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)

The beta-oxidation of long chain fatty acids was investigated in a preparation of rat heart mitochondria. The acyl-CoA esters of the cis and trans isomers of delta9-hexadecenoic, delta9-octadecenoic, delta11-eicosenoic, and delta13-docosenoic acids were prepared. Rates of the acyl-CoA reaction were determined with an extract from rat heart mitochondria. The apparent Michaelis constant (Km) and maximum velocity (Vmax) were calculated for each substrate. In general, apparent Vmax values decreased with increasing chain length of the monoenoic substrates. Reduced activity of acyl-CoA dehydrogenase with long chain acyl-CoA esters could have contributed to accumulation of lipids in hearts of rats fed diets containing long chain fatty acids.
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PMID:Studies on long chain cis- and trans-acyl-CoA esters and Acyl-CoA dehydrogenase from rat heart mitochondria. 84 1

We have used radio-high pressure liquid chromatography to study the acyl-CoA ester intermediates and the acylcarnitines formed during mitochondrial fatty acid oxidation. During oxidation of [U-14C]hexadecanoate by normal human fibroblast mitochondria, only the saturated acyl-CoA and acylcarnitine esters can be detected, supporting the concept that the acyl-CoA dehydrogenase step is rate-limiting in mitochondrial beta-oxidation. Incubations of fibroblast mitochondria from patients with defects of beta-oxidation show an entirely different profile of intermediates. Mitochondria from patients with defects in electron transfer flavoprotein and electron transfer flavoprotein:ubiquinone oxido-reductase are associated with slow flux through beta-oxidation and accumulation of long chain acyl-CoA and acylcarnitine esters. Increased amounts of saturated medium chain acyl-CoA and acylcarnitine esters are detected in the incubations of mitochondria with medium chain acyl-CoA dehydrogenase deficiency, whereas long chain 3-hydroxyacyl-CoA dehydrogenase deficiency is associated with accumulation of long chain 3-hydroxyacyl- and 2-enoyl-CoA and carnitine esters. These studies show that the control strength at the site of the defective enzyme has increased. Radio-high pressure liquid chromatography analysis of intermediates of mitochondrial fatty acid oxidation is an important new technique to study the control, organization and defects of the enzymes of beta-oxidation.
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PMID:Quantitation of acyl-CoA and acylcarnitine esters accumulated during abnormal mitochondrial fatty acid oxidation. 174 86

Urinary organic acid profiles in patients with inherited defects of fatty acid metabolism and ketogenesis are described. Medium-chain acyl-CoA dehydrogenase, short-chain acyl-CoA dehydrogenase, multiple acyl-CoA dehydrogenase, and 3-hydroxy-3-methyl-glutaryl-CoA lyase deficiencies can be recognized at the metabolite level. Data on long-chain acyl-CoA dehydrogenase and systemic carnitine deficiencies are scarce. In the latter disorders, dicarboxylic aciduria is rather nonspecific and points to a modest omega-oxidation of long chain fatty acids.
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PMID:Chemical diagnosis of inherited defects of fatty acid metabolism and ketogenesis. 332 28

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

Fatty acyl-CoA dehydrogenase deficiencies are defined as disorders of the metabolism of straight chain acyl-CoA esters at the level of short chain acyl-CoA, general (medium chain) acyl-CoA and long chain acyl-CoA dehydrogenases. Patients with proven or indicated defects in either general (medium chain) or long chain acyl-CoA dehydrogenase have been reported. In recent years assays for the enzymatic diagnosis in cells, especially cultured skin fibroblasts, from such patients have been developed. The different methods are reviewed. The urinary excretion profile of organic acids from patients with fatty acyl-CoA dehydrogenase deficiencies are characterized by the presence of different compounds originating from the primary accumulated acyl-CoA ester(s). The most important biochemical processes involved in the formation of these compounds are glycine conjugation and omega/omega-1 oxidation. The biochemistry of these pathways is discussed and the knowledge gained from in vitro and in vivo studies is used to explain the excretion pattern in some of the patients with general (medium chain) acyl-CoA dehydrogenase deficiency.
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PMID:Fatty acyl-CoA dehydrogenase deficiency: enzyme measurement and studies on alternative metabolism. 643 41

Three straight chain acyl-CoA dehydrogenases were purified to apparent homogeneity from bovine liver using 40-70% (NH4)2SO4 precipitation, gel filtration, DEAE-cellulose column chromatography, and preparative electrophoresis. Separation of the acyl-CoA dehydrogenases by these procedures has been efficiently monitored by two newly developed analytical methods: (i) native staining of acyl-CoA dehydrogenases following separation by electrophoresis in polyacrylamide gels and (ii) determination of general acyl-CoA dehydrogenase by means of a specific substrate, 4-cis-decenoyl-CoA. The three acyl-CoA dehydrogenases were classified into short chain, general, and long chain acyl-CoA dehydrogenases on the basis of their chain length specificities according to the nomenclature proposed by Hall and Kamin (Hall, C. L., and Kamin, H. (1975) J. Biol. Chem. 250, 3470-3486). The enzymes gave single protein bands in polyacrylamide gel electrophoresis under denaturing and nondenaturing conditions, and their subunit and native molecular weights were estimated to be 40,300 and 188,000 for short chain acyl-CoA dehydrogenase, 43,300 and 205,000 for general acyl-CoA dehydrogenase, and 45,200 and 172,000 for long chain acyl-CoA dehydrogenase. Long chain and general acyl-CoA dehydrogenases markedly differed in their substrate specificities toward unsaturated acyl-CoA esters with a double bond at position 4. The former oxidized 4-cis-decenoyl-CoA at a rate of only 2.7% of that obtained with decanoyl-CoA as substrate, while for the latter enzyme 4-cis-decenoyl-CoA was even a slightly better substrate than decanoyl-CoA. 2-trans,4-cis-Decenoyl-CoA was identified as the product of this reaction.
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PMID:Purification and properties of acyl coenzyme A dehydrogenases from bovine liver. Formation of 2-trans,4-cis-decadienoyl coenzyme A. 654 82

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

Three acyl-CoA dehydrogenases and electron transfer flavoprotein, which catalyze the initial step of mitochondrial fatty acid beta-oxidation, were purified from livers of rats fed a diet containing di(2-ethylhexyl)phthalate. Three acyl-CoA dehydrogenases, classified into short chain, general, and long chain acyl-CoA dehydrogenases on the basis of their substrate specificities, each consisted of four subunits of identical size: the molecular weights of the native enzymes were 169,000 for short chain acyl-CoA dehydrogenase, 182,000 for general acyl-CoA dehydrogenase, and 168,000 for long chain acyl-CoA dehydrogenase. Electron transfer flavoprotein with a molecular weight of 57,000 consisted of heterogeneous subunits with molecular weight of 33,500 and 25,100. The catalytic properties and molecular structures of rat liver acyl-CoA dehydrogenases were similar to those of the enzymes purified from other mammalian tissues such as pig heart, pig liver, and beef kidney. We could not obtain purified preparations of the three acyl-CoA dehydrogenases from livers of the control rats although the three dehydrogenases were completely separated from each other. The enzymes from the control and the di(2-ethylhexyl)phthalate-treated rats were compared and no differences were found in molecular sizes of the native enzymes and of their subunits, substrate specificities and immunochemical reactivities.
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PMID:Purification and properties of rat liver acyl-CoA dehydrogenases and electron transfer flavoprotein. 733 8

We have used molecular modeling and site-directed mutagenesis to identify the catalytic residues of human long chain acyl-CoA dehydrogenase. Among the acyl-CoA dehydrogenases, a family of flavoenzymes involved in beta-oxidation of fatty acids, only the three-dimensional structure of the medium chain fatty acid specific enzyme from pig liver has been determined (Kim, J.-J.P., Wang, M., & Paschke, R. (1993) Proc. Natl. Acad. Sci. U.S.A. 90, 7523-7527). Despite the overall sequence homology, the catalytic residue (E376) of medium chain acyl-CoA dehydrogenase is not conserved in isovaleryl- and long chain acyl-CoA dehydrogenases. A molecular model of human long chain acyl-CoA dehydrogenase was derived using atomic coordinates determined by X-ray diffraction studies of the pig medium chain specific enzyme, interactive graphics, and molecular mechanics calculations. The model suggests that E261 functions as the catalytic base in the long-chain dehydrogenase. An altered dehydrogenase in which E261 was replaced by a glutamine was constructed, expressed, purified, and characterized. The mutant enzyme exhibited less than 0.02% of the wild-type activity. These data strongly suggest that E261 is the base that abstracts the alpha-proton of the acyl-CoA substrate in the catalytic pathway of this dehydrogenase.
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PMID:Identification of the catalytic base in long chain acyl-CoA dehydrogenase. 815 43

Short chain (SCAD), medium chain (MCAD), and long chain acyl-CoA dehydrogenases (LCAD) catalyze the first step of fatty acid oxidation, while isovaleryl-CoA dehydrogenase (IVD) is involved in leucine oxidation. They are homologous flavoproteins belonging to the acyl-CoA dehydrogenase (ACD) family. Electron transfer flavoprotein (ETF) serves as an obligatory electron acceptor for these reactions. We demonstrated that the expression of SCAD, MCAD, and LCAD and the alpha-subunit of ETF (alpha-ETF) showed a similar developmental pattern, while that of IVD was distinctly different from others. The ontogenic pattern of each enzyme in the liver differed distinctly from that in the heart. The degree of glucagon-enhanced ACD expression in vivo and in vitro in both the liver and heart was especially high in fasted rats. Dexamethasone induced all ACD mRNAs in the heart. In contrast, it strongly suppressed mRNAs of all ACDs and alpha-ETF mRNA in the liver, except IVD mRNA. Dexamethasone induced IVD mRNA in both the liver and heart. Starvation strongly stimulated expression of all five genes in various tissues, with the highest in the heart, except the IVD gene which was down-regulated. The degree of induction by 3-day starvation differed in different age groups of rats. Feeding the rats a fat-free diet for 7 days caused a marked increase of IVD mRNA in the heart, whereas the high fat diet for the same period resulted in a severe decrease of the same degree, suggesting a protein-sparing mechanism. However, these manipulations of dietary fat content had little effect on the expression of other ACD genes.
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PMID:Developmental, nutritional, and hormonal regulation of tissue-specific expression of the genes encoding various acyl-CoA dehydrogenases and alpha-subunit of electron transfer flavoprotein in rat. 822 58


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