Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.3.1.8 (acyl-CoA dehydrogenase)
 785 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recent studies indicate that retinoid-mediated pathways play a pivotal role in cardiac morphogenesis and function. To identify proteins that serve as interacting partners of the retinoid X receptor alpha (RXRalpha) in heart, DNA-protein binding studies were performed with an RXR-responsive element (NRRE-1) derived from the medium chain acyl-CoA dehydrogenase gene promoter and nuclear protein extracts prepared from adult rat heart. NRRE-1 is a pleiotropic RXR-responsive element comprised of three potential recognition sites for class II members of the nuclear receptor superfamily. Gel mobility shift assays performed with an NRRE-1 probe in the absence or presence of bacterially overproduced RXRalpha and nuclear protein extracts prepared from adult rat heart, liver, or brain identified a cardiac-specific, RXR-dependent DNA-protein interaction. The NRRE-1-RXR.cardiac-enriched RXR-interacting protein (CERIP) complex exhibited a distinct mobility compared with NRRE-1-RXR.peroxisome proliferator-activated receptor, NRRE-1-RXR.retinoic acid receptor, or NRRE-1-RXR.thyroid receptor complexes. Mutational analysis demonstrated that two of the three potential binding half-sites of NRRE-1 (an everted repeat separated by an 8-base pair spacer) are required for the NRRE-1-RXR. CERIP interaction. Gel mobility shift assays demonstrated that CERIP interacted with RXRalpha and RXRgamma but not with RXRbeta, indicating a receptor subtypespecific binding preference and suggesting an RXR AB region-dependent interaction. The RXR.CERIP complex did not form on NRRE-1 when a mutant GST-RXRalpha fusion protein lacking the NH(2)-terminal AB region (but containing the receptor dimerization domain) of RXRalpha was added in place of the full-length RXRalpha, confirming a role for the AB region in the RXR. CERIP interaction. DNA-protein cross-linking studies demonstrated that CERIP is a DNA-binding protein of approximately 110 kDa. These results provide evidence for the existence of a cardiac-enriched DNA-binding protein that interacts with RXRalpha via the AB region and suggest a mechanism whereby cardiac retinoid signaling is controlled in an RXR subtype-specific manner.
J Biol Chem 1999 Sep 03
PMID:Evidence for a novel cardiac-enriched retinoid X receptor partner. 1046 3

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.
Microbiology (Reading) 1999 Sep
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 gene encoding the precursor for a novel member of the human acyl-CoA dehydrogenase (ACD) gene family has been isolated which maps to human chromosome 11q25. The cDNA contains an open reading frame of 1248 nucleotides encoding a predicted 415-amino-acid peptide, and shares considerable sequence similarity with other members of the ACD family.
Biochim Biophys Acta 1999 Sep 03
PMID:Isolation and characterisation of a cDNA encoding the precursor for a novel member of the acyl-CoA dehydrogenase gene family. 1052 12

Retinoid x receptor alpha (RXRalpha) serves as an active partner of peroxisome proliferator-activated receptor (PPARalpha). In order to dissect the functional role of RXRalpha and PPARalpha in PPARalpha-mediated pathways, the hepatocyte RXRalpha-deficient mice have been challenged with physiological and pharmacological stresses, fasting and Wy14,643, respectively. The data demonstrate that RXRalpha and PPARalpha deficiency are different in several aspects. At the basal untreated level, RXRalpha deficiency resulted in marked induction of apolipoprotein A-I and C-III (apoA-I and apoC-III) mRNA levels and serum cholesterol and triglyceride levels, which was not found in PPARalpha-null mice. Fasting-induced PPARalpha activation was drastically prevented in the absence of hepatocyte RXRalpha. Wy14,643-mediated pleiotropic effects were also altered due to the absence of hepatocyte RXRalpha. Hepatocyte RXRalpha deficiency did not change the basal acyl-CoA oxidase, medium chain acyl-CoA dehydrogenase, and malic enzyme mRNA levels. However, the inducibility of those genes by Wy14,643 was markedly reduced in the mutant mouse livers. In contrast, the basal cytochrome P450 4A1, liver fatty acid-binding protein, and apoA-I and apoC-III mRNA levels were significantly altered in the mutant mouse livers, but the regulatory effect of Wy14,643 on expression of those genes remained the same. Wy14,643-induced hepatomegaly was partially inhibited in hepatocyte RXRalpha-deficient mice. Wy14,643-induced hepatocyte peroxisome proliferation was preserved in the absence of hepatocyte RXRalpha. These data suggested that in comparison to PPARalpha, hepatocyte RXRalpha has its unique role in lipid homeostasis and that the effect of RXRalpha, -beta, and -gamma is redundant in certain aspects.
J Biol Chem 2000 Sep 08
PMID:Peroxisome proliferator-activated receptor alpha-mediated pathways are altered in hepatocyte-specific retinoid X receptor alpha-deficient mice. 1086 95

The mechanism(s) by which impaired mitochondrial respiratory function and the accumulation of lipid droplets and mitochondria in hearts of copper-deficient rats occur remains unclear. It is not known whether specific components of the regulatory pathway involved in mitochondrial biogenesis, such as mitochondrial transcription factor A (mtTFA) and nuclear respiratory factors 1 and 2 (NRF-1 and NRF-2), are activated in copper deficiency. Little is known about gene expression of enzymes involved in fatty acid oxidation (FAO) in hearts of copper-deficient rats. Male weanling rats were fed copper-adequate (CuA), copper-deficient (CuD) or pair-fed (CuP) diets for 5 wk. Mitochondria and lipid droplet volume densities from electron micrographs were greater and there was an elevation in the mtTFA protein level in hearts of copper-deficient rats. DNA binding activities of NRF-1 and NRF-2 did not differ among the groups. Northern blot analysis of cardiac tissue revealed that transcripts of F(1)F(0)-ATP synthase subunit c were greater, but mRNA levels of ATP synthase beta subunit and the FAO enzyme, medium-chain acyl-CoA dehydrogenase (MCAD), were lower in hearts of copper-deficient rats. Long-chain acyl-CoA dehydrogenase (LCAD) mRNA levels did not differ among treatment groups. These results suggest that certain components of the mitochondrial biogenesis program are activated in hearts of copper-deficient rats. F(1)F(0)-ATP synthase beta subunit and MCAD transcript levels remain low, which may contribute to impaired mitochondrial respiratory function, decreased fatty acid utilization and lipid droplet accumulation in hearts of copper-deficient rats.
J Nutr 2000 Sep
PMID:Mitochondrial transcription factor A is increased but expression of ATP synthase beta subunit and medium-chain acyl-CoA dehydrogenase genes are decreased in hearts of copper-deficient rats. 1095 5

Electron-transferring flavoproteins (ETFs) from human and Paracoccus denitrificans have been analyzed by small angle x-ray scattering, showing that neither molecule exists in a rigid conformation in solution. Both ETFs sample a range of conformations corresponding to a large rotation of domain II with respect to domains I and III. A model of the human ETF.medium chain acyl-CoA dehydrogenase complex, consistent with x-ray scattering data, indicates that optimal electron transfer requires domain II of ETF to rotate by approximately 30 to 50 degrees toward domain I relative to its position in the x-ray structure. Domain motion establishes a new "robust engineering principle" for electron transfer complexes, tolerating multiple configurations of the complex while retaining efficient electron transfer.
J Biol Chem 2001 Sep 07
PMID:Protein dynamics enhance electronic coupling in electron transfer complexes. 1142 3

Short chain acyl-CoA dehydrogenase (SCAD) is a homotetrameric flavoenzyme that catalyzes the first intramitochondrial step in the beta-oxidation of fatty acids. Two polymorphisms in the coding region of the SCAD gene, 511C>T (R147W) and 625G>A (G185S), have been shown to be associated with an increased level of ethylmalonic acid excretion in urine, a clinical characteristic of SCAD deficiency. To characterize the biochemical consequences of these variations, in vitro site-directed mutagenesis and prokaryotic expression were used to produce the corresponding SCAD variant proteins. Both variant proteins were unstable when produced in Escherichia coli, but could be rescued and subsequently purified by coexpressing them with the bacterial chaperonin GroEL/ES. The k(cat)/K(m) values of the green wild-type, R147W, and G185S SCAD enzymes coexpressed with GroEL/ES were 33, 30, and 10 microM(-)(1) s(-)(1), respectively. There were minimal differences in the kinetic parameters measured for the green, degreened, and wild-type enzymes coexpressed with GroEL/ES, and the R147W variant when butyryl-CoA was used as a substrate. The catalytic efficiency of the G185S variant enzyme, however, was reduced compared to that of the wild-type enzyme. The thermal and guanidine HCl stability of the purified enzymes as determined by fluorescence, far-UV CD spectroscopy, and incubation-induced rest activity showed the following order of relative stability: wild-type enzyme > R147W > G185S. Near-UV CD spectroscopy indicated that these impairments are caused by decreased flexibility in the tertiary conformation of the two mutant enzymes. The common SCAD polymorphisms may lead to clinically relevant alterations in enzyme function.
Biochemistry 2002 Sep 17
PMID:Purification and characterization of two polymorphic variants of short chain acyl-CoA dehydrogenase reveal reduction of catalytic activity and stability of the Gly185Ser enzyme. 1222 Jan 77

Cardiac expression of genes involved in fatty acid metabolism may suffer alterations depending on the substrate availability. We studied how troglitazone, an antidiabetic drug that selectively activates peroxisome proliferator-activated receptor gamma (PPARgamma), affected the expression of several of these genes. A single-day troglitazone administration (100 mg/kg/day) did not significantly alter plasma free fatty acids or triglyceride levels. In contrast, a 10-day period of troglitazone treatment significantly reduced plasma free fatty acids and triglyceride levels by 74% (P < 0.001) and 56% (P < 0.01), respectively. Cardiac mRNA expression of acyl-CoA oxidase (ACO) increased (8.3-fold induction) after 1-day troglitazone treatment, whereas after 10 days of treatment ACO mRNA levels were dramatically reduced (98% reduction, P < 0.02), as well as those of uncoupling protein 3 (41% reduction, P = 0.05). The mRNA expression of PPARalpha and several PPAR target genes, such as medium chain acyl-CoA dehydrogenase or fatty acid translocase were not altered after 10 days of troglitazone treatment, whereas muscle-type carnitine palmitoyltransferase I increased 1.7-fold (P < 0.05). The reduction in ACO expression in the hearts of 10-day troglitazone-treated mice was accompanied by an increase in the protein levels of the transcriptional repressor chicken ovalbumin upstream promoter transcription factor II (COUP-TF II). Electrophoretic mobility shift assays performed with COUP-TF II antibody to examine its interaction with a labeled peroxisome proliferator response element probe showed enhanced binding of COUP-TFII in cardiac nuclear extracts from troglitazone-treated mice for 10 days but not in the control nuclear extracts. Overall, the findings presented here show that 10 days of troglitazone treatment decreased expression of the ACO gene through a mechanism involving the transcriptional repressor COUP-TF II.
Mol Pharmacol 2003 Sep
PMID:Down-regulation of acyl-CoA oxidase gene expression in heart of troglitazone-treated mice through a mechanism involving chicken ovalbumin upstream promoter transcription factor II. 1292 Feb 14

We report a case of myopathic form of very-long-chain acyl-CoA dehydrogenase (VLCAD) deficiency with adolescent onset which presented with recurrent rhabdomyolysis and was diagnosed by immunostain of biopsy muscle. She was an 18-year-old woman who showed recurrent episodes of rhabdomyolysis after exercise since the age of 15. The diagnosis was made by the immunostain using anti-VLCAD antibody and the measurement of acyl-CoA dehydrogenase activity for the biopsy muscle. Her elder sister had also showed recurrent episodes of rhabdomyolysis at least two times. The analysis of genomic DNA on blood samples of the patient and her sister was performed and the same mutations were identified. Hence, these sister were revealed to have VLCAD deficiency. We should keep in mind this disorder for those presenting with recurrent rhabdomyolysis. In addition, as far as we know, this is the first report that a correct diagnosis was obtained by immunostain. Immunostain is probably a useful diagnostic procedure to identify an uncommon myopathy.
Rinsho Shinkeigaku 2003 Sep
PMID:[A case of very-long-chain acyl-CoA dehydrogenase deficiency with adolescent onset being diagnosed by immunostain of biopsy muscle]. 1472 66

A subject of great practical importance that has not received much attention is the question of the sensitivity of molecular dynamics simulations to the initial X-ray structure used to set up the calculation. We have found two cases in which seemingly similar structures lead to quite different results, and in this article we present a detailed analysis of these cases. The first case is acyl-CoA dehydrogenase, and the chief difference of the two structures is attributed to a slight shift in a backbone carbonyl that causes a key residue (the proton-abstracting base) to be in a bad conformation for reaction. The second case is xylose isomerase, and the chief difference of the two structures appears to be the ligand sphere of a Mg2+ metal cofactor that plays an active role in catalysis.
Protein Sci 2004 Sep
PMID:Sensitivity of molecular dynamics simulations to the choice of the X-ray structure used to model an enzymatic reaction. 1532 78


<< Previous 1 2 3 4 5 6 7 Next >>