Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:1.1.1.41 (isocitrate dehydrogenase)
3,101 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Conformational changes induced by binding of ligands to cytosolic NADP(+)-specific isocitrate dehydrogenase from lactating bovine mammary gland were assessed using circular dichroism and fluorescence techniques. The secondary structure of isocitrate dehydrogenase, as monitored by CD spectra in the far-UV region, is unaltered by enzyme-ligand interactions; in contrast, dramatic changes occur in the near-UV region (270-290 nm) assigned to tyrosine and/or solvent-exposed tryptophan residues. Both the coenzyme analog, 2'-phosphoadenosine 5'-diphosphoribose, and NADPH have an effect on the CD spectrum which is opposite to that produced by metal complexes of either isocitrate or citrate. A CD band at 292 nm assigned to approximately 2 tryptophan residues in a hydrophobic environment is unchanged by binding of substrate or coenzyme. Approximately 30% of the intrinsic fluorescence of isocitrate dehydrogenase, corresponding to approximately 2 tryptophan residues, is not quenched by acrylamide in the absence of 6.3 M guanidine hydrochloride and remains unquenched in the enzyme-substrate complex. The constancy in the proportion of buried and exposed tryptophan residues implicates tyrosine in the observed near-UV CD spectral changes. Since binding of ligands does not influence quaternary structure (Seery, V.L., and Farrell, H. M., Jr. (1989) Arch. Biochem. Biophys. 274, 453-462), activation of isocitrate dehydrogenase may be related to a substrate-induced conformational transition.
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PMID:Spectroscopic evidence for ligand-induced conformational change in NADP+:isocitrate dehydrogenase. 221 54

In order to ascertain the pathogenesis of myocardial cell vulnerability in spontaneously hypertensive rats (SHR), several enzyme activities were examined by using subcellular fractions of myocardium and compared to those in Wistar-Kyoto rats (WKY). In the normotensive WKY heart, both 5'-nucleotidase and Na+/K(+)-ATPase, which are plasma membrane associated enzymes, increased with age. But in the SHR heart, both enzymes were lower at 16 weeks than they were at 10 weeks of age. Moreover, at 16 weeks of age they were lower in SHR than in WKY. On the other hand, NADP(+)-isocitrate dehydrogenase activity, a mitochondria associated enzyme, was higher in SHR than in WKY at 6 weeks, but lower at 10 and again at 16 weeks of age. The activities of both acid phosphatase and N-acetyl-beta-glucosaminidase, which are lysosomal enzymes, decreased with age in SHR but not in WKY. These results suggest that an enzymatic alteration in the plasma membrane and mitochondria may be one of important factors behind myocardial vulnerability in the SHR heart.
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PMID:Some enzyme characteristics of spontaneously hypertensive rats myocardium. 223 22

Cytoplasmic NADP(+)-dependent isocitrate dehydrogenase (isocitrate: NADP+ oxidoreductase (decarboxylating), EC 1.1.1.42) was purified 290-fold from the 15,000 x g supernatant fraction of porcine corpora lutea. The major purification step was by anion-exchange chromatography with an FPLC mono P column. Enzyme lability was overcome by including Mg2+, DL-isocitrate, dithiothreitol and glycerol in the elution buffers. The molecular weight of the denatured enzyme was found to be 48,000 by SDS-polyacrylamide gel electrophoresis. The Stokes' radius was estimated to be 3.7 nm by gel filtration and the isoelectric point was 4.8 as determined by chromatofocusing. The purified enzyme had a specific activity of 57.8 units/mg and a broad optimal pH for activity from 7.5 to 9.0. The Km for the substrates DL-isocitrate and NADP+ were 13 and 12 microM, respectively. Polyclonal antibodies were raised against the purified enzyme. Protein (Western) blotting showed an immunological similarity between the cytoplasmic enzyme of the ovary, liver, adrenal gland and heart. A difference was demonstrated between the ovarian enzyme and the heart mitochondrial enzyme. The substrate turnover number and Mr of the ovarian enzyme were similar to those found for the enzyme from the liver and adrenal gland.
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PMID:Purification and properties of NADP(+)-dependent isocitrate dehydrogenase from the corpus luteum. 235 93

NAD(+)-dependent isocitrate dehydrogenase from pig heart is an allosteric enzyme that is activated by ADP and is inhibited by NADPH in the presence of NADH. Transferred nuclear Overhauser effect measurements, made at a range of times to ensure that observed effects are due to direct dipole-dipole transfer and not to spin diffusion, were used to determine the conformations of pyridine nucleotide coenzymes and of the allosteric effector ADP. For NAD+, significant effects were observed on the N2 proton (on the nicotinamide ring) when the N1' proton (on the nicotinamide ribose) was saturated and on the N6 proton when the N2' proton was saturated, indicating that the conformation of the nicotinamide-ribose moiety is anti. The anti conformation is expected because of the stereospecificity of NAD(+)-dependent isocitrate dehydrogenase and is the same as for NADP(+)-dependent isocitrate dehydrogenase. For the adenosine moiety of NAD+, the predominant nuclear Overhauser effect on the A8 proton is found when the A2' proton is saturated. This result implies that the adenine-ribose bond is anti with respect to the ribose. Previous kinetic and binding studies of ADP activation have shown an influence of divalent metal ions. The conformation of bound ADP, in the presence of Mg2+ and/or Ca2+, is found to be anti about the adenine-ribose bond. The 3'H-8H distance increases when Ca2+ is added to the Mg-ADP-enzyme complex. Changes in the 4'H-1'H distance upon addition of isocitrate are indicative of interactions between the ADP activator site and the isocitrate site.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Conformations of the coenzymes and the allosteric activator, ADP, bound to NAD(+)-dependent isocitrate dehydrogenase from pig heart. 237 74

The possibility that 2-oxoglutarate may supply acetyl units for the cytosolic synthesis of acetylcholine in rat brain synaptosomes was investigated. The contribution of [14C]2-oxoglutarate to the synaptosomal synthesis of [14C]acetylcholine was found to be negligible despite evidence for its uptake and oxidation. The activity of the enzymes NADP-isocitrate dehydrogenase (EC 1.1.1.42), aconitate hydratase (EC 4.2.1.3), and ATP citrate-lyase (EC 4.1.3.8) were measured in the synaptosol. NADP-isocitrate dehydrogenase and aconitate hydratase are present at three- to 1.5-fold higher activities than ATP citrate-lyase. It seems likely that these enzymes contribute to the metabolism of citrate and prevent detectable formation of cytosolic acetyl-CoA from exogenously added 2-oxoglutarate (or citrate). The data further suggest that ATP citrate-lyase may in part be associated with the mitochondrial fraction.
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PMID:2-Oxoglutarate: oxidation and role as a potential precursor of cytosolic acetyl-CoA for the synthesis of acetylcholine in rat brain synaptosomes. 249 71

Equilibrium binding studies demonstrate that purified Escherichia coli isocitrate dehydrogenase binds isocitrate, alpha-ketoglutarate, NADP, and NADPH at 1:1 ratios of substrate to enzyme monomer. The phosphorylated enzyme, which is completely inactive, is unable to bind isocitrate but retains the ability to bind NADP and NADPH. Replacement of serine 113, which is the site of phosphorylation, by aspartate results in an inactive enzyme that is unable to bind isocitrate. Replacement of the same serine with other amino acids (lysine, threonine, cysteine, tyrosine, and alanine) produces active enzymes that bind both substrates. Hence, the negative charge of an aspartate or a phosphorylated serine at site 113 inactivates the enzyme by preventing the binding of isocitrate.
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PMID:Phosphorylation inactivates Escherichia coli isocitrate dehydrogenase by preventing isocitrate binding. 251 Dec 4

Needle biopsies from m. gluteus medius of 22 horses which had suffered from repeated attacks of exertional myopathy were studied at various times after an attack, to determine if metabolic alterations can be demonstrated by enzyme histochemistry. Morphological changes and activity of 25 enzymes were studied. Immediately after onset of an attack, some large rounded fibres with a defect of the oxidative phosphorylation were seen. After some hours these fibres lost their glycolytic enzyme activity, followed by disappearance of mitochondrial enzyme activity with accumulation of Ca2+-containing substances. After 16 h inflammatory cells were found in and around necrotic fibres with a strong activity of acid phosphatase and of the 2 oxidative enzymes of the pentose phosphate pathway. The 4th d after onset of the myopathy regenerating fibres could be observed with a strong activity of both NADPH-producing enzymes of the pentose phosphate pathway. The activity of the decarboxylating enzymes NADP+-malate dehydrogenase and NADP+-isocitrate dehydrogenase was increased in these fibres as well. After some month the studied skeletal muscles were completely normal again. Metabolic interpretations based on the histochemical findings are discussed and compared with those given in literature.
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PMID:[Histochemical changes in skeletal muscles of racehorses susceptible to rhabdomyolysis after exertion. II. Later myopathological and regeneration phenomena]. 253 42

A study was made of the effect of alimentary deficiency of niacin and of exogenous nicotinamide (500 mg/kg) on the activity of the key enzymes of the pentose phosphate pathway and NADP-dependent malate and isocitric dehydrogenase in the epididymal fatty tissue of rats. It is established that vitamin depletion in the animals' body brings about a 3-fold decrease in the content of NADP+ and a 1.7-fold decrease in the content of NADPH, a 43-percent inhibition of the activity of glucose 6-phosphate dehydrogenase and a 39-percent reduction with respect to transketolase. Nicotinamide suppresses the activity of glucose 6-phosphate dehydrogenase by 35% and that of isocitric dehydrogenase by 40% 12 hours after intraperitoneal injection. It is suggested that NADPH production in the fatty tissue of rats undergoes appreciable changes under the effect of niacin.
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PMID:[The role of niacin in regulating the pentosophosphate pathway and production of NADP-H in fatty tissue]. 253 4

Escherichia coli isocitrate dehydrogenase is completely inactivated by phosphorylation of a single serine residue per subunit. We have examined the conformations of the active and phosphorylated forms of the enzyme using circular dichroism spectroscopy. The results support the view that phosphorylation prevents the binding of NADP, probably by direct blocking of the coenzyme-binding site. Labelling studies suggest that an arginine residue at the coenzyme-binding site may be close to the phosphorylatable serine residue. The phosphorylation of isocitrate dehydrogenase is thus unusual in that it occurs at the active site of the enzyme. We therefore investigated the recognition of isocitrate dehydrogenase by isocitrate dehydrogenase kinase/phosphatase. The kinase activity of this enzyme can phosphorylate intact isocitrate dehydrogenase but not proteolytic fragments derived from it, nor a synthetic peptide corresponding to the sequence round the phosphorylation site.
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PMID:Studies of the phosphorylation of Escherichia coli isocitrate dehydrogenase. Recognition of the enzyme by isocitrate dehydrogenase kinase/phosphatase and effects of phosphorylation on its structure and properties. 255 94

Estimates of the activities (Vmax) of four enzymes that generate the coenzyme NADPH, an absolute requirement for tissue fatty-acid synthesis, and of the concentration of NADP plus NADPH were made in lines of mice differing in fat content. These lines had been selected from the same base population for 20 generations, and 3 high, 3 low replicates and 1 unselected control were used. Analyses were performed on liver and gonadal fat pad (GFP) of males at 5 and 10 weeks of age. In both the liver and the GFP, measurable activities of the four enzymes: glucose-6-phosphate dehydrogenase (G6PDH), 6-phosphogluconate dehydrogenase (6PGDH), isocitrate dehydrogenase (IDH) and malic enzyme (ME) expressed per mg soluble protein were, with minor exceptions, higher in the Fat (F) than in the Lean (L) lines at both ages; the highest ratio being 2.2 for ME in the GFP. The relationships between these measurable activities (Vmax) and in vivo lipogenesis are not however known. When expressed per gram tissue, the ratios for F to L in the GFP were less than 1 in most cases, presumably because of the very different adipocyte numbers and/or sizes between the lines. There were no significant differences between the lines in the concentration of NADP plus NADPH per gram tissue in liver or GFP, suggesting that F lines converted NADP to NADPH faster than L lines. It is predicted that selection on the enzyme activities would be less efficient than direct selection at changing fat content.
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PMID:Analysis of lines of mice selected for fat content. 1. Correlated responses in the activities of NADPH-generating enzymes. 261 1


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