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)

Five distinct acyl-CoA dehydrogenases are currently known. These are short, medium, long and 2-methyl-branched-chain acyl-CoA dehydrogenases, and isovaleryl-CoA dehydrogenase. We tested these five acyl-CoA dehydrogenases for their ability to dehydrogenate valproyl-CoA using pure enzyme preparations isolated from rat liver mitochondria. The activities of the pure human short-chain, medium-chain and isovaleryl enzymes purified from post-mortem livers, and a long-chain acyl-CoA dehydrogenase preparation partially purified from placental mitochondria, were also tested. Valproyl-CoA was dehydrogenated at a significant rate (0.167 mumol/min per mg protein) only by rat 2-methyl-branched-chain acyl-CoA dehydrogenase. Human 2-methyl-branched-chain acyl-CoA dehydrogenase has not been purified; therefore, it could not be tested. Since four other human acyl-CoA dehydrogenases did not dehydrogenate isobutyryl-CoA, 2-methylbutyryl-CoA (obligatory intermediates from valine and isoleucine, respectively) nor valproyl-CoA, it is reasonable to assume that valproyl-CoA is dehydrogenated by 2-methyl-branch-chain acyl-CoA dehydrogenase in man as well. We identified 2-propyl-2-pentenoyl-CoA as the reaction product from valproyl-CoA by mass spectral analysis of the acyl moiety. Valproyl-CoA, at 0.3 mM, moderately inhibited human acyl-CoA dehydrogenases with the exception of the long-chain enzyme. 5 mM free valproic acid inhibited the activities of various acyl-CoA dehydrogenases only very weakly.
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PMID:The enzymatic basis for the metabolism and inhibitory effects of valproic acid: dehydrogenation of valproyl-CoA by 2-methyl-branched-chain acyl-CoA dehydrogenase. 211 56

Inactivation of five distinct acyl-CoA dehydrogenases by (methylenecyclopropyl)acetyl-CoA (MCPA-CoA), the toxic metabolite of hypoglycin from unripe ackee fruit, was investigated using purified enzyme preparations. Short-chain acyl-CoA (SCADH), medium-chain acyl-CoA (MCADH) and isovaleryl-CoA (IVDH) dehydrogenases were severely and irreversibly inactivated by MCPA-CoA, while 2-methyl-branched chain acyl-CoA dehydrogenase (2-meBCADH) was only slowly and mildly inactivated. Long-chain acyl-CoA dehydrogenase (LCADH) was not significantly inactivated, even after prolonged incubation with MCPA-CoA. Inactivation of SCADH, MCADH and IVDH was effectively prevented by the addition of substrate. This mode of inactivation by MCPA-CoA explains the urinary metabolite profile in hypoglycin treated-rats, which includes large amounts of metabolites from fatty acids and leucine, and relatively small amounts of those from valine and isoleucine. Spectrophotometric titration of SCADH and MCADH with MCPA-CoA, together with the protective effects of substrate, indicates that MCPA-CoA is acted upon by, and exerts in turn irreversible inactivation of, SCADH and MCADH, confirming that MCPA-CoA is a suicide inhibitor (Wenz et al. (1981) J. Biol. Chem. 256, 9809-9812). Spectrophotometric titration data of LCADH and MCPA-CoA is typical of non-reacting CoA ester.
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PMID:Selective inactivation of various acyl-CoA dehydrogenases by (methylenecyclopropyl)acetyl-CoA. 233 85

Pig kidney medium-chain acyl-CoA dehydrogenase (EC 1.3.99.3) is irreversibly and stoichiometrically inactivated by [1-14C]-2-octynoyl coenzyme A. The linkage is stable at pH 2-6, but labile under basic conditions. The inhibitor labels a unique tryptic peptide, Ile-Tyr-Gln-Ile-Tyr-Glu-Gly-Thr-Ala-Gln-Ile-Gln-Arg, close to the C-terminus of the protein. The peptide is labeled at Glu-401 with the acyl moiety of the inhibitor but does not contain detectable coenzyme A. Both the inactivation of the dehydrogenase and the appearance of an absorption band at 800 nm show large primary deuterium isotope effects using 4,4'-dideuterio-2-octynoyl-CoA (7.3 and 6.3, respectively). Thus, 2-octynoyl-CoA is a mechanism-based inactivator of the dehydrogenase and is activated by rate-limiting gamma-proton abstraction. Glutamate-401 may be the base that abstracts the pro-R alpha-proton during the dehydrogenation of normal substrates.
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PMID:2-octynoyl coenzyme A is a mechanism-based inhibitor of pig kidney medium-chain acyl coenzyme A dehydrogenase: isolation of the target peptide. 323 92

A 2-year-old female was well until 12 months of age when she was found to be anemic and had dilated cardiomyopathy. Total plasma carnitine was 6 microM and acylcarnitine analysis while receiving carnitine supplement revealed an increase in the four-carbon species. Urine organic acids were normal. In vitro analysis of the mitochondrial pathways for beta oxidation, and leucine, valine, and isoleucine metabolism was performed in fibroblasts using stable isotope-labeled precursors to these pathways followed by acylcarnitine analysis by tandem mass spectrometry. 16-2H3-palmitate was metabolized normally down to the level of butyryl-CoA thus excluding SCAD deficiency. 13C6-leucine and 13C6-isoleucine were also metabolized normally. 13C5-valine incubation revealed a significant increase in 13C4-isobutyrylcarnitine without any incorporation into propionylcarnitine as is observed normally. These same precursors were also evaluated in fibroblasts with proven ETF-QO deficiency in which acyl-CoA dehydrogenase deficiencies in each of these pathways was clearly identified. These results indicate that in the human, there is an isobutyryl-CoA dehydrogenase which exists as a separate enzyme serving only the valine pathway in addition to the 2-methyl branched-chain dehydrogenase which serves both the valine and the isoleucine pathways in both rat and human.
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PMID:Isolated isobutyryl-CoA dehydrogenase deficiency: an unrecognized defect in human valine metabolism. 988 13

The cloning, using a PCR approach, of genes from both Streptomyces coelicolor and Streptomyces avermitilis encoding an acyl-CoA dehydrogenase (AcdH), putatively involved in the catabolism of branched-chain amino acids, is reported. The deduced amino acid sequences of both genes have a high similarity to prokaryotic and eukaryotic short-chain acyl-CoA dehydrogenases. When the S. coelicolor and S. avermitilis acyl-CoA dehydrogenase genes (acdH) were expressed in Escherichia coli, each of the AcdH flavoproteins was able to oxidize the branched-chain acyl-CoA derivatives isobutyryl-CoA, isovaleryl-CoA and cyclohexylcarbonyl-CoA, as well as the short straight-chain acyl-CoAs n-butyryl-CoA and n-valeryl-CoA in vitro. NMR spectral data confirmed that the oxidized product of isobutyryl-CoA is methacrylyl-CoA, which is the expected product at the acyl-CoA dehydrogenase step in the catabolism of valine in streptomycetes. Disruption of the S. avermitilis acdH produced a mutant unable to grow on solid minimal medium containing valine, isoleucine or leucine as sole carbon sources. Feeding studies with 13C triple-labelled isobutyrate revealed a significant decrease in the incorporation of label into the methylmalonyl-CoA-derived positions of avermectin in the acdH mutant. In contrast the mutation did not affect incorporation into the malonyl-CoA-derived positions of avermectin. These results are consistent with the acdH gene encoding an acyl-CoA dehydrogenase with a broad substrate specificity that has a role in the catabolism of branched-chain amino acids in S. coelicolor and S. avermitilis.
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PMID:Genes encoding acyl-CoA dehydrogenase (AcdH) homologues from Streptomyces coelicolor and Streptomyces avermitilis provide insights into the metabolism of small branched-chain fatty acids and macrolide antibiotic production. 1051 85

A 4.8-kilobase (kb) repetitive sequence element generated with KpnI digestion was cloned from the Leptospira interrogans serovar icterohaemorrhagiae strain Ictero No. 1. The sequence, repeated in tandem, was located on the 280-kb fragment between the FseI and AscI sites on the chromosome by hybridization using the 4.8-kb fragment as a probe. We cloned the fragment containing the element for the Ictero No. 1 strain in a lambda EMBL3 bacteriophage DNA, and one out of 5 clones was sequenced. Within the sequenced 9-kb segment that partially repeated, 9 putative open-reading frames and 2 transfer RNA genes, for alanine and isoleucine, were identified. A similarity search for the products deduced from the sequenced data revealed that the repeated sequence includes both beta-oxidation enzymes, acyl-CoA dehydrogenase and enoyl-CoA hydratase, and hydroxythiazole kinase protein homologues. Hybridization experiments against different leptospiral strains using the element as a probe showed a similar sequence in the strains of L. interrogans and L. kirschneri, but not in any strains of L. borgpetersenii, L. weillii, L. meyeri or L. biflexa. Results indicated that the highly repeated element in the Ictero No. 1 strain exists as a well conserved sequence, though at a moderate level of repetition, in certain strains of L. interrogans and L. kirschneri. PCR amplification targeting the repetitive element was successful and indicated that the procedure provides a sensitive and specific probe to detect leptospires.
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PMID:Repetitive sequence of Leptospira interrogans serovar icterohaemorrhagiae strain Ictero No. 1: a sensitive probe for demonstration of Leptospira interrogans strains. 1052 8

An acyl-CoA dehydrogenase has been identified as part of the mitochondrial beta-oxidation pathway in the ascomycete fungus Aspergillus nidulans. Disruption of the scdA gene prevented use of butyric acid (C(4)) and hexanoic acid (C(6)) as carbon sources and reduced cellular butyryl-CoA dehydrogenase activity by 7.5-fold. While the mutant strain exhibited wild-type levels of growth on erucic acid (C(22:1)) and oleic acid (C(18:1)), some reduction in growth was observed with myristic acid (C(14)). The DeltascdA mutation was found to be epistatic to a mutation downstream in the beta-oxidation pathway (disruption of enoyl-CoA hydratase). The DeltascdA mutant was also unable to use isoleucine or valine as a carbon source. Transcription of scdA was observed in the presence of either fatty acids or amino acids. When the mutant was grown in medium containing either isoleucine or valine, organic acid analysis of culture supernatants showed accumulation of 2-oxo acid intermediates of branched chain amino acid catabolism, suggesting feedback inhibition of the upstream branched-chain alpha-keto acid dehydrogenase.
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PMID:A single acyl-CoA dehydrogenase is required for catabolism of isoleucine, valine and short-chain fatty acids in Aspergillus nidulans. 1765 40

Short/branched chain acyl-CoA dehydrogenase (SBCAD) deficiency, also known as 2-methylbutyryl-CoA dehydrogenase deficiency, is a recently described autosomal recessive disorder of isoleucine metabolism. Most patients reported thus far have originated from a founder mutation in the Hmong Chinese population. While the first reported patients had severe disease, most of the affected Hmong have remained asymptomatic. In this study, we describe 11 asymptomatic non-Hmong patients brought to medical attention by elevated C5-carnitine found by newborn screening and one discovered because of clinical symptoms. The diagnosis of SBCAD deficiency was determined by metabolite analysis of blood, urine, and fibroblast samples. PCR and bidirectional sequencing were performed on genomic DNA from five of the patients covering the entire SBCAD (ACADSB) gene sequence of 11 exons. Sequence analysis of genomic DNA from each patient identified variations in the SBCAD gene not previously reported. Escherichia coli expression studies revealed that the missense mutations identified lead to inactivation or instability of the mutant SBCAD enzymes. These findings confirm that SBCAD deficiency can be identified through newborn screening by acylcarnitine analysis. Our patients have been well without treatment and call for careful follow-up studies to learn the true clinical impact of this disorder.
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PMID:Characterization of new ACADSB gene sequence mutations and clinical implications in patients with 2-methylbutyrylglycinuria identified by newborn screening. 2054 83

Short/branched chain acyl-CoA dehydrogenase (SBCAD) deficiency is an autosomal recessive disorder of isoleucine metabolism biochemically characterized by accumulation of 2-methylbutyrylglycine (2MBG) and 2-methylbutyric acid (2MB). Affected patients present predominantly neurological symptoms, whose pathophysiology is not yet established. In the present study, we investigated the in vitro effects of 2MBG and 2MB on important parameters of oxidative stress in cerebral cortex of young rats and C6 glioma cells. 2MBG increased thiobarbituric acid-reactive species (TBA-RS), indicating an increase of lipid oxidation. 2MBG induced sulfhydryl oxidation in cortical supernatants and decreased glutathione (GSH) in these brain preparations, as well as in C6 cells, indicating a reduction of nonenzymatic brain antioxidant defenses. In contrast, 2MB did not alter any of these parameters and 2MBG and 2MB did not affect carbonyl formation (protein damage). In addition, 2MBG-induced increase of TBA-RS levels and decrease of GSH were prevented by free radical scavengers, implying that reactive species were involved in these effects. Furthermore, the decrease of GSH levels caused by 2MBG was not due to a direct oxidative action since this metabolite did not alter sulfhydryl content from a commercial solution of GSH. Nitric oxide production was not altered by 2MBG and 2MB, suggesting that reactive oxygen species possibly underlie 2MBG effects. Finally, we verified that 2MBG did not induce cell death in C6 cells. The present data show that 2MBG induces lipid oxidative damage and reduces the antioxidant defenses in rat brain. Therefore, it may be postulated that oxidative stress induced by 2MBG is involved, at least in part, in the pathophysiology of the brain damage found in SBCAD deficiency.
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PMID:2-Methylbutyrylglycine induces lipid oxidative damage and decreases the antioxidant defenses in rat brain. 2296 64

Short/branched chain acyl-CoA dehydrogenase (SBCAD), isovaleryl-CoA dehydrogenase (IVD), and isobutyryl-CoA dehydrogenase (IBD) are involved in metabolism of isoleucine, leucine, and valine, respectively. These three enzymes all belong to acyl-CoA dehydrogenase (ACD) family, and catalyze the dehydrogenation of monomethyl branched-chain fatty acid (mmBCFA) thioester derivatives. In the present work, the catalytic properties of rat SBCAD, IVD, and IBD, including their substrate specificity, isomerase activity, and enzyme inhibition, were comparatively studied. Our results indicated that SBCAD has its catalytic properties relatively similar to those of straight-chain acyl-CoA dehydrogenases in terms of their isomerase activity and enzyme inhibition, while IVD and IBD are different. IVD has relatively broader substrate specificity than those of the other two enzymes in accommodating various substrate analogs. The present study increased our understanding for the metabolism of monomethyl branched-chain fatty acids (mmBCFAs) and branched-chain amino acids (BCAAs), which should also be useful for selective control of a particular reaction through the design of specific inhibitors.
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PMID:Comparative studies of Acyl-CoA dehydrogenases for monomethyl branched chain substrates in amino acid metabolism. 2347 14


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