amino acids (Mr 37,755). Amino acid sequence comparison between S. cerevisiae IDH2 and S. cerevisiae NADP(+)-dependent isocitrate dehydrogenase shows no significant sequence identity, whereas comparison of IDH2 and Escherichia coli NADP(+)-dependent isocitrate dehydrogenase reveals a 33% sequence identity. To confirm the identity of the IDH2 gene and examine the relationship between IDH1 and IDH2, the IDH2 gene was disrupted by genomic replacement in a haploid yeast strain. The disruption strain expressed no detectable IDH2, as determined by Western blot analysis, and was found to lack NAD(+)-dependent isocitrate dehydrogenase activity, indicating that IDH2 is essential for a functional enzyme. Overexpression of IDH2, however, did not result in increased NAD(+)-dependent isocitrate dehydrogenase activity, suggesting that both IDH1 and IDH2 subunits are required for catalytic activity. The disruption strain was unable to utilize acetate as a carbon source and exhibited a 2-fold slower growth rate than wild type strains on glycerol or lactate. This growth phenotype is consistent with NAD(+)-dependent isocitrate dehydrogenase performing an essential role in the oxidative function of the citric acid cycle.

Amino Acid Sequence↗

PubMed2002

[Genetic control of the isocitrate dehydrogenase and shikimate dehydrogenase isoenzyme systems in Sesame (Sesamun indicum L.)].

Taking into consideration that the ideal manipulation of isozymic markers needs knowledge of their genetic control, the aim of this study was to establish the inheritance and linkage degree of loci that control the expression of two sesame isozyme systems: isocitrate dehydrogenase (IDH) and shikimate dehydrogenase (SKD). The F2 electrophoretic behaviour of IDH and SKD from cultivars Turen x Arawaca cross was evaluated. The results suggest that IDH is controlled by two loci, Idh1 and Idh2 meanwhile SKD by only one, Skd1. The loci Idh1 and Skd1 showed three distinguishable patterns, corresponding to the homocygote genotypes and the heterocygote one, adjusted to a one-character common mendelian segregation 1:2:1. Cosegregation between Idh1 and Skd1 was independent.

Alcohol Oxidoreductases↗

PubMed2003

Homologous binding sites in yeast isocitrate dehydrogenase for cofactor (NAD+) and allosteric activator (AMP).

Yeast NAD(+)-specific isocitrate dehydrogenase (IDH) is an allosterically regulated octameric enzyme composed of two types of homologous subunits designated IDH1 and IDH2. Based on sequence comparisons and structural models, both subunits are predicted to have adenine nucleotide binding sites. This was tested by alanine replacement of residues in putative sites in each subunit. Targets included adjacent aspartate/isoleucine residues implicated as important for determining cofactor specificity in related dehydrogenases and a residue in each IDH subunit in a position occupied by histidine in other cofactor binding sites. The primary kinetic effects of D286A/I287A and of H281A replacements in IDH2 were found to be a dramatic reduction in apparent affinity of the holoenzyme for NAD(+) and a concomitant reduction in V(max). Ligand binding assays also showed that the H281A mutant enzyme fails to bind NAD(+) under conditions that are saturating for the wild-type enzyme. In contrast, the primary effect of corresponding D279A/D280A and of R274A replacements in IDH1 is a reduction in holoenzyme binding of AMP, with concomitant alterations in kinetic and isocitrate binding properties normally associated with activation by this allosteric effector. These results suggest that the nucleotide cofactor binding site is primarily contributed by the IDH2 subunit, whereas the homologous nucleotide binding site in IDH1 has evolved for regulatory binding of AMP. These results are consistent with previous studies demonstrating that the catalytic isocitrate binding sites are comprised of residues primarily contributed by IDH2, whereas sites for regulatory binding of isocitrate are contributed by analogous residues of IDH1. In this study, we also demonstrate that a prerequisite for holoenzyme binding of NAD(+) is binding of isocitrate/Mg(2+) at the IDH2 catalytic site. This is comparable to the dependence of AMP binding upon binding of isocitrate at the IDH1 regulatory site.

Adenosine Monophosphate↗

PubMed1993

Kinetic analysis of NAD(+)-isocitrate dehydrogenase with altered isocitrate binding sites: contribution of IDH1 and IDH2 subunits to regulation and catalysis.

NAD(+)-dependent isocitrate dehydrogenase from Saccharomyces cerevisiae is an allosterically regulated enzyme that exists as an octamer composed of two nonidentical subunits, designated IDH1 and IDH2. To determine the contribution of each subunit to regulation and catalysis, a conserved serine residue at the proposed active site of each subunit was mutated to alanine. This mutation in IDH1 resulted in a 6-fold decrease in Vmax and a decrease in cooperativity, but little change in S0.5 for isocitrate. The mutant IDH2, in contrast, exhibited a 60-fold decrease in maximal velocity and a 2-fold reduction in S0.5 for isocitrate, but the cooperativity was unaffected. Responses to the allosteric modifier AMP also differed for the two mutant enzymes. The IDH1 mutant enzyme was not activated by AMP, whereas the IDH2 mutant enzyme exhibited an increase in isocitrate affinity in the presence of AMP similar to that observed with the wild-type enzyme. On the basis of these kinetic results, a model is presented which proposes that IDH1 functions as a regulatory subunit while IDH2 functions in catalysis. To determine if IDH1 or IDH2 alone is catalytically active, we also expressed the individual subunits in yeast strains in which the gene encoding the other subunit had been disrupted. Mitochondrial extracts from strains overexpressing solely IDH1 or IDH2 contained no detectable activity in the presence or absence of AMP. Gel filtration of these extracts showed that both IDH1 and IDH2 behaved as monomers, suggesting that the major subunit interactions within the octamer are between IDH1 and IDH2.

Adenosine Monophosphate↗

PubMed1995

Characterization of a cDNA clone for human NAD(+)-specific isocitrate dehydrogenase alpha-subunit and structural comparison with its isoenzymes from different species.

A 0.6 kb cDNA fragment encoding the human NAD(+)-specific isocitrate dehydrogenase alpha-subunit (H-IDH alpha) was amplified by PCR using oligonucleotide primers synthesized on the basis of pig tryptic peptide sequences [Huang and Colman (1990) Biochemistry 29, 8266-8273]. With the amplified cDNA as a probe, cDNA clones for IDH alpha were isolated from a human heart lambda gt11 cDNA library. The deduced protein sequence of the largest cDNA clone (2628 bp) rendered a precursor protein of 366 amino acids (39,591 Da) and a mature protein of 339 amino acids (36,640 Da). The deduced H-IDH alpha protein sequence is highly similar to the partial peptide sequences of the pig enzyme. It is 55, 43 and 44% identical with yeast NAD(+)-specific IDH2, yeast NAD(+)-specific IDH1 and monkey NAD(+)-specific IDH gamma-subunit (IDH gamma) respectively. However, it has less similarity (about 30%) to NADP(+)-specific IDH from Escherichia coli and bovine mitochondria. These results indicate that the structure of IDH alpha closely resembles that of IDH2, the catalytic subunit of the yeast enzyme. Structural analysis of the deduced H-IDH alpha protein revealed that the amino acids responsible for the binding of isocitrate, Mg2+ and NAD+ are highly conserved. It also has two conserved motifs for the binding sites of ATP and ADP, but a canonical Ca(2+)-binding motif was not recognized. Unusual penta-(ATTTA) and tri-(TAA or ATT) nucleotides which are respectively believed to interact with RNA-binding proteins and be near the endonuclease cleavage sites were frequently recognized in its 3' untranslated region, indicating the possibility of an additional method of regulation of this enzyme. Northern-blot analysis suggests that one mRNA transcript (2.8 kb) exists in cultured HeLa cells. Genomic DNA Southern-blot analysis indicates that the IDH alpha gene is not closely related to that of the other IDH isoenzymes, and IDH alpha appears to be encoded by a single gene.

Amino Acid Sequence↗

PubMed1985

Linkage of the MBG locus to another functionally hemizygous gene locus (IDH2) on chromosome Z3 in Chinese hamster ovary cells.

To gain insight into the nature of hemizygosity in Chinese hamster ovary (CHO) cells and the mechanisms by which it has arisen, we are attempting to map and determine linkage relationships for as many hemizygous loci as possible. In this study, we have shown by segregation analysis of intraspecific somatic cell hybrids that the hemizygous gene locus associated with resistance to methylglyoxalbisguanyl hydrazone (MBG) in CHO cells is linked to the hemizygous IDH2 locus on chromosome Z3. Nine of the ten autosomal hemizygous gene loci that have been mapped to date in CHO cells are clustered on three chromosomes, with five such markers on chromosome 2, two on chromosome 8, and now two on the Z3 chromosome. With the mapping of MBG to the Z3 chromosome, selectable drug resistance markers are now available on eight different CHO chromosomes.

Animals↗

PubMed2026

IDH2 clonal hematopoiesis and IKAROS loss cooperate in a B-ALL subtype after lenalidomide therapy for multiple myeloma.

Lenalidomide, a maintenance treatment in multiple myeloma first-line therapy, increases the risk of secondary malignancies, including B-cell precursor acute lymphoblastic leukemia (B-ALL). We present a comprehensive molecular characterization of 57 patients with lenalidomide-associated B-ALL (LenB-ALL), revealing 3 mutational subgroups: (1) TP53mt (30%); (2) IDH2mt (p.R140Q) (23%); and (3) other, including NRAS/KRASmt. Remarkably, IDH2 R140Q mutations were highly enriched in LenB-ALL compared with those in primary B-ALL (P< .001). Furthermore, IKZF1 intragenic deletions, often subclonal and likely RAG recombinase-mediated, were observed in 54% (7/13) of IDH2mt patients with LenB-ALL. IDH2 mutations were not restricted to the leukemic clone: they persisted during measurable residual disease-negative remission and were identified in lymphoid as well as myeloid cell populations using fluorescence-activated cell sorting and single-cell RNA sequencing. This indicates a preleukemic origin of the IDH2 mutation within the context of clonal hematopoiesis. Transcriptomic and DNA methylation analyses revealed a distinct gene expression profile and a DNA hypermethylation phenotype in IDH2mt LenB-ALL, including IDH2mt-specific as well as lenalidomide-associated features. We propose that lenalidomide promotes the expansion of IDH2-mutated clonal hematopoiesis and, via IKAROS downregulation, induces a maturation arrest at the B-cell precursor stage. Subsequent genetic or epigenetic alterations render leukemogenesis independent of ongoing lenalidomide exposure. All these data define IDH2mt B-ALL as a distinct molecular subtype that is markedly overrepresented after lenalidomide treatment and highlight clonal hematopoiesis as a key contributing factor in the development of LenB-ALL.

Humans↗