Activities of citrate synthase and NAD+-linked and NADP+-linked isocitrate dehydrogenase in muscle from vertebrates and invertebrates
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1. The activities of citrate synthase, NAD+-linked and NADP+-linked isocitrate dehydrogenase were measured in muscles from a large number of animals, in order to provide some indication of the importance of the citric acid cycle in these muscles. According to the differences in enzyme activities, the muscles can be divided into three classes. First, in a number of both vertebrate and invertebrate muscles, the activities of all three enzymes are very low. It is suggested that either the muscles use energy at a very low rate or they rely largely on anaerobic glycolysis for higher rates of energy formation. Second, most insect flight muscles contain high activities of citrate synthase and NAD+-linked isocitrate dehydrogenase, but the activities of the NADP+-linked enzyme are very low. The high activities indicate the dependence of insect flight on energy generated via the citric acid cycle. The flight muscles of the beetles investigated contain high activities of both isocitrate dehydrogenases. Third, other muscles of both vertebrates and invertebrates contain high activities of citrate synthase and NADP+-liniked isocitrate dehydrogenase. Many, if not all, of these muscles are capable of sustained periods of mechanical activity (e.g. heart muscle, pectoral muscles of some birds). Consequently, to support this activity fuel must be supplied continually to the muscle via the circulatory system which, in most animals, also transports oxygen so that energy can be generated by complete oxidation of the fuel. It is suggested that the low activities of NAD+-linked isocitrate dehydrogenase in these muscles may be involved in oxidation of isocitrate in the cycle when the muscles are at rest. 2. A comparison of the maximal activities of the enzymes with the maximal flux through the cycle suggests that, in insect flight muscle, NAD+-linked isocitrate dehydrogenase catalyses a non-equilibrium reaction and citrate synthease catalyses a near-equilibrium reaction. In other muscles, the enzyme-activity data suggest that both citrate synthase and the isocitrate dehydrogenase reactions are near-equilibrium.Keywords:
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Introduction . Glioblastoma multiforme (GBM) is the most malignant primary brain tumor in adults. Recent whole-genome studies revealed novel GBM prognostic biomarkers such as mutations in metabolic enzyme IDH—isocitrate dehydrogenases (IDH1 and IDH2). The distinctive mutation IDH1 R132H was uncovered to be a strong prognostic biomarker for glioma patients. We investigated the prognostic role of IDH1 R132H mutation in GBM patients in West Bohemia. Methods . The IDH1 R132H mutation was assessed by the RT-PCR in the tumor samples from 45 GBM patients treated in the Faculty Hospital in Pilsen and was correlated with the progression free and overall survival. Results . The IDH1 R132H mutation was identified in 20 from 44 GBM tumor samples (45.4%). The majority of mutated tumors were secondary GBMs (16 in 18, 89.9%). Low frequency of IDH1 mutations was observed in primary GBMs (4 in 26, 15.3%). Patients with IDH R132H mutation had longer PFS, 136 versus 51 days (P < 0.021 P < 0.024
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A recent cancer genome-sequencing project revealed that that novel point mutations in isocitrate dehydrogenase 1(IDH1) in the majority of gliomas at WHO Grade Ⅱ and Ⅲ and secondary glioblastomas at grade IV.IDH1 mutations are early events in the development of gliomas,and are related with prolonged survival in gliomas at various grades.Mutated IDH1 shows an altered catalytic activity that results in the elevated levels of α-ketoglutarate and 2-hydroxyglutarate.The correlations among the gliomas pathological diagnosis,tumor genesis,the therapeutic potential for targeting mutant IDH enzymes are discussed in this review.
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Isocitrate dehydrogenase 1 (IDH1) mutations have been discovered to be frequent and highly conserved in secondary glioblastoma multiforme and lower-grade gliomas. Although IDH1 mutations confer a unique genotype that has been associated with a favorable prognosis, the role of the mutated IDH1 enzyme and its metabolites in tumor initiation and maintenance remains unresolved. However, given that IDH1 mutations are homogeneously expressed and are limited solely to tumor tissue, targeting this mutation could potentially yield novel treatment strategies for patients with glioblastoma multiforme.
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Purpose of review Isocitrate dehydrogenases, IDH1 and IDH2, decarboxylate isocitrate to α-ketoglutarate (α-KG) and reduce NADP to NADPH. Point mutations of IDH1 and IDH2 have been discovered in gliomas. IDH mutations cause loss of native enzymatic activities and confer novel activity of converting α-KG to 2-hydroxyglutarate (2-HG). The mechanisms of IDH mutations in gliomagenesis, and their value as diagnostic, prognostic marker and therapeutic target have been extensively studied. This review is to summarize the findings of these studies. Recent findings Crystal structural studies revealed conformation changes in mutant IDHs, which may explain the gain of function by mutant IDHs. The product of mutant IDHs, 2-HG, is an inhibitor of α-KG-dependent dioxygenases, which may cause genome-wide epigenetic changes in human gliomas. IDH mutations are a favorable prognostic factor for human glioma and can be used as biomarker for differential diagnosis and subclassification rather than predictor of response to treatment. Preliminary data suggested that inhibiting production of the substrate of mutant IDH enzymes caused slow-down of glioma cell growth. Summary As valuable diagnostic and prognostic markers of human gliomas, there is still a lack of knowledge on biological functions of mutant IDHs, making targeting IDHs in glioma both difficult and unsecured.
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Diffuse gliomas and secondary glioblastomas (GBMs) that develop from low-grade gliomas are a common and incurable class of brain tumor. Mutations in the metabolic enzyme glioblastomas (IDH1) represent a distinguishing feature of low-grade gliomas and secondary GBMs. IDH1 mutations are one of the most common and earliest detectable genetic alterations in low-grade diffuse gliomas, and evidence supports this mutation as a driver of gliomagenesis. Here, the authors highlight the biological consequences of IDH1 mutations in gliomas, the clinical and therapeutic/diagnostic implications, and the molecular subtypes of these tumors. They also explore, in brief, the non-IDH1–mutated gliomas, including primary GBMs, and the molecular subtypes and drivers of these tumors. A fundamental understanding of the diversity of GBMs and lower-grade gliomas will ultimately allow for more effective treatments and predictors of survival.
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Isocitrate dehydrogenase 1 and 2 mutations are known to be early events in gliomagenesis and have a definite role in tumor progression.Isocitrate dehydrogenase1/2 mutation status is considered to be one of the most powerful independent positive predictor of outcome amongst all molecular markers described in association with gliomas. The inclusion of this parameter in the 2016 update of the World Health Organization Classification of Tumors of The Central Nervous System reinforced its importance in glioma classification and prognostication. As a result, now there is enough evidence to prove that Isocitrate dehydrogenase-mutant and Isocitrate dehydrogenase- wildtypegliomas are two biologically distinct categories of gliomas with likely different pathways of tumorigenesis, different clinical outcomes, and respond differently to similar treatment strategies. Increasing knowledge aboutthe role of IDH1/2 mutation in gliomagenesis has resulted in many novel targeting strategies being developed and evaluated forusefulness in the clinical setting. This literature review aims to highlight the diagnostic and prognostic importance of Isocitrate dehydrogenase1/2 gene mutations in adult gliomas.
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