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)

The measurement of acyl-CoA dehydrogenase activity is an essential part of the investigation of patients with suspected defects of fatty acid oxidation, and recently the organometallic oxidant ferricenium hexafluorophosphate has been introduced as an electron acceptor for these assays. However, we show that when medium-chain acyl-CoA dehydrogenase activity was measured in cultured skin fibroblasts and platelets from patients with proven defects of this enzyme, there was considerable residual enzyme activity when this electron acceptor was used. The ferricenium assay is not as specific as the anaerobic ETF-linked assay in the biochemical diagnosis of medium-chain acyl-CoA dehydrogenase deficiency in fibroblasts, and therefore is of limited clinical applicability in its present form.
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PMID:Measurement of acyl-CoA dehydrogenase activity in cultured skin fibroblasts and blood platelets. 143 12

Plasma concentrations of octanoate and cis-4-decenoate were measured by gas chromatography-mass spectrometry in children with deficiencies of medium-chain acyl-CoA dehydrogenase (MCAD), long-chain 3-hydroxyacyl-CoA dehydrogenase (3LHAD) and multiple acyl-CoA dehydrogenase (MAD) deficiency. Children receiving medium- and long-chain lipid supplements were also studied. Octanoate was elevated in all but one of the children with MCAD deficiency, in MAD deficiency and in children receiving medium-chain triglyceride supplementation. Cis-4-decenoate was only elevated in MCAD and MAD deficiency. It is concluded that measurement of plasma cis-4-decenoate provides a sensitive and specific test for defects of medium-chain acyl CoA dehydrogenase.
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PMID:Rapid diagnosis of medium-chain acyl CoA dehydrogenase deficiency by measurement of cis-4-decenoic acid in plasma. 177 11

The free two-electron-reduced form of medium-chain acyl-CoA dehydrogenase is reoxidized by 120 microM molecular oxygen (50 mM phosphate buffer, pH 7.6, 2 degrees C) with a half-time of approximately 7 s. Reoxidation yields hydrogen peroxide as a major product with only traces of the superoxide anion. In contrast, enzyme reduced with octanoyl-CoA is extremely slowly reoxidized oxygen, and so a series of 14 different substrate analogues have been tested to assess the structural factors responsible for this effect. Complexes with redox-inactive ligands such as 3-thia- and 2-azaoctanoyl-CoA lead to an approximately 3000-fold slowing of the rate of reoxidation of the free dihydroflavin form of the enzyme. Comparable ligands lacking the thioester carbonyl function are much less effective with rates some 1.3-4-fold slower than the free enzyme. The strong suppression of oxygen reactivity observed with certain ligands is probably not simply a steric effect but may reflect desolvation of the active site and consequent destabilization of the superoxide anion intermediate formed during reoxidation of the flavin. The profound differences in oxygen reactivity between acyl-CoA dehydrogenase and acyl-CoA oxidase and the unusual stability of certain flavoprotein semiquinones in air are discussed in terms of these thermodynamic and kinetic arguments.
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PMID:Reactivity of medium-chain acyl-CoA dehydrogenase toward molecular oxygen. 186 64

Long-chain acyl-CoA dehydrogenase (LCAD) deficiency is a disorder of mitochondrial fatty acid oxidation that is characterized by hypoglycemia, muscle weakness, and hepato- and cardiomegaly. To characterize variant LCAD, we first carried out preliminary experiments using pure enzyme preparations. Despite the significant sequence similarity of LCAD to medium-chain acyl-CoA dehydrogenase, the antibody raised against rat LCAD was monospecific for human and rat LCAD and did not cross-react with either human or rat medium-chain acyl-CoA dehydrogenase. Immunoblot analysis of variant LCAD in cultured fibroblasts from nine patients with LCAD deficiency revealed a single LCAD band in all nine LCAD-deficient cell lines. Each variant LCAD was comparable in molecular size and quantity to normal LCAD, suggesting that the LCAD mutation in each of these cell lines is likely to be a point mutation that produces a stable variant LCAD. The uniform nature of variant LCAD suggests that only a single, or at most a few, prevalent point mutations may be found in the majority of LCAD-deficient patients. If this is the case, it should be possible to devise a molecular diagnostic method for LCAD deficiency.
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PMID:Immunochemical characterization of variant long-chain acyl-CoA dehydrogenase in cultured fibroblasts from nine patients with long-chain acyl-CoA dehydrogenase deficiency. 194 57

Inactivation of five distinct acyl-CoA dehydrogenases by (methylenecyclopropyl)acetyl-CoA (MCPA-CoA), the toxic metabolite of hypoglycin from unripe ackee fruit, was investigated using purified enzyme preparations. Short-chain acyl-CoA (SCADH), medium-chain acyl-CoA (MCADH) and isovaleryl-CoA (IVDH) dehydrogenases were severely and irreversibly inactivated by MCPA-CoA, while 2-methyl-branched chain acyl-CoA dehydrogenase (2-meBCADH) was only slowly and mildly inactivated. Long-chain acyl-CoA dehydrogenase (LCADH) was not significantly inactivated, even after prolonged incubation with MCPA-CoA. Inactivation of SCADH, MCADH and IVDH was effectively prevented by the addition of substrate. This mode of inactivation by MCPA-CoA explains the urinary metabolite profile in hypoglycin treated-rats, which includes large amounts of metabolites from fatty acids and leucine, and relatively small amounts of those from valine and isoleucine. Spectrophotometric titration of SCADH and MCADH with MCPA-CoA, together with the protective effects of substrate, indicates that MCPA-CoA is acted upon by, and exerts in turn irreversible inactivation of, SCADH and MCADH, confirming that MCPA-CoA is a suicide inhibitor (Wenz et al. (1981) J. Biol. Chem. 256, 9809-9812). Spectrophotometric titration data of LCADH and MCPA-CoA is typical of non-reacting CoA ester.
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PMID:Selective inactivation of various acyl-CoA dehydrogenases by (methylenecyclopropyl)acetyl-CoA. 233 85

There are still many problems with the diagnosis and classification of inherited disorders of mitochondrial beta-oxidation. At present only the acyl-CoA dehydrogenase step of the beta-oxidation spiral has been explored in any detail and a large number of patients have disorders that cannot be properly characterized. beta-Oxidation defects may present in a wide variety of ways, the most dramatic being acute encephalopathy with hepatic involvement (atypical Reye's syndrome) or 'sudden' death. Investigations may include urinary and plasma organic acids, metabolic stress tests and assays of overall metabolic pathways or of specific enzymes in cultured fibroblasts, lymphocytes, or other material. Early postnatal diagnosis presents particular difficulties but in medium-chain acyl-CoA dehydrogenase deficiency the diagnosis may be apparent from careful examination of urine. There is as yet little general experience in prenatal diagnosis of this group of disorders except for glutaric aciduria type II. Single prenatal diagnoses of medium-chain acyl-CoA dehydrogenase deficiency and of an incompletely characterized defect of medium-chain fatty acid oxidation have been performed.
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PMID:Disorders of mitochondrial beta-oxidation: prenatal and early postnatal diagnosis and their relevance to Reye's syndrome and sudden infant death. 250 9

4-Thiaacyl-CoA analogues, in which the 4-methylene group is replaced by a thioether sulfur atom, represent new chromophoric substrates of acyl-CoA dehydrogenases and oxidase. The corresponding 4-thia-trans-2-enoyl-CoA products exhibit a strong new absorption band (extinction coefficient 22 mM-1 cm-1) that is red shifted from 312 to 338 nm upon binding to the medium-chain acyl-CoA dehydrogenase. 4-Thiaoctanoyl-CoA reduces the dehydrogenase several-fold slower than octanoyl-CoA, although in turnover it is dehydrogenated 1.5-fold faster. The redox potential of 4-thia analogues is some 30 mV more negative than that of their unsubstituted counterparts. 4-Thia-trans-2-enoyl-CoA derivatives are slowly hydrated by enoyl-CoA hydratase (EC 4.2.1.17) to the corresponding thiohemiacetal which fragments nonenzymatically to 1 equiv each of malonylsemialdehyde-CoA and alkanethiol. This fragmentation reaction might explain the release of methanethiol during the transamination pathway of methionine degradation. 4-Oxaoctanoyl-CoA is a much poorer substrate and kinetic reductant of acyl-CoA dehydrogenase and oxidase than the 4-thia analogue. The corresponding enoyl-CoA product is also fragmented by the hydratase, yielding butanol and malonylsemialdehyde-CoA. Thus, 4-heterosubstituted acyl-CoA derivatives provide new tools for the study of beta-oxidation enzymes.
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PMID:4-Thia-trans-2-alkenoyl-CoA derivatives: properties and enzymatic reactions. 260 83

A 12-year-old girl was shown to have carnitine-deficient lipid storage myopathy and organic aciduria compatible with multiple acylcoenzyme A (acyl-CoA) dehydrogenase deficiency. In muscle mitochondria, activities of both short-chain acyl-CoA dehydrogenase (SCAD) and medium-chain acyl-CoA dehydrogenase (MCAD) were 35% of normal. Antibodies against purified SCAD, MCAD, and electron-transfer flavoprotein were used for detection of cross-reacting material (CRM) in the patient's mitochondria. Western blot analysis showed absence of SCAD-CRM, reduced amounts of MCAD-CRM, and normal amounts of electron-transfer flavoprotein-CRM. The patient, who was unresponsive to treatment with oral carnitine, improved dramatically with daily administration of 100 mg oral riboflavin. Increase in muscle bulk and strength and resolution of the organic aciduria were associated with normalization of SCAD activity and "reappearance" of SCAD-CRM. In contrast, both MCAD activity and MCAD-CRM remained lower than normal. These results suggest that in some patients with multiple acyl-CoA dehydrogenase deficiency riboflavin supplementation may be effective in restoring the activity of SCAD, and possibly of other mitochondrial flavin-dependent enzymes.
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PMID:Normalization of short-chain acylcoenzyme A dehydrogenase after riboflavin treatment in a girl with multiple acylcoenzyme A dehydrogenase-deficient myopathy. 277 89

A man with a painful proximal myopathy had excess lipid deposition in skeletal muscle, excretion of dicarboxylic acids in urine and low acyl-CoA dehydrogenase activities in skeletal muscle mitochondria. In addition he had little immunoreactive short-chain and medium-chain acyl-CoA dehydrogenase enzyme protein compared with normal controls. Following treatment with riboflavin there was considerable improvement in his clinical condition which was confirmed by further biochemical and morphological investigations.
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PMID:Lipid storage myopathy associated with low acyl-CoA dehydrogenase activities. 304 86

Genetic deficiency of short-chain acyl-coenzyme A (CoA) dehydrogenase activity was demonstrated in cultured fibroblasts from a 2-yr-old female whose early postnatal life was complicated by poor feeding, emesis, and failure to thrive. She demonstrated progressive skeletal muscle weakness and developmental delay. Her plasma total carnitine level (35 nmol/ml) was low-normal, but was esterified to an abnormal degree (55% vs. control of less than 10%). Her skeletal muscle total carnitine level was low (7.6 nmol/mg protein vs. control of 14 +/- 2 nmol/mg protein) and was 75% esterified. Mild lipid deposition was noted in type I muscle fibers. Fibroblasts from this patient had 50% of control levels of acyl-CoA dehydrogenase activity towards butyryl-CoA as substrate at a concentration of 50 muM in a fluorometric assay based on the reduction of electron transfer flavoprotein. All of this residual activity was inhibited by an antibody against medium-chain acyl-CoA dehydrogenase. These data demonstrated that medium-chain acyl-CoA dehydrogenase accounted for 50% of the activity towards the short-chain substrate, butyryl-CoA, under these conditions, but that antibody against that enzyme could be used to unmask the specific and virtually complete deficiency of short-chain acyl-CoA dehydrogenase in this patient. Fibroblasts from her parents had intermediate levels of activity towards butyryl-CoA, consistent with the autosomal recessive inheritance of this metabolic defect.
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PMID:Genetic deficiency of short-chain acyl-coenzyme A dehydrogenase in cultured fibroblasts from a patient with muscle carnitine deficiency and severe skeletal muscle weakness. 333 34


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