Influence of a rickets-inducing diet on citrate metabolism
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Isocitrate dehydrogenase
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.
Isocitrate dehydrogenase
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In heart muscle, NADP-linked isocitrate dehydrogenase activity is particularly high when compared with that of the other representative NADPH-generating enzyme, glucose-6-phosphate dehydrogenase. Approximately 80% of cardiac NADP-linked isocitrate dehydrogenase activity originates in the mitochondria. Adriamycin inhibited the activity of both mitochondrial and cytoplasmic NADP-linked isocitrate dehydrogenase dose dependently but had no effect on glucose-6-phosphate dehydrogenase. The inhibition was kinetically distinguished as noncompetitive. Preincubation of crude cardiac enzyme preparations with adriamycin enhanced the inhibition time dependently for 45 min. However, there was no evidence to suggest that the metabolites of adriamycin produced in this system were active as inhibitors. Adriamycin-binding protein was fractionated by affinity chromatography, but NADP-linked isocitrate dehydrogenase activity was not detected in this fraction.
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Abstract The metabolic function of NAD(P)‐glycohydrolase in the streptomycyin‐producing Streptomyces griseus was investigated. Phospho‐adenosinediphospho‐ribose, the product of NAD(P)‐glycohydrolase reaction was shown to interfere as a competitive inhibitor not only with the glucose‐6‐phosphate dehydrogenase (Voronina et al. 1978) but also with the NADP‐dependent isocitrate and 6‐phospho‐gluconate dehydrogenases. Inhibition kinetics were studied with isocitrate dehydrogenase from pig heart and 6‐phosphogluconate dehydrogenase from yeast as well as with mycelial extracts of a mutant of S. griseus lacking NAD(P)‐glycohydrolase.
Isocitrate dehydrogenase
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Isocitrate dehydrogenase
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Isocitrate dehydrogenase
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Children with calcium-deficiency rickets may have increased vitamin D requirements and respond differently to vitamin D(2) and vitamin D(3). Our objective was to compare the metabolism of vitamins D(2) and D(3) in rachitic and control children. We administered an oral single dose of vitamin D(2) or D(3) of 1.25 mg to 49 Nigerian children--28 with active rickets and 21 healthy controls. The primary outcome measure was the incremental change in vitamin D metabolites. Baseline serum 25-hydroxyvitamin D [25(OH)D] concentrations ranged from 7 to 24 and 15 to 34 ng/mL in rachitic and control children, respectively (p < .001), whereas baseline 1,25-dihydroxyvitamin D [1,25(OH)(2)D] values (mean ± SD) were 224 ± 72 and 121 ± 34 pg/mL, respectively (p < .001), and baseline 24,25-dihydroxyvitamin D [24,25(OH)(2)D] values were 1.13 ± 0.59 and 4.03 ± 1.33 ng/mL, respectively (p < .001). The peak increment in 25(OH)D was on day 3 and was similar with vitamins D(2) and D(3) in children with rickets (29 ± 17 and 25 ± 11 ng/mL, respectively) and in control children (33 ± 13 and 31 ± 16 ng/mL, respectively). 1,25(OH)(2)D rose significantly (p < .001) and similarly (p = .18) on day 3 by 166 ± 80 and 209 ± 83 pg/mL after vitamin D(2) and D(3) administration, respectively, in children with rickets. By contrast, control children had no significant increase in 1,25(OH)(2)D (19 ± 28 and 16 ± 38 pg/mL after vitamin D(2) and D(3) administration, respectively). We conclude that in the short term, vitamins D(2) and D(3) similarly increase serum 25(OH)D concentrations in rachitic and healthy children. A marked increase in 1,25(OH)(2)D in response to vitamin D distinguishes children with putative dietary calcium-deficiency rickets from healthy children, consistent with increased vitamin D requirements in children with calcium-deficiency rickets. © 2010 American Society for Bone and Mineral Research.
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Isocitrate dehydrogenase
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