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:1.3.99.3 (acyl-CoA dehydrogenase)
1,425 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Unadapted rats and other animal species have a limited capacity to metabolize monounsaturated fatty acids with 22 carbons (22:1). Excess amounts in the diet of fats containing these fatty acids cause a transient accumulation (lipidosis) of triacylglycerol in the heart and other tissues but not in the liver, which seems to export the 22:1 fatty acids as very low density lipoproteins to the blood plasma. The acute lipidosis most probably is explained by a slow oxidation of 22:1 acyl-CoA by the mitochondrial acyl-CoA dehydrogenase combined with an inhibitory effect of this CoA ester on the oxidation of acyl-CoA esters of a more "normal" chain length. Other fatty acid metabolizing enzymes also show slow reaction rates with the 22:1 fatty acids. Upon continued feeding of diets with 22:1 fatty acids, an adaptation takes place and the lipidosis disappears. This adaptation coincides with the development of an increased capacity to chain-shorten the 22:1 fatty acids, especially in the liver, but also in the heart. The chain-shortening seems to be due to a partial beta-oxidation of the 22:1 fatty acids by the peroxisomal beta-oxidation enzyme system which shows an increased activity in adapted rats. In such rats, less 22:1 fatty acids circulate in the plasma very low density lipoproteins than in unadapted rats. The drug clofibrate (ethyl-p-chlorophenoxyisobutyrate) which induces increased activity of the peroxisomal beta-oxidation enzymes, provides partial protection against the lipidosis in unadapted animals. Hydrogenated fish oil (containing different 22:1 isomers and many fatty acids with trans double bonds) is more efficient as an inducer of the chain-shortening of erucic acid in the liver than is rapeseed oil, which contains only one 22:1 fatty acid isomer and no fatty acids with trans double bonds. The hydrogenated fish oil causes less lipidosis than does rapeseed oil when diets containing the same amount of 22:1 fatty acids are fed. It is suggested that CoA esters that are poorly oxidized by the mitochondria (e.g., esters of erucic acid, of some fatty acids with trans double bonds, and of clofibric acid) may trigger the adaptation process.-Bremer, J., and K. R. Norum. Metabolism of very long-chain monounsaturated fatty acids (22:1) and the adaptation to their presence in the diet.
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PMID:Metabolism of very long-chain monounsaturated fatty acids (22:1) and the adaptation to their presence in the diet. 704 78

Yellow butyryl-CoA dehydrogenase and general acyl-CoA dehydrogenase are "greened" by a mixture of coenzyme A plus elemental sulfur. The resultant stable complex contains an identical ligand with that present in native green butyryl-CoA dehydrogenase and has the same broad absorption band centered at 710 nm. Evidence is presented that the greening ligand is a CoA persulfide, possibly a mimic of the substrate carbanion thought to be generated early in the normal catalytic cycle. Variation in the position of the long wavelength band on replacement of FAD by a series of analogs of differing oxidation-reduction potential is consistent with a charge-transfer complex between a persulfide as the donor and oxidized flavin as the acceptor. The possible physiological and metabolic significance is discussed.
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PMID:Evidence that the greening ligand in native butyryl-CoA dehydrogenase is a CoA persulfide. 706 37

1. Oxygen consumption was measured by means of an O2 electrode in mitochondrial suspensions from riboflavin-deficient and pair-fed control rats, using six different substrates. Whereas consumption of O2 by glutamate was only slightly depressed in mitochondria from deficient animals, the consumption of O2 by hexanoate and by palmitoyl-L-carnitine was depressed to approximately half the control value: a highly significant difference. A comparable magnitude of depression was observed for stearoyl-, oleoyl-, and linoleoyl-L-carnitine. There were no major or consistent differences between groups of animals receiving two different types, and two different levels, of fat in their diet. 2. The activity of acyl coenzyme A dehydrogenase (EC 1.3.99.3) in hepatic mitochondrial fragments, measured by cytochrome c reduction with palmitoyl-coenzyme A as substrate, and expressed as maximum velocity (Vmax) with respect to phenazine methosulphate, was also reduced to approximately half the control value in deficient animals. 3. In hepatic microsomes, cytochrome b5 reductase (EC 1.6.2.2) activity was unaffected by riboflavin deficiency, although NADPH-cytochrome c reductase (EC 1.6.2.4) and microsomal flavin content were diminished to approximately half the control values. Acyl CoA (delta 9) desaturase activity (EC 1.14.99.5) was virtually identical in deficient, pair-fed, and ad lib.-fed control groups. 4. It is concluded that the depression of mitochondrial beta-oxidation of fatty acids which is observed in riboflavin-deficient animals is not a secondary result of inanition, and may account for the observed changes in fatty acid profiles of triglycerides and phospholipids. Failure of the microsomal fatty acid desaturation system is less likely to be a major consequence of riboflavin deficiency.
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PMID:Lipid metabolism in riboflavin-deficient rats. 2. Mitochondrial fatty acid oxidation and the microsomal desaturation pathway. 708 27

Rats were maintained on fat-free high carbohydrate diets either with or without orotic acid (1%, w/w), pantethine (1%, w/w), adenine (0.25%, w/w), and/or p-chlorophenoxyisobutyrate (0.25%, w/w). Oxidation of fatty acid by liver mitochondria was inhibited to less than half that of the control after administration of orotic acid. Activities of acyl-CoA dehydrogenases were markedly decreased by orotic acid administration, but the following enzyme activities were not, or only slightly decreased: acyl-CoA synthetase, carnitine acyltransferases, enoyl-CoA hydratase, 3-hydroxyacyl-CoA dehydrogenase and 3-ketoacyl-CoA thiolase. Simultaneous addition of pantethine in the orotic acid-containing diet prevented induction of fatty liver. It also prevented decreases in fatty acid oxidation capacity and acyl-CoA dehydrogenase activity. Introduction of adenine or p-chlorophenoxyisobutyrate, which reverse orotic acid-induced fatty liver, reversed oxidation and acyl-CoA dehydrogenase activities to control levels. The oxidation capacity of the peroxisomal system remained unchanged after administration of orotic acid.
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PMID:Reduction of beta-oxidation capacity of rat liver mitochondria by feeding orotic acid. 710 78

Weanling rats were fed a riboflavin-deficient diet. The mitochondrial fatty acid oxidation in liver was depressed in riboflavin deficiency but restored after supplementation of riboflavin. Among the enzymes involved in this system, only the acyl-CoA dehydrogenase (EC 1.3.99.2 and 1.3.99.3) activities varied with the change in fatty acid oxidation. An accumulation of the apoforms of acyl-CoA dehydrogenases was found in riboflavin deficiency. The levels of electron transfer flavoprotein and other enzymes involved in the beta-oxidation system remained unchanged. The peroxisomal fatty acid oxidation and levels of individual enzymes of this system remained constant. No accumulation of the apoform of acyl-CoA oxidase was observed under simple, riboflavin-deficient conditions. However, accumulation of a large amount of apo-acyl-CoA oxidase was observed when the peroxisomal system was induced by administration of a peroxisome proliferator, di(2-ethylhexyl)phthalate, under riboflavin-deficient conditions.
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PMID:Riboflavin deficiency and beta-oxidation systems in rat liver. 714 48

A number of recently described inherited disorders interfere with the oxidation of fatty acids. In these disorders at least three different metabolic steps may be affected: (1) transport of long chain fatty acids into the mitochondria as in carnitine deficiency and carnitine palmitoyl transferase deficiency (CPT); (2) multiple acyl CoA dehydrogenase deficiency or glutaric aciduria type II (GAII) due presumably to a defective common electron transfering flavoprotein or iron sulfur flavoprotein; (3) specific long or medium chain fatty acyl CoA dehydrogenase deficiency as in inherited dicarboxylic aciduria. In order to develop a system for the detection and the study of the consequences of defects such as these on the oxidation of fatty acids, we investigated the metabolism of oleate (18 carbons), octanoate (eight carbons) and butyrate (four carbons) in intact cultured fibroblasts from patients with CPT deficiency, GAII, and dicarboxylic aciduria. In CPT deficient cells there was a markedly deficient ability to oxidize [1-14C] and [U-14C] oleate (19 and 5% of normal, respectively), whereas oxidations of [1-14C] octanoate and [1,4-14C] succinate were significantly increased (150 and 222%, respectively), and [1-14C] butyrate oxidation was normal. GAII cells displayed a nearly complete defect in the oxidation of [1-14C] and [U-14C] oleate (8 and 1%, respectively), as well as of [1-14C] octanoate and [1-14C] butyrate (8 and 5% of normal, respectively). The oxidation of [1,4-14C] succinate by GAII cells was normal. Cells from a patient with dicarboxylic aciduria showed a significant reduction in [14CO2] production from [U-14C] oleate (57%) and [1-14C] octanoate (31%) and a normal oxidation of [1-14C] oleate, [1-14C] butyrate, and [1,4-14C] succinate. These observations are consistent with available information on the normal metabolism of fatty acids in liver and muscle and also with the hypothesis about the molecular localization of the defects in GAII and inherited dicarboxylic aciduria. They demonstrate that intact cultured skin fibroblasts represent a reliable and convenient model for the investigation of fatty acid oxidation in man. Many aspects of the human acyl CoA dehydrogenases and their physiologic functions remain unknown, among them the problem of their acyl chain length specificity. Studies in cultured fibroblasts from patients with presumed mutations affecting the metabolism of fatty acids provide a means for the elucidation of these defects and at the same time give information on normal metabolic functions. It appears likely that a number of previously unrecognized defects in this area of metabolism remain to be found. The availability of a model system for their study in cultured fibroblasts should facilitate their discovery.
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PMID:Oxidation of fatty acids in cultured fibroblasts: a model system for the detection and study of defects in oxidation. 714 11

The flavoenzyme pig kidney general acyl-CoA dehydrogenase (EC 1.3.99.3) is inactivated by cyclohexane-1,2-dione in borate buffer in a reaction that exhibits pseudo-first-order kinetics. Strong protection is afforded by the substrate octanoyl-CoA, as well as by heptadecyl-CoA, a potent competitive inhibitor of the dehydrogenase that does not reduce enzyme flavin. Enzyme exhibiting 10% residual activity in borate buffer contains about 1.3 modified arginine residues per flavin molecule. Very little reduction of the modified enzyme in borate buffer occurs at high concentrations of octanoyl-CoA, in marked contrast with the stoicheiometric reduction of the native enzyme. However, in phosphate buffer alone, the modified enzyme exhibits 55% residual activity and, although binding of substrate is still seriously impaired (apparent Kd=14 microM), excess substrate effects the formation of the characteristic reduced flavin X enoyl-CoA charge-transfer complex. These results suggest that the susceptible arginine residue, though not catalytically essential, is probably within the acyl-CoA-binding site of general acyl-CoA dehydrogenase.
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PMID:Modification of an arginine residue in pig kidney general acyl-coenzyme A dehydrogenase by cyclohexane-1,2-dione. 716 2

A zymogram method has been developed for fatty acyl CoA dehydrogenase and used to examine the electrophoretic properties of butyryl CoA dehydrogenase (BCD) from mouse tissues. A single form of BCD is present in extracts of liver, kidney, heart, and intestine. Ontogenetic, tissue distribution, and subcellular fractionation results are consistent with the mitochondrial origin previously reported for this enzyme. A genetic variant for BCD-1 was used to provide evidence for a locus determining the electrophoretic properties of this enzyme (designated Bcd-1), which is linked to Dao-1 (encoding D-amino acid oxidase).
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PMID:Genetics and ontogeny of butyryl CoA dehydrogenase in the mouse and linkage of Bcd-1 with Dao-1. 724 36

Pig kidney general acyl-CoA dehydrogenase is irreversibly inactivated by methylenecyclopropylacetyl-CoA, a metabolite of the hypoglycemic amino acid hypoglycin from Blighia sapida, to less that 2% of native activity. Octanoyl-CoA affords strong protection against this inhibition. During inactivation, about 80% of the enzyme FAD is covalently and irreversibly modified with the residual inhibition possibly resulting from modification of the protein. Denaturation of the inactivated enzyme yields several modified flavin derivatives in addition to about 20% unmodified FAD. From spectral comparison, the structure of one of these species is tentatively assigned to a derivative of 4a,5-dihydroflavin, while two further products resemble 6-, and 8-substituted flavins. These results suggest that methylenecyclopropylacetyl-CoA (and consequently the methylenecyclopropylmethano moiety of hypoglycin) be considered "suicide" substrates.
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PMID:Inactivation of general acyl-CoA dehydrogenase from pig kidney by a metabolite of hypoglycin A. 727 79

The interaction of two long-chain acyl-CoA analogs with pig kidney general acyl-CoA dehydrogenase (EC 1.3.99,3) was examined. The effect of S-heptadecyl-CoA and heptadecan-2-onyl-dethio-CoA on the flavo-protein was observed spectrophotometrically using the flavin as an active-site probe. The S-heptadecyl thioether analog bound strongly to the enzyme (Kd = 17 nM) and was a powerful competitive inhibitor (Ki less than 40 nM). In contrast to the thioether analog, the dethiocarba derivative, heptadecan-2-onyl-dethio-CoA, was a substrate inthe standard assay system being dehydrogenated at about 60% of the rate shown by palmitoyl-CoA. These results support the proposal that alpha-carbanion formation is an early event in the dehydrogenation of acyl-CoA substrates.
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PMID:Interaction of long-chain acyl-CoA analogs with pig kidney general acyl-CoA dehydrogenase. 728 23


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