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evolution
Arabidopsis thaliana has three NADP-ICDH genes At1g65930, At5g14590, and At1g54340, coding for the proteins NP_176768, NP_196963, and BT025983, respectively, that are located in different subcellular compartments, i.e. cytosol, chloroplasts, mitochondria, and peroxisomes
evolution
based on the phylogenetic analysis, IDHs can be divided into three subfamilies: Type I IDHs, Type II IDHs and monomeric IDHs. The enzyme BlIDH from Bifidobacterium longum belongs to the type II subfamily. NAD+ use is an ancestral trait and NADP+ use by bacterial IDHs arose on or about the time that eukaryotic mitochondria first appeared, some 3.5 billion years ago
evolution
phylogenetic analysis and evolutionary relationships between YlIDP and IDPs from other yeasts or yeast-related species
evolution
the overall fold of the enzyme protein is resolved into large domain, small domain and a clasp domain. The monomeric structure reveals also a terminal domain involved in dimerization, a very unique domain when compared to other IDHs. The small domain and clasp domain show significant differences when compared to other IDHs of the same subfamily. The structure of TtIDH reveals the absence of helix at the clasp domain, which is mainly involved in oligomerization in other IDHs. Also, helices/beta sheets are absent in the small domain, when compared to other IDHs of the same subfamily. The overall TtIDH structure exhibits a closed conformation with the conserved catalytic triad residues Tyr144, Asp248, and Lys191. Oligomerization of the protein is determined using interface area and subunitsubunit interactions between protomers. The TtIDH structure with the terminal domain may be categorized as a first structure of a type IV subfamily
evolution
three NADP+-dependent isocitrate dehydrogenase (IDH) isozymes of a psychrophilic bacterium, Colwellia psychrerythraea strain 34H, are analyzed: two monomeric (IDH-IIa and IDH-IIb) and one dimeric (IDH-I) IDHs
evolution
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phylogenetic analysis and evolutionary relationships between YlIDP and IDPs from other yeasts or yeast-related species
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evolution
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Arabidopsis thaliana has three NADP-ICDH genes At1g65930, At5g14590, and At1g54340, coding for the proteins NP_176768, NP_196963, and BT025983, respectively, that are located in different subcellular compartments, i.e. cytosol, chloroplasts, mitochondria, and peroxisomes
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evolution
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three NADP+-dependent isocitrate dehydrogenase (IDH) isozymes of a psychrophilic bacterium, Colwellia psychrerythraea strain 34H, are analyzed: two monomeric (IDH-IIa and IDH-IIb) and one dimeric (IDH-I) IDHs
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evolution
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based on the phylogenetic analysis, IDHs can be divided into three subfamilies: Type I IDHs, Type II IDHs and monomeric IDHs. The enzyme BlIDH from Bifidobacterium longum belongs to the type II subfamily. NAD+ use is an ancestral trait and NADP+ use by bacterial IDHs arose on or about the time that eukaryotic mitochondria first appeared, some 3.5 billion years ago
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malfunction
autophagic response to ionizing radiation in A-172 glioma cells transfected with small interfering RNA (siRNA) targeting the IDPm gene. Autophagy in A-172 transfectant cells is associated with enhanced autophagolysosome formation and GFP-LC3 punctuation/aggregation. The inhibition of autophagy by chloroquine augments apoptotic cell death of irradiated A-172 cells transfected with IDPm siRNA. The activity of cytosolic NADP+-dependent isocitrate dehydrogenase (IDPc) is not affected by the transfection of IDPm siRNA. The decreased activity caused by knockdown of IDPm siRNA is also observed in U87MG glioma cell line. When cultured A172 cells are treated with gamma-radiation, an increase in cell death is observed, but A172 cells transfected with IDPm siRNA are significantly more sensitive than control cells in this respect
malfunction
mitochondrial NADP+-dependent isocitrate dehydrogenase deficiency exacerbates mitochondrial and cell damage after kidney ischemia-reperfusion injury, Idh2 gene deletion exacerbates ROS production and oxidative stress after ischemia-reperfusion, and causes I/R-induced mitochondrial dysfunction and morphologic fragmentation, resulting in severe apoptosis in kidney tubule cells, it impairs reduction of NADP+ and GSSG within mitochondria
malfunction
transfection of H9c2 clonal myoblastic cells with small interfering RNA (siRNA) specific for IDPm markedly attenuates IDPm expression and substantially induces apoptosis, senescence, and hypertrophy as indicated by increased atrial natriuretic peptide gene expression, a marker of cardiomyocyte hypertrophy, and a larger cell size. Knockdown of IDPm expression results in the modulation of cellular and mitochondrial redox status, mitochondrial function, and cellular oxidative damage. The suppression of IDP expression by siRNA induces apoptosis and hypertrophy of cultured cardiomyocytes through the disruption of cellular redox balance. IDPm knockdown alters cellular redox status and induces oxidative damage. Apoptosis induced by IDPm knockdown is ROS-mediated. Substantially increased desmin and vimentin abundance is observed in IDPm siRNA-transfected H9c2 cells compared to the control cells. Mitochondrial fission and fusion involve enzymatic reactions mediated by large dynamin-associated GTPases. IDPm knockdown induces mitochondrial damage by altering the redox status
malfunction
two mutant forms (R132H and R132C) of isocitrate dehydrogenase 1 (IDH1) have been associated with a number of cancers including glioblastoma and acute myeloid leukemia. These mutations confer a neomorphic activity of 2-hydroxyglutarate (2-HG) production, and 2-HG has previously been implicated as an oncometabolite. Inhibitors of mutant IDH1 can potentially be used to treat these diseases
malfunction
enzyme deficiency increases cisplatin-induced oxidative damage in kidney tubule cells, inducing more severe nephrotoxicity
malfunction
enzyme knockout mice are more susceptible to high fat diet-induced obesity than wild type mice.Brown adipose tissue dysfunction in the enzyme knockout mice is due to mitochondrial dysfunction
malfunction
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mitochondrial NADP+-dependent isocitrate dehydrogenase deficiency exacerbates mitochondrial and cell damage after kidney ischemia-reperfusion injury, Idh2 gene deletion exacerbates ROS production and oxidative stress after ischemia-reperfusion, and causes I/R-induced mitochondrial dysfunction and morphologic fragmentation, resulting in severe apoptosis in kidney tubule cells, it impairs reduction of NADP+ and GSSG within mitochondria
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metabolism
IDH1 is critical in cellular metabolism
metabolism
metabolite profiling identifies elevated 2-hydroxyglutarate levels in IDH1 mutant R132H expressing cells compared to wild-type
metabolism
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NAD(P)+-dependent isocitrate dehydrogenase is a key enzyme in tricarboxylic acid cycle
metabolism
NADP-isocitrate dehydrogenase catalyses the first oxidative decarboxylation reaction of the tricarboxic acid cycle, yielding 2-oxoglutarate, CO2, and NADPH from isocitrate via a two-step reaction
metabolism
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in the tricarboxylic acid cycle, NADP+-specific isocitrate dehydrogenase catalyzes oxidative decarboxylation of isocitric acid to form 2-oxoglutaric acid with NADP+ as a cofactor. NADP+-ICDH may work independently of NAD+-ICDH, EC 1.1.1.41, as one of the TCA cycle regulatory enzymes, especially in relation to citric acid production by Aspergillus niger
metabolism
the enzyme catalyzes an essential rate-limiting step in the citric acid cycle
metabolism
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NAD(P)+-dependent isocitrate dehydrogenase is a key enzyme in tricarboxylic acid cycle
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metabolism
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NADP-isocitrate dehydrogenase catalyses the first oxidative decarboxylation reaction of the tricarboxic acid cycle, yielding 2-oxoglutarate, CO2, and NADPH from isocitrate via a two-step reaction
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physiological function
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part of citric acid cycle
physiological function
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cICDH is involved in amino acid synthesis, and plays a role in redox signalling linked to pathogen responses, but cICDH is not required for plant development and primary metabolism in optimal growth conditions
physiological function
elective pressures in the brain environment may specifically favor the cell growth or survival of tumor cells with mutations in IDH1, regardless of primary tumor site
physiological function
elective pressures in the brain environment may specifically favor the cell growth or survival of tumor cells with mutations in IDH2, regardless of primary tumor site
physiological function
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IDH1 mutation predicts outcome in grade 2, 3, and 4 gliomas
physiological function
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IDH1 regulates HIF-1alpha levels by controlling the level of 2-oxoglutarate. IDH1 appears to function as a tumor suppressor that, when mutationally inactivated, contributes to tumorigenesis in part through induction of the HIF-1 pathway. IDH1 is likely to function as a tumor suppressor gene rather than as an oncogene
physiological function
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IDP3 provides the NADPH required for beta-oxidation of some fatty acids in the peroxisome
physiological function
mutation at R172 in the active site of IDH2 leads to a change in the molecular mechanism of enzyme catalysis, resulting in production and accumulation of elevated 2-hydroxyglutarate in acute myelogenous leukemia. The mutation reduces the affinity for isocitrate, and increases the affinity for NADPH and 2-oxoglutarate, preventing the oxidative decarboxylation of isocitrate to 2-oxoglutarate, and facilitating the conversion of 2-oxoglutarate to 2-hydroxyglutarate
physiological function
mutations at R132 in the active site of IDH1 lead to a change in the molecular mechanism of enzyme catalysis, resulting in production and accumulation of elevated 2-hydroxyglutarate in acute myelogenous leukemia. The mutations reduce the affinity for isocitrate, and increase the affinity for NADPH and 2-oxoglutarate, preventing the oxidative decarboxylation of isocitrate to 2-oxoglutarate, and facilitating the conversion of 2-oxoglutarate to 2-hydroxyglutarate
physiological function
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the mitochondrial NADP+-dependent isocitrate dehydrogenase controls the mitochondrial redox balance by supplying NADPH for antioxidant systems
physiological function
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in the cytoplasm, NADP+-IDH often contributes significantly to the NADPH pool required for reductive fatty acid biosynthesis
physiological function
isocitrate dehydrogenase plays pivotal role in the growth and pathogenesis of the bacteria
physiological function
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ICDH is a key enzyme that regulates the TCA cycle
physiological function
isocitrate dehydrogenase of Microcystis aeruginosa plays important roles in energy and biosynthesis metabolisms and its catalytic product 2-oxoglutarate provides the carbon skeleton for ammonium assimilation and also constitutes a signaling molecule of nitrogen starvation in cyanobacteria
physiological function
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membranes in cardiolipin-modified liposomes are dehydrated by ICDH binding. Liposomes induce a conformational change in ICDH, indicating that cardiolipin-rich membrane domains can inhibit ICDH activity. Lipid membranes, including cardiolipin molecules, can act as a platform to regulate ICDH-related metabolic pathways such as the tricarboxylic acid cycle and lipid synthesis
physiological function
mitochondrial NADP+-dependent isocitrate dehydrogenase (IDH2) catalyzes the oxidative decarboxylation of isocitrate to 2-oxooglutarate, synthesizing NADPH, which is essential for mitochondrial redox balance
physiological function
mitochondrial NADP+s-dependent isocitrate dehydrogenase (IDPm) functions as an antioxidant and antiapoptotic protein by supplying NADPH to antioxidant systems
physiological function
NADP+-dependent IDH generates NADPH, which provides the reducing power for biosynthesis, maintains the redox state of the cell, and takes part in CO2 assimilation
physiological function
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the cytosolic homodimeric isocitrate dehydrogenase (hICDH) is involved in the regulation of tumorogenesis
physiological function
the enzyme dictates the flow of carbon as part of the Krebs cycle thereby controlling the virulence and biofilm formation
physiological function
the enzyme dictates the flow of carbon as part of the Krebs cycle thereby controlling the virulence and biofilm formation
physiological function
enzyme-overexpressing transgenic poplars show an increased expression of glutamine synthetase, glutamate decarboxylase and other genes associated with vascular differentiation. Furthermore, these plants exhibit increased growth in height, longer internodes and enhanced vascular development in young leaves and the apical region of stem
physiological function
the enzyme is critical in the NADPH-associated mitochondrial antioxidant system and is involved in cisplatin nephrotoxicity. The mitochondrial enzyme-NADPH-glutathione antioxidant system is a target for the prevention of cisplatin-induced kidney cell death
physiological function
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cICDH is involved in amino acid synthesis, and plays a role in redox signalling linked to pathogen responses, but cICDH is not required for plant development and primary metabolism in optimal growth conditions
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physiological function
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IDP3 provides the NADPH required for beta-oxidation of some fatty acids in the peroxisome
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physiological function
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mitochondrial NADP+-dependent isocitrate dehydrogenase (IDH2) catalyzes the oxidative decarboxylation of isocitrate to 2-oxooglutarate, synthesizing NADPH, which is essential for mitochondrial redox balance
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physiological function
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part of citric acid cycle
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physiological function
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NADP+-dependent IDH generates NADPH, which provides the reducing power for biosynthesis, maintains the redox state of the cell, and takes part in CO2 assimilation
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physiological function
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isocitrate dehydrogenase plays pivotal role in the growth and pathogenesis of the bacteria
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physiological function
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the enzyme dictates the flow of carbon as part of the Krebs cycle thereby controlling the virulence and biofilm formation
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additional information
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all tumors with complete 1p19q codeletion are mutated in the IDH1 or IDH2 gene. Glioma patients having IDH1/IDH2 mutations show inproved median overall survival, different outcomes in WHO grade II and III gliomas according to the 1p19q and IDH1/IDH2 statusses, overview
additional information
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enzyme mutation R132H is involved in myelodysplastic syndrome
additional information
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heterozygous mutations in the gene encoding IDH1 occur in certain human brain tumors, IDH is a strong factor in the development of gliomas. Tumor-derived IDH1 mutations impair the enzyme's affinity for its substrate and dominantly inhibit wild-type IDH1 activity through the formation of catalytically inactive heterodimers. HIF-1alpha levels are higher in human gliomas harboring an IDH1 mutation than in tumors without a mutation. Rise in HIF-1alpha levels occur, reversible by an 2-oxoglutarate derivative
additional information
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knockdown of IDPc expression in HEK293 cells greatly enhances apoptosis induced by cadmium. DNA fragmentation is enhanced in IDPc siRNA-transfected HEK293 cells compared to control cells upon exposure to cadmium
additional information
mutations in the enzyme cytosolic IDH1 at R132 are a common feature of a major subset of primary human brain cancers, especially in grade II-III gliomas and secondary glioblastomas. The mutations result in loss of the enzyme's ability to catalyze conversion of isocitrate to 2-oxoglutarate. Expression of R132H mutant IDH1 results in no measurable production of NADPH from isocitrate, and isocitrate-dependent NADPH production increases with increasing amounts of wild-type enzyme
additional information
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mutations in the enzyme cytosolic IDH1 at R132 are a common feature of a major subset of primary human brain cancers, especially in grade II-III gliomas and secondary glioblastomas. The mutations result in loss of the enzyme's ability to catalyze conversion of isocitrate to 2-oxoglutarate. Expression of R132H mutant IDH1 results in no measurable production of NADPH from isocitrate, and isocitrate-dependent NADPH production increases with increasing amounts of wild-type enzyme
additional information
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siRNA-mediated knockdown of IDPm suppresses hypoxia-induced stimulation of HIF-1alpha protein expression in PC-3 human prostate cancer cells
additional information
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molecular enzyme structure and active site modelling, QM/MM calculations, and structure-function analysis, detailed overview
additional information
three-dimensional structure modelling, isocitrate substrate docking, overview
additional information
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three-dimensional structure modelling, isocitrate substrate docking, overview
additional information
three-dimensional structure modelling, isocitrate substrate docking, overview
additional information
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three-dimensional structure modelling, isocitrate substrate docking, overview
additional information
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three-dimensional structure modelling, isocitrate substrate docking, overview
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