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)

A trifunctional beta-oxidation protein, designated TFP, was purified to apparent homogeneity from oleate-induced mycelia of Neurospora crassa. 2-Enoyl-CoA hydratase, L-3-hydroxyacyl-CoA dehydrogenase, and 3-hydroxyacyl-CoA epimerase activities copurified in constant ratios with this protein when crude extracts were subjected to cation-exchange, dye-ligand, and adsorption chromatography. Trifunctionality was substantiated by coinciding enzyme activity ratios during the last two purification steps and additional chromatographic steps. The enzyme was shown to be a 365-kDa tetramer of subunits with a molecular mass of 93 kDa. Several lines of evidence suggest that these subunits are identical. Monospecific antibodies raised against the homogenous protein specifically precipitated the three enzymatic activities of TFP. Immunoblotting of fractions obtained after sucrose density gradient centrifugation of a crude extract indicated that TFP was exclusively localized in glyoxysome-like microbodies. The beta-oxidation system of N. crassa is structurally related to those of peroxisomes despite the presence of an acyl-CoA dehydrogenase rather than an acyl-CoA oxidase. A mitochondrial 2-enoyl-CoA hydratase activity was separated from TFP and purified to apparent homogeneity. The absence of all other beta-oxidation activities from mitochondria suggests that this organelle and its 2-enoyl-CoA hydratase are not involved in fatty acid degradation in N. crassa.
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PMID:The beta-oxidation system in catalase-free microbodies of the filamentous fungus Neurospora crassa. Purification of a multifunctional protein possessing 2-enoyl-CoA hydratase, L-3-hydroxyacyl-CoA dehydrogenase, and 3-hydroxyacyl-CoA epimerase activities. 183 48

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

1. The effects of 3-, 4- and 5-thia-substituted fatty acids on mitochondrial and peroxisomal beta-oxidation have been investigated. When the sulphur atom is in the 4-position, the resulting thia-substituted fatty acid becomes a powerful inhibitor of beta-oxidation. 2. This inhibition cannot be explained in terms of simple competitive inhibition, a phenomenon which characterizes the inhibitory effects of 3- and 5-thia-substituted fatty acids. The inhibitory sites for 4-thia-substituted fatty acids are most likely to be the acyl-CoA dehydrogenase in mitochondria and the acyl-CoA oxidase in peroxisomes. 3. The inhibitory effect of 4-thia-substituted fatty acids is expressed both in vitro and in vivo. The effect in vitro is instantaneous, with up to 95% inhibition of palmitoylcarnitine oxidation. The effect in vivo, in contrast, is dose-dependent and increases with duration of treatment. 4. Pretreatment of rats with a 3-thia-substituted fatty acid rendered mitochondrial beta-oxidation less sensitive to inhibition by 4-thia-substituted fatty acids.
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PMID:Effects of thia-substituted fatty acids on mitochondrial and peroxisomal beta-oxidation. Studies in vivo and in vitro. 239 76

Peroxisomal and mitochondrial beta-oxidation of dicarboxylic acids (DCAs) were investigated and compared. When isolated hepatocytes were incubated with DCAs of various chain lengths, H2O2 was derived from peroxisomal beta-oxidation, the rates of its generation being comparable to those seen with monocarboxylic acids (MCAs), whereas the rates of ketone body production, a measure of mitochondrial beta-oxidation, were much lower than those with MCAs. Peroxisomal beta-oxidation measured by cyanide-insensitive NAD reduction exhibited similar chain-length specificities for both dicarboxylyl-CoAs (DC-CoAs) and monocarboxylyl-CoAs (MC-CoAs), except that the activities for DC-CoAs with 10-16 carbon atoms were about half of those of the corresponding MC-CoAs. In contrast, mitochondrial beta-oxidation measured by antimycin A-sensitive O2 consumption had no activity for DCAs. In the study with purified enzymes, the reactivities of mitochondrial carnitine palmitoyltransferase and acyl-CoA dehydrogenase for DC-CoAs were much lower than those for MC-CoAs, while the reactivity of peroxisomal acyl-CoA oxidase for DC-CoAs was comparable to that for the corresponding MC-CoAs. Accordingly, the properties of carnitine palmitoyltransferase and acyl-CoA dehydrogenase must be the rate-limiting factors for mitochondrial beta-oxidation, with the result that DCAs might hardly be oxidized in mitochondria. Comparative study of beta-oxidation capacities of peroxisomes and mitochondria in the liver showed that DC12-CoA was hardly subjected to mitochondrial beta-oxidation, and that the beta-oxidation of DCAs in rat liver, therefore, must be carried out exclusively in peroxisomes.
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PMID:Compartmentation of dicarboxylic acid beta-oxidation in rat liver: importance of peroxisomes in the metabolism of dicarboxylic acids. 291 48

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 peroxisomal beta-oxidation of omega-phenyl fatty acids (PFAs) as model compounds for xenobiotic acyl compounds was investigated. In isolated hepatocytes, omega-phenyllauric acid (PFA12) was chain-shortened to PFAs having an even number of carbon atoms in the acyl side chain. Associated with this reaction, H2O2 generation was observed, the rate of which was markedly enhanced by clofibrate treatment of rats. Also when using isolated peroxisomes, such a chain-shortening of PFA12 occurred, associated with stoichiometrical production of NADH and acetyl-CoA. The CoA-ester form of PFA12 as a substrate and NAD as a cofactor were required in this reaction, indicating the participation of peroxisomal beta-oxidation in the chain-shortening of PFA12. When using PFAs with various chain lengths, the rates of H2O2 generation measured as the peroxisomal beta-oxidation in isolated hepatocytes were similar to those with the corresponding fatty acids, whereas the rates of ketone body production measured as the mitochondrial beta-oxidation were much lower than that with any fatty acid examined. From the study with isolated mitochondria and purified enzymes, it was found that the mitochondrial beta-oxidation of PFAs was carnitine-dependent, and that the activities of carnitine palmitoyltransferase for PFA-CoAs are low. Moreover, the activities of acyl-CoA dehydrogenase for PFA-CoAs were lower than those for fatty acyl-CoAs, while the activities of acyl-CoA oxidase for PFA-CoAs were comparable to those for fatty acyl-CoAs. As a result, relatively long chain PFAs were hardly subjected to mitochondrial beta-oxidation. Based on the maximum enzyme activities of the beta-oxidation, which were measured by following acyl-CoA-dependent NAD reduction in isolated peroxisomes and O2 consumption in isolated mitochondria, about 60% of the beta-oxidation of PFA12 in the rat liver was peroxisomal. In clofibrate-treated rats, the value reached about 85%. From these results it is concluded that the peroxisome is one of the important sites of degradation of xenobiotic acyl compounds.
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PMID:Participation of peroxisomes in the metabolism of xenobiotic acyl compounds: comparison between peroxisomal and mitochondrial beta-oxidation of omega-phenyl fatty acids in rat liver. 365 89

Long-chain monocarboxylic, omega-hydroxymonocarboxylic and dicarboxylic acids were activated approximately at the same rate by rat liver homogenates into their CoA esters (2-3 U/g liver). These acyl-CoA were substrates for rat liver peroxisomal beta-oxidation. The distribution of the peroxisomal oxidation of these substrates was also studied in various tissues. Rat liver mitochondria were capable of oxidizing long-chain monocarboxyl- and omega-hydroxymonocarboxylyl-CoAs but not dicarboxylyl-CoAs. When the mitochondrial preparations were incubated in coupling conditions, the addition of either free decanoic acid or free 10-hydroxydecanoic acid resulted in an increase of the oxygen uptake conversely to the addition of decanedioic acid. The comparative study of the chain-length substrate specificity of peroxisomal fatty acyl-CoA oxidase and mitochondrial fatty acyl-CoA dehydrogenase activities revealed that, actually, both types of organelles, peroxisomes and mitochondria, contain "oxido-reductases" active on long-chain monocarboxylyl-CoAs, omega-hydroxymonocarboxylyl-CoAs and dicarboxylyl-CoAs.
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PMID:Interactions between the omega- and beta-oxidations of fatty acids. 366 64

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

The activities of hepatic fatty acid oxidation enzymes in rats fed perilla oil rich in alpha-linolenic acid (alpha-18:3) were compared with those fed saturated fats or safflower oil (the mixture of safflower oil and olive oil, 94:8, w/w) containing the same amount of polyunsaturated fatty acids with perilla oil exclusively as linoleic acid (18:2). When the rats were fed the diets containing 15% coconut, safflower, and perilla oils for 1 week, the rate of mitochondrial and peroxisomal oxidation of palmitoyl-CoA (16:0-CoA) in the liver homogenates was the highest in rats fed perilla oil. Among the rats fed the diets containing 15% palm, safflower, and perilla oils for 2 weeks, the rates of mitochondrial and peroxisomal oxidations of 16:0-, 18:2-, and alpha-18:3-CoAs were the highest in rats fed perilla oil, and the rate of oxidation of alpha-18:3-CoA by both pathways was higher than those of other acyl-CoAs in all groups. Dietary perilla oil relative to palm and safflower oils significantly increased the activities of carnitine palmitoyltransferase, acyl-CoA dehydrogenase, acyl-CoA oxidase, and 2,4-dienoyl-CoA reductase. The substrate specificity of carnitine palmitoyltransferase appeared to be responsible for differential rates of the mitochondrial oxidation of acyl-CoAs. The substrate specificity of acyl-CoA oxidase did not account for the preferential peroxisomal oxidation of alpha-18:3 relative to 18:2. The preferential mitochondrial and peroxisomal beta-oxidation of alpha-18:3-CoA relative to 16:0- and 18:2-CoAs was also confirmed in rats fed laboratory chow irrespective of the substrate/albumin ratios in the assay mixture. It was suggested that both substrate specificities and alterations in the activities of the enzymes in beta-oxidation pathway play a significant role in the regulation of the serum lipid concentrations in rats fed a diet rich in alpha-18:3.
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PMID:Stimulation of the activities of hepatic fatty acid oxidation enzymes by dietary fat rich in alpha-linolenic acid in rats. 872 10

Very-long-chain acyl-CoA dehydrogenase (VLCAD) is one of four straight-chain acyl-CoA dehydrogenase (ACD) enzymes, which are all nuclear encoded mitochondrial flavoproteins catalyzing the initial step in fatty acid beta-oxidation. We have used the very fast, Rapid Amplification of cDNA Ends (RACE) based strategy to obtain the sequence of cDNAs encoding human VLCAD from placenta and fibroblasts. Alignment of the predicted amino acid sequence of human VLCAD with those of the other human ACD enzymes revealed extensive sequence homology. Moreover, human VLCAD and human acyl-CoA oxidase showed extensive sequence homology corroborating the notion that these genes are evolutionarily related. Southern blot analysis of genomic DNA from hybrid cell lines was used to localize the VLCAD gene to human chromosome 17p11.2-p11.13105. Using Northern and Western blot analysis to investigate the tissue specific distribution of VLCAD mRNA and protein in several human tissues we showed that VLCAD is most abundant in heart and skeletal muscle. This agrees well with the fact that cardiac and muscle symptoms are characteristic for patients with VLCAD deficiency. Northern blot analysis and sequencing of cloned PCR amplified VLCAD cDNA from four unrelated patients with VLCAD deficiency showed that VLCAD mRNA was undetectable in one patient and that the other three have mutations in both VLCAD alleles. Western blot analysis of patient fibroblasts showed that the identified mutations result in severely reduced amounts of VLCAD protein. None of the patients harbored identical mutations suggesting that the mutational heterogeneity in VLCAD deficiency is large.
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PMID:Cloning and characterization of human very-long-chain acyl-CoA dehydrogenase cDNA, chromosomal assignment of the gene and identification in four patients of nine different mutations within the VLCAD gene. 884 38


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