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)

From 65 reported cases of medium chain acyl-CoA dehydrogenase deficiency, we found an average presenting age of 13.5 months and a mean age at death of 18.5 months. One quarter of patients died of a Reye-like syndrome and/or sudden infant death. In half the cases there had been at least one sibling death. Asymptomatic cases were not uncommon (12% of cases). The crises were generally induced by a prolonged fast and after a viral prodromal phase in three quarters of cases. The crises consisted of somnolence progressing to lethargy which could lead to coma. Vomiting was frequent (60% of cases). Seizures, which were found in 29% of cases, represented a bad prognosis. The physical examinations revealed frequently a variable and regressive anicteric hepatomegaly. Blood and urine analysis revealed in most instances hypoglycaemia (96% of cases) with hypoketonuria and sometimes metabolic acidosis. Hepatic and muscular cytolytic enzymes were frequently raised, as were plasma ammonia, urea, and uric acid. Plasma total or free carnitine concentrations, especially non-fasting, were diminished in most cases. Plasma saturated medium chain fatty acids and particularly unsaturated cis-4-decenoate were on the other hand raised during the crises or during fasting. Urinary organic acid analysis revealed a characteristic profile of medium chain aciduria: C6-C10 dicarboxylic acids, hydroxy acids, glycine conjugates, and carnitine conjugates. Oral loading tests with carnitine or phenylpropionate allow a precise diagnosis. The diagnosis is confirmed by specific assays in various tissues. Avoidance of prolonged fasting seems to be the mainstay of treatment.
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PMID:Medium chain acyl-CoA dehydrogenase deficiency. 173 32

Developmental profiles were determined for the activities of eight enzymes involved in fatty acid beta-oxidation in rat brain. The enzymes studied were the palmitoyl-CoA, octanoyl-CoA, butyryl-CoA, glutaryl-CoA, and 3-hydroxyacyl-CoA dehydrogenases, the enoyl-CoA hydratase (crotonase), and the C4- and C10-thiolases. With the exception of the thiolases, all of the activities (expressed on the basis of brain weight) increased during the postnatal period of brain maturation. The activity of octanoyl-CoA dehydrogenase was elevated markedly compared to that of palmitoyl-CoA dehydrogenase at all developmental stages and in all brain regions in the rat. A similar relationship between these enzymes was observed in various regions of adult human brain. Comparisons of the activities of the beta-oxidation enzymes in human brain versus human skeletal muscle and in cultured neural cell lines (neuroblastoma and glioma) versus cultured skin fibroblasts revealed that the elevated activity of octanoyl-CoA dehydrogenase relative to palmitoyl-CoA dehydrogenase was specific to the neural tissues. This relationship was particularly evident when the enzyme activities were normalized to the activity of crotonase. The data support previous findings with radiochemical tracers, indicating that the brain is capable of utilizing fatty acids as substrates for oxidative energy metabolism. The relatively high activity of the medium-chain fatty acyl-CoA dehydrogenase in neural tissue may represent an adaptive mechanism to protect the brain from the known encephalopathic effects of octanoate and other medium-chain fatty acids that readily cross the blood-brain barrier.
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PMID:Enzymes of fatty acid beta-oxidation in developing brain. 289 30

Evidence is presented that Saccharomyces cerevisiae can metabolize fatty acids via the inducible peroxisomal beta-oxidation pathway even when these acids are not the sole carbon source. The fatty acids of chain length of C10-C18 induce acyl-CoA oxidase simultaneously with catalase A but have no effect on catalase T and acyl-CoA dehydrogenase. The coinduction of both acyl-CoA oxidase and catalase A is recorded in strains with both active catalase A and T or displaying only catalase A activity. In mutants lacking catalase A, the induction of acyl-CoA oxidase is observed without a concomitant increase in catalase activity. After centrifugation in a linear Ficoll gradient of the particulate fraction from the cells grown on ethanol and oleate the activity of acyl-CoA oxidase cosediments with catalase A. The relationship of catalase A to acyl-CoA oxidase is discussed.
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PMID:Study of the coinduction by fatty acids of catalase A and acyl-CoA oxidase in standard and mutant Saccharomyces cerevisiae strains. 328 21

The activities of peroxisomal and mitochondrial beta-oxidation and carnitine acyltransferases changed during the process of development from embryo to adult chicken, and the highest activities of peroxisomal beta-oxidation, palmitoyl-CoA oxidase, and carnitine acetyltransferase were found at the hatching stage of the embryo. The profiles of these alterations were in agreement with those of the contents of triglycerides and free fatty acids in the liver. The highest activities of mitochondrial beta-oxidation and palmitoyl-CoA dehydrogenase were observed at the earlier stages of the embryo; then the activities decreased gradually from embryo to adult chicken. The ratio of activities of carnitine acetyltransferase in peroxisomes and mitochondria (peroxisomes/mitochondria) increased from 0.54 to 0.82 during the development from embryo to adult chicken. The ratio of activities of carnitine palmitoyltransferase decreased from 0.82 to 0.25 during the development. The affinity of fatty acyl-CoA dehydrogenase toward the medium-chain acyl-CoAs (C6 and C8) was high in the embryo and decreased with development, whereas the substrate specificity of fatty acyl-CoA oxidase did not change. The substrate specificity of mitochondrial carnitine acyltransferases did not change with development. The affinity of peroxisomal carnitine acyltransferases toward the long-chain acyl-CoAs (C10 to C16) was high in the embryo, but low in adult chicken.
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PMID:Developmental changes in the activities of peroxisomal and mitochondrial beta-oxidation in chicken liver. 397 May 42

Various types of dicarboxylic aciduria are known, most of them are accompanied by non-ketotic hypoglycaemia. For the differential diagnosis of these conditions several methods of investigation have been used: (1) analysis of urinary organic acids in both native and hydrolysed samples, (2) analysis of free and esterified carnitine, the latter by means of chromatographic separation and identification of acyl moieties, (3) analysis of plasma organic acids, including the so-called free fatty acids, (4) a prolonged fasting test with serial measurements of the aforementioned parameters and close monitoring of the blood glucose and (5) an oral loading test with medium chain triglycerides accompanied by the same measurements as those named in item (4). So far differentiation has been made between patients with a metabolite profile most probably characteristic of medium chain acyl-CoA dehydrogenase deficiency and other dicarboxylic acidurias, among the latter systemic carnitine deficiency. Patients belonging to the first group accumulate octanoate, decanoate and cis-4-decenoate in their plasma; they excrete hexanoylglycine, octanoylcarnitine and suberylglycine in addition to the usual C6-C10 dicarboxylic acids. There was a high prevalence of an increased plasma free fatty acid/3-hydroxybutyrate ratio.
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PMID:The differential diagnosis of dicarboxylic aciduria. 643 45

Urinary analysis of the pattern of 23 organic acid metabolites derived from fatty acids in three patients with general (medium-chain) acyl-CoA dehydrogenase deficiency was performed. Although there exist quantitative differences in the excreted amounts of the different metabolites in the three patients the qualitative picture was the same. The excretion of adipic, suberic and sebacic acids was substantial, whereas that of dodecanedioic acid was within or just above control limit. The monounsaturated C6-C10-dicarboxylic acid excretion was only marginally or not increased. 5-OH-hexanoic acid and hexanoylglycine were excreted in excessive amounts, whereas 7-OH-octanoic acid, 9-OH-decanoic acid, octanoylglycine and decanoylglycine were excreted in limited amounts. The excreted amounts of 6-OH-hexanoic, 8-OH-octanoic and 10-OH-decanoic acids were not or only marginally elevated compared to controls. In one of the patients the excretion of ethylmalonic and methylsuccinic acids was enhanced, whereas the excretion of these two acids in the two other patients was comparable to that in controls. The urinary excretion of hexanoic, octanoic, decanoic and dodecanoic acids was just a little above the control limit, whereas the esterified hexanoic and octanoic acids were excreted in appreciable amounts. It is argued that the microsomal omega- and omega-1-oxidation systems are involved in the dicarboxylic and omega-1-OH-monocarboxylic acids formation at C10 and C12 level and that the C8-C6-dicarboxylic and omega-1-OH-monocarboxylic acids are formed from higher chained acids by beta-oxidation in both mitochondria and peroxisomes.
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PMID:General (medium-chain) acyl-CoA dehydrogenase deficiency (non-ketotic dicarboxylic aciduria): quantitative urinary excretion pattern of 23 biologically significant organic acids in three cases. 661 73

Seven infants in one kindred died: one was stillborn; the others, who were floppy at birth and were breast-fed, developed a disorder with the odor of sweaty feet and died in early infancy. In two further pregnancies, 3-hydroxvisovaleric, glutaric, and C6-C10-dicarboxylic acids were demonstrated in the mother's urine during the seventh month. Riboflavin therapy in the last trimester of pregnancy and a riboflavin-rich diet given the infants prevented this syndrome. The presence of abnormal erythrocyte glutathione-reductase activity in the mother while she excreted normal amounts of riboflavin in her urine indicates a probable disorder of riboflavin metabolism resulting in multiple acyl-CoA dehydrogenase deficiency.
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PMID:Multiple acyl-CoA dehydrogenase deficiency occurring in pregnancy and caused by a defect in riboflavin metabolism in the mother. Study of a kindred with seven deaths in infancy: Value of riboflavin therapy in preventing this syndrome. 688 4

Mitochondrial fatty acid beta-oxidation was studied by incubating stable isotope-labeled fatty acid probes with human fibroblasts in the presence of L-carnitine. The acylcarnitine intermediates produced were analyzed by tandem mass spectrometry. Oxidation by normal fibroblasts produced specific acylcarnitine intermediates corresponding to acyl-CoA dehydrogenase substrates mainly of 10 or less carbons. These probes demonstrated that the pathway, involving all beta-oxidative steps, could be examined. Oxidation of the same precursors by cells with medium chain acyl-CoA dehydrogenase (EC 1.3.99.2) (MCAD) deficiency, which is caused by different DNA mutations, produced acylcarnitine profiles which appear to be specific to this enzyme defect, regardless of the DNA mutation. Increased amounts of octanoyl-, decanoyl-, or decenoylcarnitine were detected. The ratios of octanoylcarnitine to decanoyl- or decenoylcarnitine appear specific for MCAD deficiency. Even though the concentration of labeled decenoylcarnitine (C10:1) was elevated in incubations of MCAD-deficient cells with labeled linoleate or with a fatty acid mixture which included palmitate, oleate, and linoleate, the predominant intermediate was octanoylcarnitines. These results suggest that MCAD-deficient cells readily convert decanoyl-CoA into octanoyl-CoA. This in vitro system could be utilized to study fatty acid oxidation disorders and to study the origins of metabolic intermediates associated with them.
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PMID:Investigation of beta-oxidation intermediates in normal and MCAD-deficient human fibroblasts using tandem mass spectrometry. 755 18

Long-chain-acyl-CoA dehydrogenase (LCADH) has been produced by recombinant techniques from the human cDNA and purified after expression in Escherichia coli. Pig kidney LCADH was purified using an optimized method which also produces apparently pure short-chain-acyl-CoA dehydrogenase (SCADH) and medium-chain-acyl-CoA dehydrogenase (MCADH) in good yields. LCADH from both sources has a maximal turnover rate (Vmax of 650-700 min(-1) at pH 7.6) with the best substrates, which is approximately fivefold higher than reported previously. The human enzyme has an approximately fivefold higher Km compared with the pig kidney enzyme with substrates of chain length from C10 to C18 and a significantly different dependence of Vmax on the chain length. Pig kidney LCADH has a similar Vmax/Km with C10 to C14 substrates as MCADH does with C6 to C10 substrates. Recombinant human LCADH, however, is significantly less efficient (approximately fourfold with C12) than purified pig kidney enzyme. We conclude that human LCADH is either quantitatively less important in beta-oxidation than in the pig, or that post-translational modifications, not present in the recombinant human enzyme, are required to optimize human LCADH activity. Our results demonstrate that LCADH is as important as the other acyl-CoA dehydrogenases in fatty acid oxidation at physiological, mitochondrial pH with optimal substrates of chain length C10-C14. The extent of the LCADH-flavin cofactor reduction observed with most substrates and the rate of the subsequent reoxidation with oxygen are markedly different from those found with human medium chain acyl-CoA dehydrogenase. Both LCADH are inactivated by the substrate analogue 2-octynoyl-CoA, possibly via covalent modification of Glu261, the active-site residue involved in deprotonation of the substrate (alpha)C-H.
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PMID:Characterization of human and pig kidney long-chain-acyl-CoA dehydrogenases and their role in beta-oxidation. 918 95

Diazoxide and 5-hydroxydecanoate (5-HD; C10:0) are reputed to target specifically mitochondrial ATP-sensitive K(+) (K(ATP)) channels. Here we describe K(ATP) channel-independent targets of diazoxide and 5-HD in the heart. Using submitochondrial particles isolated from pig heart, we found that diazoxide (10-100 microM) dose-dependently decreased succinate oxidation without affecting NADH oxidation. Pinacidil, a non-selective K(ATP) channel opener, did not inhibit succinate oxidation. However, it selectively inhibited NADH oxidation. These direct inhibitory effects of diazoxide and pinacidil cannot be explained by activation of mitochondrial K(ATP) channels. Furthermore, application of either diazoxide (100 microM) or pinacidil (100 microM) did not decrease mitochondrial membrane potential, assessed using TMRE (tetramethylrhodamine ethyl ester), in isolated guinea-pig ventricular myocytes. We also tested whether 5-HD, a medium-chain fatty acid derivative which blocks diazoxide-induced cardioprotection, was 'activated' via acyl-CoA synthetase (EC 6.2.1.3), an enzyme present both on the outer mitochondrial membrane and in the matrix. Using analytical HPLC and electrospray ionisation mass spectrometry, we showed that 5-HD-CoA (5-hydroxydecanoyl-CoA) is indeed synthesized from 5-HD and CoA via acyl-CoA synthetase. Thus, 5-HD-CoA may be the active form of 5-HD, serving as substrate for (or inhibiting) acyl-CoA dehydrogenase (beta-oxidation) and/or exerting some other cellular action. In conclusion, we have identified K(ATP) channel-independent targets of 5-HD, diazoxide and pinacidil. Our findings question the assumption that sensitivity to diazoxide and 5-HD implies involvement of mitochondrial K(ATP) channels. We propose that pharmacological preconditioning may be related to partial inhibition of respiratory chain complexes.
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PMID:K(ATP) channel-independent targets of diazoxide and 5-hydroxydecanoate in the heart. 1215 68


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