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)

Kinetics of inactivation of general acyl-CoA dehydrogenase from pig kidney by methylenecyclopropaneacetyl-CoA have been analyzed using the theoretical treatment and exact steady-state kinetic solutions reported by Tatsunami (Tatsunami, S., Yago, N., and Hosoe, M. (1981) Biochim. Biophys. Acta 662, 226-235). Thus practical application of these analytical solutions for an important class of enzyme:substrate reactions has been demonstrated for the first time.
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PMID:Kinetics of suicide substrate:enzyme inactivation. Methylenecyclopropaneacetyl-CoA and general acyl-CoA dehydrogenase. 361 32

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

We have determined reduction potentials for porcine mitochondrial general fatty acyl-CoA dehydrogenase (GAD) and electron transfer flavoprotein (ETF) using an anaerobic spectroelectrochemical titration method. Computer simulation techniques were used to analyze the absorbance data. Nernst plots of the simulated data gave E'0, 7.1, quinone/semiquinone = -0.014 V and E'0, 7.1, semiquinone/hydroquinone = -0.036 V for ETF and E'0, 7.1, quinone/semiquinone = -0.155 V and E'0, 7.1, semiquinone/hydroquinone = -0.122 V for GAD. Using these techniques we have also determined a conditional reduction potential of -0.156 V for the chromophore producing fatty acyl-CoA substrate beta-2-furylpropionyl-CoA. From this value and our previous determination of the equilibrium constant for the transhydrogenation reaction between beta-2-furylpropionyl-CoA and the oxidized substrate crotonyl-CoA (Keq = 10.4), we have determined a reduction potential of -0.126 V for the butyryl-CoA/crotonyl-CoA couple. In light of the structural similarity between butyryl-CoA and octanoyl-CoA, the optimal substrate for GAD, the reduction potential for octanoyl-CoA should be similar to that for butyryl-CoA; i.e. fatty acyl-CoA substrates and GAD are essentially isopotential. The ability of octanoyl-CoA to reduce GAD quantitatively (Keq = 9.0) poses a dilemma in light of the nearly equal reduction potentials. We postulate that the stable charge-transfer complex formed between enzyme and optimal product is significantly lower in energy than enzyme and product and thus is responsible for pulling the reaction toward completion.
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PMID:Energetics of beta-oxidation. Reduction potentials of general fatty acyl-CoA dehydrogenase, electron transfer flavoprotein, and fatty acyl-CoA substrates. 371 Nov 5

The flavoprotein medium-chain acyl coenzyme A (acyl-CoA) dehydrogenase from pig kidney exhibits an intrinsic hydratase activity toward crotonyl-CoA yielding L-3-hydroxybutyryl-CoA. The maximal turnover number of about 0.5 min-1 is 500-1000-fold slower than the dehydrogenation of butyryl-CoA using electron-transferring flavoprotein as terminal acceptor. trans-2-Octenoyl- and trans-2-hexadecenoyl-CoA are not hydrated significantly. Hydration is not due to contamination with the short-chain enoyl-CoA hydratase crotonase. Several lines of evidence suggest that hydration and dehydrogenation reactions probably utilize the same active site. These two activities are coordinately inhibited by 2-octynoyl-CoA and (methylenecyclopropyl)acetyl-CoA [whose targets are the protein and flavin adenine dinucleotide (FAD) moieties of the dehydrogenase, respectively]. The hydration of crotonyl-CoA is severely inhibited by octanoyl-CoA, a good substrate of the dehydrogenase. The apoenzyme is inactive as a hydratase but recovers activity on the addition of FAD. Compared with the hydratase activity of the native enzyme, the 8-fluoro-FAD enzyme exhibits a roughly 2-fold increased activity, whereas the 5-deaza-FAD dehydrogenase is only 20% as active. A mechanism for this unanticipated secondary activity of the acyl-CoA dehydrogenase is suggested.
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PMID:Medium-chain acyl coenzyme A dehydrogenase from pig kidney has intrinsic enoyl coenzyme A hydratase activity. 375 34

The kinetic properties of general acyl-CoA dehydrogenase from pig kidney have been investigated using normal butyryl-CoA as well as an alpha-deutero, beta-deutero- and perdeutero-butyryl-CoA. In turnover catalysis, isotope effects of 2, 3.6, and 9 were found respectively. In the reductive half reaction the isotope effects were 2.5, 14, and 28 for the same substrates, and 21 for (2R,3R)-(2,3-D2)butyryl-CoA. No intermediates are apparent during the reduction of oxidized enzyme to the presumed complex of reduced enzyme and crotonyl-CoA. The results are interpreted as indicating a high degree of concertedness during the rupture of the alpha and beta C-H bonds. They are compatible with a mechanism in which simultaneously the alpha-hydrogen is abstracted as a proton, while the beta-hydrogen is transferred to the oxidized flavin as a hydride.
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PMID:Studies on the reaction mechanism of general acyl-CoA dehydrogenase. Determination of selective isotope effects in the dehydrogenation of butyryl-CoA. 376 16

3,4-Pentadienoyl-CoA, an allenic substrate analog, is a potent inhibitor of the flavoprotein pig-kidney general acyl-CoA dehydrogenase. The analog reacts very rapidly (k = 2.4 X 10(3) min-1) with the native oxidized enzyme to form a covalent flavin adduct probably involving the isoalloxazine position N-5. This species is inactive, but activity may be regained by two pathways. The allenic thioester can be displaced (k = 0.3 min-1) by a large excess of octanoyl-CoA substrate upon reversal of covalent adduct formation. Alternatively, the enzyme inactivator adduct slowly decomposes (t1/2 = 75 min) to form the strongly thermodynamically favoured 2,4-diene and catalytically active, oxidized enzyme. During this latter process 15-20% of the activity is irreversibly lost probably due to covalent modification of the protein. These data suggest that 3,4-pentadienoyl-CoA should be considered a suicide substrate of the acyl-CoA dehydrogenase. The mechanism of the reactions, and in particular the 3,4----2,4 tautomerization, are consistent with a catalytic sequence initiated by abstraction of an alpha-hydrogen as a proton.
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PMID:Studies with general acyl-CoA dehydrogenase from pig kidney. Inactivation by a novel type of "suicide" inhibitor, 3,4-pentadienoyl-CoA. 383 10

Acyl-CoA dehydrogenation deficiencies are defined as disorders of the metabolism of branched chain and straight chain acyl-CoA esters and of glutaryl-CoA. The acyl-CoA dehydrogenation process is comprised of three enzymes, i.e. acyl-CoA dehydrogenase (isovaleryl-CoA, isobutyryl-CoA/2-Me-butyryl-CoA, short-chain acyl-CoA, general (medium-chain) acyl-CoA, long-chain acyl-CoA or glutaryl-CoA), electron transfer flavoprotein (ETF) and electron transfer flavoprotein dehydrogenase (ETF DH). Patients with isovaleryl-CoA dehydrogenase deficiency, glutaryl-CoA dehydrogenase deficiency and general (medium-chain) acyl-CoA dehydrogenase deficiency have been reported. Assays for the enzymatic diagnosis in cells from such patients (especially cultured skin fibroblasts) have been developed and the different methods are reviewed. Patients with apparent defects in all acyl-CoA dehydrogenation processes, designated multiple acyl-CoA dehydrogenation deficiencies, have also been found. I. e. glutaric aciduria type II, ethylmalonicadipic aciduria and riboflavin responsive multiple acyl-CoA dehydrogenation defect. The enzymatic diagnosis has not yet been performed in any of these cases, but the different approaches in this respect are discussed. The excretion pattern of organic acids in urine from patients with acyl-CoA dehydrogenation deficiencies - as measured by means of gas chromatography/mass spectrometry - offers in most cases a tentative diagnosis of the enzyme defect. These excretion patterns are characterized by the presence in urine of different compounds originating from the primary accumulated acyl-CoA ester(s). The most important biochemical processes involved in the formation of these patterns seem to be glycine conjugation, omega-and omega-1-oxidation, carboxylation and dioxygenation. The enzymatic basis for these processes is discussed with respect to the enzyme affinities for acyl-CoA esters relevant to the acyl-CoA dehydrogenation deficiencies. And the knowledge gained from such affinity studies is used to explain the excretion pattern in the different patients, thus increasing the diagnostic power of the gas chromatographic/mass spectrometric analyses. The pathophysiological manifestations in patients with acyl-CoA dehydrogenation deficiencies resemble in many respect those seen in patients with Reye's syndrome, in which the fatty acid oxidation also seems to be compromised. Ethiological factors have not been identified in Reye's syndrome, but in many patients blood accumulation of short- and medium-chain fatty acids has been found.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:The acyl-CoA dehydrogenation deficiencies. Recent advances in the enzymic characterization and understanding of the metabolic and pathophysiological disturbances in patients with acyl-CoA dehydrogenation deficiencies. 389 50

The mechanisms of the initial interactions of three rat liver acyl-CoA dehydrogenases (short-chain, medium-chain, and long-chain acyl-CoA dehydrogenases) and their fatty acyl-CoA substrate were studied using enzyme-catalyzed deuterium exchange. The reaction products were identified and quantitated using mass spectroscopy and 1H-NMR. When fatty acyl-CoA substrates were incubated with catalytic amounts of acyl-CoA dehydrogenase in D2O in the absence of an electron acceptor, a rapid monodeuteration of the substrate occurred to replace one of the prochiral C-2 hydrogens, while no C-3 hydrogens were exchanged with deuterium. The C-2 monodeuteration proceeded to the extent of 80% of the total amount of substrate added at 90 min and almost to completion at 120 min. The pKa values and optimum pD values for the C-2 proton/deuteron exchange reactions were 6.0 and 7.5, respectively, for each of the three acyl-CoA dehydrogenases. The apparent turnover numbers were 3.0, 3.3, and 0.5 s-1 for short-chain, medium-chain, and long-chain acyl-CoA dehydrogenases, respectively. These results provide the first direct evidence for carbanion formation via abstraction of a C-2 hydrogen by a base in the enzyme, as the first step of the catalytic pathway of acyl-CoA dehydrogenation. When the acyl-CoA dehydrogenases were reacted with moderate excesses of acyl-CoA substrates in D2O in the absence of an electron acceptor, maximum bleaching of the FAD absorbance and the appearance of the long wavelength absorbance, attributed to a charge transfer complex, were observed. However, the dehydrogenation products, 2-enoyl-CoAs, were produced either not at all or in an amount which represented only a minor fraction of the amount of the enzyme added, while the substrates in the enzyme-substrate complexes rapidly turned over as indicated by the extensive monodeuteration which concomitantly occurred. Unlike previous hypothesis, these results indicate that the hydride ion transfer from C-3 of the substrate to the enzyme-FAD is not yet complete in the charge-transfer complex. The transfer of the hydride ion to alloxazine N-5 and the release of products are completed only in the presence of electron-transfer flavoprotein or another suitable electron acceptor.
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PMID:Mechanism of action of short-chain, medium-chain, and long-chain acyl-CoA dehydrogenases. Direct evidence for carbanion formation as an intermediate step using enzyme-catalyzed C-2 proton/deuteron exchange in the absence of C-3 exchange. 396 64

Mitochondrial 2-enoyl-CoA reductase from bovine liver was purified and characterized. A simple three-step purification was developed, involving ion-exchange chromatography to separate the bulk of the NADPH-dependent 2,4-dienoyl-CoA reductase, followed by chromatography on Blue Sepharose and adenosine 2',5'-bisphosphate-Sepharose. Homogeneous enzyme with a subunit Mr of 35 500 is obtained in 35% yield. The Mr of the native enzyme, determined by three different methods, yielded values that suggest that the enzyme is dimeric. NADPH is required as cofactor, and cannot be replaced by NADH. The activity of the purified enzyme towards 2-trans-double bonds in 2-monoene and 2,4-diene structures was investigated. 2-Enoyl-CoA reductase reduced the double bonds in a series of 2-trans-monoenoyl-CoA esters with different chain lengths, but did not exhibit significant activity towards 2-trans-double bonds of 2,4-dienoyl-CoA esters. This result is discussed in the light of analogous observations with enoyl-CoA hydratase.
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PMID:Purification and characterization of 2-enoyl-CoA reductase from bovine liver. 399 91


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