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:1.3.1.8 (acyl-CoA dehydrogenase)
785 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Inherited defects in myocardial long-chain fatty acid metabolism are increasingly recognized as a cause of cardiomyopathy and sudden death in children. To evaluate whether the phenotypic expression of these genetic diseases could be delineated using positron emission tomography (PET), 11 patients with inherited defects in fatty acid metabolism were evaluated and results were compared with those of 6 nonaffected siblings. Myocardial perfusion, myocardial oxygen consumption (MVO2), and long-chain fatty acid metabolism were determined noninvasively with PET using quantitative mathematical models. There were no differences in haemodynamics, perfusion, MVO2 or plasma substrate levels between groups. Patients with defects in enzymes of fatty acid beta-oxidation (acyl-CoA dehydrogenase and 3-hydroxyacyl-CoA dehydrogenase deficiencies) (n = 5) had diminished myocardial palmitate oxidation compared with healthy siblings (3.2 +/- 3.0 vs. 13.0 +/- 5.6 nmol/g per min, p < 0.03) and a decrease in the percentage of MVO2 accounted for by palmitate (2% +/- 3% vs. 9% +/- 5%, p < 0.04). In these patients, extracted palmitate was shunted into a slow-turnover compartment (predominantly reflecting esterification to triglycerides) with expansion of palmitate in that pool (185 +/- 246 compared with 27 +/- 67 nmol/g in healthy siblings,p < 0.02). In contrast, myocardium of patients with carnitine deficiency (n = 6) (all on oral carnitine therapy) had normal palmitate extraction but expansion of the interstitial/cytosolic fatty acid pool (617 +/- 399 vs. 261 +/- 73 nmol/g in healthy siblings, p < 0.04), suggesting different mechanisms for handling upstream fatty acyl intermediates. Thus, PET can be used to noninvasively assess abnormal myocardial handling of fatty acids in patients with inherited defects of metabolism. This approach should be useful in the assessment of altered myocardial fatty acid metabolism associated with cardiomyopathy as well as for evaluating the efficacy of therapeutic interventions in affected patients.
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PMID:Characterization of altered myocardial fatty acid metabolism in patients with inherited cardiomyopathy. 1176 85

The primary result of myocardial ischaemia is reduced oxygen consumption and adenosine triphosphate (ATP) formation in the mitochondria, and accelerated anaerobic glycolysis, lactate accumulation and cell acidosis. Classic pharmacotherapy for demand-induced ischaemia is aimed at restoring the balance between ATP synthesis and breakdown by increasing the oxygen delivery (i.e. with long acting nitrates or Ca2+ channel antagonist) or by decreasing cardiac power by reducing blood pressure and heart rate (i.e. with beta-blocker or Ca2+ channel antagonist). Animal studies show that fatty acids are the primary mitochondrial substrate during moderate severity myocardial ischaemia, and that they inhibit the oxidation of carbohydrate and drive the conversion of pyruvate to lactate. Drugs that partially inhibit myocardial fatty acid oxidation increase carbohydrate oxidation, which results in reduced lactate production and a higher cell pH during ischaemia. Trimetazidine (1-[2,3,4-trimethoxibenzyl]-piperazine) is the first and only registered drug in this class, and is available in over 90 countries world-wide. Trimetazidine selectively inhibits the fatty acid beta-oxidation enzyme 3-keto-acyl-CoA dehydrogenase (3-KAT), and is devoid of any direct haemodynamic effects. In double-blind placebo-controlled trials trimetazidine significantly improved symptom-limited exercise performance in stable angina patients when used either as monotherapy or in combination with beta-blockers or Ca2+ channel antagonists. Given available evidence, trimetazidine is an excellent alternative to classic haemodynamic agents, and is unique in its ability to reduce symptoms of angina when used in patients resistant to a haemodynamic treatment as vasodilators, beta-blockers or Ca2+ channel antagonists.
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PMID:Metabolic therapy in the treatment of ischaemic heart disease: the pharmacology of trimetazidine. 1266 23

The flavoenzyme nitroalkane oxidase catalyzes the oxidation of primary and secondary nitroalkanes to the respective aldehydes or ketones, releasing nitrite. The enzyme has recently been identified as being homologous to the acyl-CoA dehydrogenase family of enzymes [Daubner, S. C., Gadda, G., Valley, M. P., and Fitzpatrick, P. F. (2002) Proc. Natl. Acad. Sci. U.S.A. 99, 2702-2707]. The glutamate which acts as an active site base in that family of enzymes aligns with Asp402 of nitroalkane oxidase. To evaluate the identification of Asp402 as an active site base, the effect of mutation of Asp402 to glutamate on the rate of cleavage of the nitroalkane C-H bond has been determined. Deuterium kinetic isotope effects on steady state kinetic parameters and direct measurement of the rate of flavin reduction establish that the mutation increases the DeltaG(++) for C-H bond cleavage by 1.6-1.9 kcal/mol. There is no effect on the rate of reaction of the reduced enzyme with oxygen. These results support the assignment of Asp402 as the active site base in nitroalkane oxidase.
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PMID:Reductive half-reaction of nitroalkane oxidase: effect of mutation of the active site aspartate to glutamate. 1274 43

The objective of the present study was to relate changes in certain muscle characteristics and indicators of metabolism in response to endurance training to the concomitant changes in time to exhaustion (T(lim)) at a work rate corresponding to maximal oxygen uptake VO(2speak). Eight healthy sedentary subjects pedalled on a cycle ergometer 2 h a day, 6 days a week, for 4 weeks. Training caused increases in VO(2peak) (by 8%), T(lim) (from 299 +/- 23 s before to 486 +/- 63 s after training), citrate synthase and 3-hydroxyl-acyl-CoA dehydrogenase (HAD) activities (by 54% and 16%, respectively) and capillary density (by 31%). Decreases in activity of lactate dehydrogenase (LDH) and muscle type of LDH (by 24% and 28%, respectively) and the phosphofructokinase/citrate synthase ratio (by 37%) were also observed. Respiratory exchange ratio (RER) tended to be lower (P < 0.1) at all relative work rates after training while the corresponding ventilation rates (VE) were unchanged. At the same absolute work rate, RER and (VE) were lower after training (P < 0.05). The improvement of T(lim) with training was related to the increases in HAD activity (r = 0.91, P = 0.0043), and to the decreases in RER calculated for Pa(peak) (r = 0.71, P = 0.0496). The present results suggest that the training-induced adaptations in fat metabolism might influence T(lim) at a work rate corresponding to VO(2peak) and stimulate the still debated and incompletely understood role of fat metabolism during short high-intensity exercise.
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PMID:Are the effects of training on fat metabolism involved in the improvement of performance during high-intensity exercise? 1584 60

The heart utilizes primarily fatty acids for energy production. During ischemia, however, diminished oxygen supply necessitates a switch from beta-oxidation of fatty acids to glucose utilization and glycolysis. Molecular mechanisms responsible for these alterations in metabolism are not fully understood. Mitochondrial acyl-CoA dehydrogenase catalyzes the first committed step in the beta-oxidation of fatty acids. In the current study, an in vivo rat model of myocardial ischemia was utilized to determine whether specific acyl-CoA dehydrogenases exhibit ischemia-induced alterations in activity, identify mechanisms responsible for changes in enzyme function, and assess the effects on mitochondrial respiration. Very long chain acyl-CoA dehydrogenase (VLCAD) activity declined 34% during 30 min of ischemia. Loss in activity appeared specific to VLCAD as medium chain acyl-CoA dehydrogenase activity remained constant. Loss in VLCAD activity during ischemia was not due to loss in protein content. In addition, activity was restored in the presence of the detergent Triton X-100, suggesting that changes in the interaction between the protein and inner mitochondrial membrane are responsible for ischemia-induced loss in activity. Palmitoyl-carnitine supported ADP-dependent state 3 respiration declined as a result of ischemia. When octanoyl-carnitine was utilized state 3 respiration remained unchanged. State 4 respiration increased during ischemia, an increase that appears specific to fatty acid utilization. Thus, VLCAD represents a likely site for the modulation of substrate utilization during myocardial ischemia. However, the dramatic increase in mitochondrial state 4 respiration would be predicted to accentuate the imbalance between energy production and utilization.
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PMID:Inhibition of very long chain acyl-CoA dehydrogenase during cardiac ischemia. 1585 May 53

The three-dimensional structure of rat-liver acyl-CoA oxidase-II (ACO-II) in a complex with a C12-fatty acid was solved by the molecular replacement method based on the uncomplexed ACO-II structure. The crystalline form of the complex was obtained by cocrystallization of ACO-II with dodecanoyl-CoA. The crystalline complex possessed, in the active-site crevice, only the fatty acid moiety that had been formed through hydrolysis of the thioester bond. The overall dimeric structure and the folding pattern of each subunit are essentially superimposable on those of uncomplexed ACO-II. The active site including the flavin ring of FAD, the crevice embracing the fatty acyl moiety, and adjacent amino acid side chains are superimposably conserved with the exception of Glu421, whose carboxylate group is tilted away to accommodate the fatty acid. One of the carboxyl oxygens of the bound fatty acid is hydrogen-bonded to the amide hydrogen of Glu421, the presumed catalytic base, and to the ribityl 2'-hydroxyl group of FAD. This hydrogen-bonding network correlates well with the substrate recognition/activation in acyl-CoA dehydrogenase. The binding mode of C12-fatty acid suggests that the active site does not close upon substrate binding, but remains spacious during the entire catalytic process, the oxygen accessibility in the oxidative half-reaction thereby being maintained.
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PMID:Three-dimensional structure of rat-liver acyl-CoA oxidase in complex with a fatty acid: insights into substrate-recognition and reactivity toward molecular oxygen. 1667 80

This study investigated the effect of prolonged whole-body low-intensity exercise on blood lipids, skeletal muscle adaptations and aerobic fitness. Seven male subjects completed a 32-day crossing of the Greenland icecap on cross-country skies and before and after this arm or leg cranking was performed on two separate days and biopsies were obtained from arm and leg muscle, and venous blood was sampled. During the crossing, subjects skied for 342+/-42 min/day and body mass was decreased by 7.1+/-0.7 kg. Peak leg oxygen uptake (4.6+/-0.2 L/min) was decreased (P<0.05) by 7% whereas peak arm oxygen uptake (3.0+/-0.2 L/min) remained unchanged. Total and low-density lipoprotein cholesterol (5.0+/-0.2 and 3.20.2 mmol/L) were decreased by 8% and 20%, respectively. Muscle beta-hydroxy-acyl-CoA dehydrogenase activity was increased with 22% in arm (P=0.08) and remained unchanged in leg muscle. Hormone sensitive lipase activity was similar in arm and leg muscle prior to the expedition and was not significantly affected by the crossing. In conclusion, an improved blood lipid profile and thus metabolic fitness was present after prolonged low-intensity training and this occurred in spite of a decreased aerobic fitness and an unchanged arm and leg muscle hormone-sensitive lipase activity.
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PMID:Low-intensity training dissociates metabolic from aerobic fitness. 1735 24

Cyclic changes in dissolved oxygen occur naturally in shallow estuarine systems, yet little is known about the adaptations and responses of estuarine organisms to cyclic hypoxia. Here we examine the responses of Palaemonetes pugio, a species of grass shrimp, to cyclic hypoxia (1.5-8 mg/l dissolved oxygen; 4.20-22.42 kPa) at both the molecular and organismal levels. We measured alterations in gene expression in hepatopancreas tissue of female grass shrimp using custom cDNA macroarrays. After short-term (3-d) exposure to cyclic hypoxia, mitochondrial manganese superoxide dismutase (MnSOD) was upregulated and 70-kd heat shock proteins (HSP70) were downregulated. After 7-d exposure, nuclear genes encoding mitochondrial proteins (ribosomal protein S2, ATP synthase, very-long-chain specific acyl-CoA dehydrogenase [VLCAD]) were downregulated, whereas mitochondrial phosphoenol pyruvate carboxykinase (PEP Cbk) was upregulated. After 14 d, vitellogenin and apolipoprotein A1 were upregulated. Taken together, these changes suggest a shift in metabolism toward gluconeogenesis and lipid export. Long-term (77-d) exposure to hypoxia showed that profiles of gene expression returned to pre-exposure levels. These molecular responses differ markedly from those induced by chronic hypoxia. At the organismal level, cyclic hypoxia reduces the number of broods and eggs a female can produce. Demographic analysis showed a lower estimated rate of population growth in grass shrimp exposed to both continuous and short-term cyclic hypoxia, suggesting population-level impacts on grass shrimp.
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PMID:Effects of cyclic hypoxia on gene expression and reproduction in a grass shrimp, Palaemonetes pugio. 1825 71

Short-chain acyl-CoA dehydrogenase deficiency (SCADD) is a rare inherited disorder of the mitochondrial beta-oxidation of fatty acids. Patients with SCADD present mainly with symptoms of neuromuscular character. In order to investigate factors involved in the pathogenesis, we studied a disease-associated variant of the SCAD protein (p.Arg83Cys, c.319C>T), which is known to compromise SCAD protein folding. We investigated the consequences of overexpressing the misfolded mitochondrial protein, and thus determined whether the misfolded p.Arg83Cys SCAD proteins can elicit a toxic reaction. Human astrocytes were transiently transfected with either wild-type or p.Arg83Cys encoding cDNA, and analyzed for insoluble proteins/aggregate-formation, alterations in mitochondrial morphology, and for the presence of reactive oxygen species (ROS) in the mitochondria. The majority of cells overexpressing the p.Arg83Cys SCAD variant protein presented with an altered mitochondrial morphology of a grain-like structure, whereas the majority of the cells overexpressing wild-type SCAD presented with a normal thread-like mitochondrial reticulum. We found this grain-like structure to be associated with an increased amount of ROS. The mitochondrial morphology change was partly alleviated by addition of the mitochondrial targeted antioxidant MitoQ, indicating a ROS-induced mitochondrial fission. We therefore propose that SCAD misfolding leads to production of ROS, which in turn leads to fission and a grain-like structure of the mitochondrial reticulum. This finding indicates a toxic response elicited by misfolded p.Arg83Cys SCAD proteins.
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PMID:Misfolding of short-chain acyl-CoA dehydrogenase leads to mitochondrial fission and oxidative stress. 2037 Nov 98

Elevated levels of cardiac mitochondrial uncoupling protein 3 (UCP3) and decreased cardiac efficiency (hydraulic power/oxygen consumption) with abnormal cardiac function occur in obese, diabetic mice. To determine whether cardiac mitochondrial uncoupling occurs in non-genetic obesity, we fed rats a high fat diet (55% kcal from fat) or standard laboratory chow (7% kcal from fat) for 3 weeks, after which we measured cardiac function in vivo using cine MRI, efficiency in isolated working hearts and respiration rates and ADP/O ratios in isolated interfibrillar mitochondria; also, measured were medium chain acyl-CoA dehydrogenase (MCAD) and citrate synthase activities plus uncoupling protein 3 (UCP3), mitochondrial thioesterase 1 (MTE-1), adenine nucleotide translocase (ANT) and ATP synthase protein levels. We found that in vivo cardiac function was the same for all rats, yet oxygen consumption was 19% higher in high fat-fed rat hearts, therefore, efficiency was 21% lower than in controls. We found that mitochondrial fatty acid oxidation rates were 25% higher, and MCAD activity was 23% higher, in hearts from rats fed the high fat diet when compared with controls. Mitochondria from high fat-fed rat hearts had lower ADP/O ratios than controls, indicating increased respiratory uncoupling, which was ameliorated by GDP, a UCP3 inhibitor. Mitochondrial UCP3 and MTE-1 levels were both increased by 20% in high fat-fed rat hearts when compared with controls, with no significant change in ATP synthase or ANT levels, or citrate synthase activity. We conclude that increased cardiac oxygen utilisation, and thereby decreased cardiac efficiency, occurs in non-genetic obesity, which is associated with increased mitochondrial uncoupling due to elevated UCP3 and MTE-1 levels.
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PMID:A high fat diet increases mitochondrial fatty acid oxidation and uncoupling to decrease efficiency in rat heart. 2131 95


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