Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.3.99.3 (acyl-CoA dehydrogenase)
 1,425 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The free fatty acid and total fatty acid profiles in plasma of nine patients with medium-chain acyl-CoA dehydrogenase (MCAD) deficiency, two with very-long-chain acyl-CoA dehydrogenase (VLCAD) deficiency and two with mild-type multiple acyl-CoA dehydrogenase (MAD-m) deficiency, were analyzed by gas chromatography-mass spectrometry. In the plasma of patients with MCAD deficiency we found increases of octanoic acid (8:0), decanoic acid (10:0), 4-decenoic acid (10:1 omega 6), and 4,7-decadienoic acid (10:2 omega 3), all present almost exclusively in free form. The patients with VLCAD deficiency showed increases of mainly 5-tetradecenoic acid (14:1 omega 9) and to a minor extent 5-dodecenoic acid (12:1 omega 7), 5,8-tetradecadienoic acid (14:2 omega 6), and 7,10-hexadecadienoic acid (16:2 omega 6), in both the free and esterified fatty acid fraction. The MAD-m patients showed variable increases of all the unusual fatty acids present in MCAD- and VLCAD-deficient plasma. The 14:1 omega 9, 14:2 omega 6, and 16:2 omega 6 fatty acids were present mainly in the esterified form. Measurement of these fatty acids in plasma by the relatively simple method presented here provides a sensitive and specific aid in the diagnosis of acyl-CoA dehydrogenase deficiency disorders.
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PMID:Identification and quantification of intermediates of unsaturated fatty acid metabolism in plasma of patients with fatty acid oxidation disorders. 758 19

The accumulation of beta-oxidation intermediates was studied by incubating normal and beta-oxidation enzyme-deficient human fibroblasts with [2H4]linoleate and L-carnitine and analyzing the resultant acylcarnitines by tandem mass spectrometry. Labeled decenoyl-, octanoyl-, hexanoyl-, and butyrylcarnitines were the only intermediates observed with normal cells. Intermediates of longer chain length, corresponding to substrates for the beta-oxidation enzymes associated with the inner mitochondrial membrane, were not observed unless a cell line was deficient in one of these enzymes, such as very-long-chain acyl-CoA dehydrogenase, long-chain 3-hydroxyacyl-CoA dehydrogenase, or electron transfer flavoprotein dehydrogenase. Matrix enzyme deficiencies, such as medium- and short-chain acyl-CoA dehydrogenases, were characterized by elevated concentrations of intermediates corresponding to their respective substrates (octanoyl- and decenoylcarnitines in medium-chain acyl-CoA dehydrogenase deficiency and butyrylcarnitine in short-chain acyl-CoA dehydrogenase deficiency). These observations agree with the notion of intermediate channeling due to the organization of beta-oxidation enzymes in complexes. The only exception is the incomplete channeling from thiolase to acyl-CoA dehydrogenase in the matrix. This situation may be a consequence of only one 3-ketoacyl-CoA thiolase being unable to interact with the several acyl-CoA dehydrogenases in the matrix.
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PMID:Evidence for intermediate channeling in mitochondrial beta-oxidation. 782 75

Long-chain acyl-CoA dehydrogenase (LCAD) deficiency is a disorder of fatty acid beta-oxidation. Its diagnosis has been made based on the reduced activity of palmitoyl-CoA dehydrogenation, i.e., in fibroblasts. We previously showed that in immunoblot analysis, an LCAD band of normal size and intensity was detected in fibroblasts from all LCAD-deficient patients tested. In the present study, we amplified via polymerase chain reaction and sequenced LCAD cDNA from three of these LCAD-deficient cell lines, and found perfectly normal LCAD sequences in two of them, indicating that at least these patients were not deficient in LCAD. The third patient was homozygous for an A to C substitution at 997, although it is unknown whether or not 997-C is a normal polymorphism. Although the LCAD sequence data were puzzling, a new enzyme, very-long-chain acyl-CoA dehydrogenase (VLCAD), was recently identified. Because VLCAD also has high activity with palmitoyl-CoA as substrate, it was possible that defective VLCAD may cause reduced palmitoyl-CoA dehydrogenating activity. We performed immunoblot analysis of VLCAD in six "LCAD-deficient" patients; VLCAD was negative in three of them, two of whom had a normal LCAD cDNA sequence. These results indicated that a considerable number of the patients who had previously been diagnosed as having LCAD deficiency in fact have VLCAD deficiency.
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PMID:Identification of very-long-chain acyl-CoA dehydrogenase deficiency in three patients previously diagnosed with long-chain acyl-CoA dehydrogenase deficiency. 835 11

Amniocytes isolated from two pregnancies at risk for fatty acid oxidation defects were incubated with stable isotopically labelled palmitate, in the presence of L-carnitine, to probe that pathway. The labelled acylcarnitines were then quantitated using tandem mass spectrometry. Amniocytes from a pregnancy at risk for medium-chain acyl-CoA dehydrogenase (MCAD) deficiency produced a characteristic acylcarnitine profile with increased levels of octanoylcarnitine and decanoylcarnitine, indicative of MCAD deficiency. DNA analysis confirmed that the fetus was homozygous for the MCAD A985G mutation. Acylcarnitine and DNA analysis of the infant's blood obtained post-partum confirmed MCAD deficiency. Amniocytes from a pregnancy at risk for an unspecified fat oxidation defect produced increased levels of long-chain acylcarnitines consistent with a deficiency in very-long-chain acyl-CoA dehydrogenase (VLCAD). Measurements of the enzymatic activity confirmed VLCAD deficiency in amniocytes. Acylcarnitine profiles of the infant's blood obtained post-partum in addition to enzyme activities measured in fibroblasts confirmed VLCAD deficiency. The successful prenatal diagnosis of VLCAD and MCAD deficiencies using in vitro probes of fatty acid oxidation in fibroblasts suggests that this approach can potentially recognize many mitochondrial fatty acid oxidation defects even if no prior diagnosis is determined in the family at risk.
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PMID:Prenatal diagnosis of mitochondrial fatty acid oxidation defects. 865 Jan 21

We present a new derivatization procedure for the simultaneous gas chromatographic-mass spectrometric analysis of free fatty acids and 3-hydroxyfatty acids in plasma. Derivatization of target compounds involved trifluoroacetylation of hydroxyl groups and tert-butyldimethylsilylation of the carboxyl groups. This new derivatization procedure had the advantage of allowing the complete baseline separation of free fatty acids and 3-hydroxyfatty acids while the superior gas chromatographic and mass spectrometric properties of tert-butyldimethylsilyl derivatives remained unchanged, permitting a sensitive analysis of the target compounds. Thirty-nine plasma samples from control subjects and patients with known defects of mitochondrial fatty acid beta-oxidation were analyzed. A characteristic increase of long-chain 3-hydroxyfatty acids was observed for all of the long-chain 3-hydroxyacyl-CoA dehydrogenase-deficient and mitochondrial trifunctional protein-deficient plasma samples. For medium-chain acyl-CoA dehydrogenase deficiency and very-long-chain acyl-CoA dehydrogenase deficiency, decenoic and tetradecenoic acids, respectively, were the main abnormal fatty acids, whereas the multiple acyl-CoA dehydrogenase-deficient patients showed variable increases of these unusual intermediates. The results showed that this selective and sensitive method is a powerful tool in the diagnosis and monitoring of mitochondrial fatty acid beta-oxidation disorders.
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PMID:Simultaneous analysis of plasma free fatty acids and their 3-hydroxy analogs in fatty acid beta-oxidation disorders. 951 Aug 49

Among the many disorders of fatty acid beta-oxidation known today, the disorders of long-chain fatty acid oxidation are the most severe and life-threatening. One remarkable abnormality, not observed in, for instance, medium-chain acyl-CoA dehydrogenase deficiency, is the moderate to severe lactic acidaemia in long-chain fatty acid beta-oxidation-deficient patients, suggesting that oxidation of pyruvate is also compromised. In order to understand the underlying basis of the lactic acidaemia in these patients, we have studied the formation of L-lactate and pyruvate in cultured skin fibroblasts incubated with D-glucose. All long-chain fatty acid beta-oxidation-deficient cell lines studied were found to show a moderate elevation of lactate when compared with control and medium-chain acyl-CoA dehydrogenase-deficient fibroblasts. Interestingly, differences were found between cells deficient in long-chain 3-hydroxyacyl-CoA dehydrogenase and very-long-chain acyl-CoA dehydrogenase, suggesting that saturated acyl-CoA esters and their 3-hydroxyacyl-CoA derivatives affect pyruvate metabolism differently.
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PMID:Lactic acidosis in long-chain fatty acid beta-oxidation disorders. 976

The consequences of two amino acid polymorphisms of human electron transfer flavoprotein (alpha-T/I171 in the alpha-subunit and beta-M/T154 in the beta-subunit) on the thermal stability of the enzyme are described. The alpha-T171 variant displayed a significantly decreased thermal stability, whereas the two variants of the beta-M/T154 polymorphism did not differ. We wished to test the hypothesis that these polymorphisms might constitute susceptibility factors and therefore determined their allele and genotype frequencies in (i) control individuals, (ii) medium-chain acyl-CoA dehydrogenase-deficient patients homozygous for the K304E mutation (MCAD E304), (iii) a group of patients with elevated urinary excretion of ethylmalonic acid (EMA) possibly due to decreased short-chain acyl-CoA dehydrogenase activity, and (iv) in patients with proven deficiency of very-long-chain acyl-CoA dehydrogenase (VLCAD). No significant overrepresentations or underrepresentations were found in the first two patient groups, suggesting that the polymorphisms studied are not significant susceptibility factors in either the MCAD E304 or the EMA patient group. However, in the VLCAD deficient patients the alpha-T171 variant (decreased thermal stability) was significantly overrepresented. Subgrouping of the VLCAD patients into three phenotypic classes (severe childhood, mild childhood, and adult presentation) revealed that the overrepresentation of the alpha-T171 variant was significant only in patients with mild childhood presentation. This is compatible with a negative modulating effect of the less-stable alpha-T171 ETF variant in this group of VLCAD patients that harbor missense mutations in at least one allele and therefore potentially display residual levels of VLCAD enzyme activity.
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PMID:A polymorphic variant in the human electron transfer flavoprotein alpha-chain (alpha-T171) displays decreased thermal stability and is overrepresented in very-long-chain acyl-CoA dehydrogenase-deficient patients with mild childhood presentation. 1035 13

The enzymes of mitochondrial beta-oxidation are thought to be organized in at least two functional complexes, a membrane-bound, long-chain-specific beta-oxidation system and a matrix system consisting of soluble enzymes with preferences for medium-chain and short-chain substrates. This hypothesis is supported by the observation that the inactivation of long-chain 3-ketoacyl-CoA thiolase by 4-bromotiglic acid (4-bromo-2-methylbut-2-enoic acid) causes the complete inhibition of palmitate beta-oxidation even though 3-ketoacyl-CoA thiolase, which acts on 3-ketopalmitoyl-CoA, remains partly active. The observed substrate specificities of long-chain acyl-CoA dehydrogenase (LCAD) and very-long-chain acyl-CoA dehydrogenase prompt the suggestion that LCAD is a functional component of the long-chain-specific beta-oxidation system. Altogether, a view is emerging of the organization of beta-oxidation enzymes in mitochondria that supports the idea of intermediate channelling and explains the apparent absence of true intermediates of beta-oxidation from mitochondria.
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PMID:Impact of the intramitochondrial enzyme organization on fatty acid oxidation. 1135 67

The degradation of unsaturated fatty acids was examined in fibroblasts from 16 patients with very-long-chain acyl-CoA dehydrogenase (VLCAD) deficiency. Analysis of acylcarnitine intermediates following incubation of intact human cells with these compounds revealed that the milder clinical phenotypes could be distinguished from the severe cardiomyopathic phenotype. These findings may reflect more effective contributions of alternate pathways in the milder forms of the disease. Incubation of VLCAD-deficient cells with cis-9 or trans-9 unsaturated fatty acids indicate that VLCAD is largely responsible for the 2,3-dehydrogenation of cis-5 or trans-5 intermediates in fibroblasts. The first two cycles of beta-oxidation with oleic and linoleic acids occur in the absence of VLCAD activity suggesting the presence of an additional acyl-CoA dehydrogenase or alternate pathway for the oxidation of these unsaturated fatty acids. These observations have clinical relevance for determining diagnosis, prognosis and strategies for dietary treatment of these patients.
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PMID:Oxidation of unsaturated fatty acids by human fibroblasts with very-long-chain acyl-CoA dehydrogenase deficiency: aspects of substrate specificity and correlation with clinical phenotype. 1158 Sep 10

We hypothesized that liver fatty acid oxidation (FAO) is compromised in the leptin-deficient obese (Lep(ob)/Lep(ob)) mouse model, and that this would be further challenged when these mice were fed a high-fat diet. Obese mice had a 3.8-fold increased body fat content and a 9-fold increased liver fat content as compared to control mice when both groups were fed a low-fat diet. The expression of liver FAO enzymes, carnitine palmitoyltransferase-1a, long-chain acyl-CoA dehydrogenase, medium-chain acyl-CoA dehydrogenase, and short-chain acyl-CoA dehydrogenase, was not affected in obese mice as compared to controls on either a low-fat or a high-fat diet. The expression of very-long-chain acyl-CoA dehydrogenase was elevated in obese mice on the control diet, as compared to control mice. For all measures evaluated, increasing the level of fat in the diet had a smaller effect than leptin deficiency. In summary, despite obese mice having an excess of fat available for mitochondrial beta-oxidation in liver, overall energy balance appeared to dictate that the net liver FAO remained at control levels.
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PMID:Evaluation of liver fatty acid oxidation in the leptin-deficient obese mouse. 1191 33


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