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)

Mitochondrial fatty acid beta-oxidation is an important energy resource for many mammal tissues. Acyl-CoA dehydrogenases (ACADs) are a family of flavoproteins that are involved in the beta-oxidation of the fatty acyl-CoA derivatives. Deficiency of these ACADs can cause metabolic disorders including muscle fatigue, hypoglycaemia, hepatic lipidosis and so on. By large scale sequencing, we identified a cDNA sequence of 3960 base pairs with a typical acyl-CoA dehydrogenase function domain. RT-PCR result shows that it is widely expressed in human tissues, especially high in liver, kidney, pancreas and spleen. It is hypothesized that this is a novel member of ACADs family.
Mol Biol Rep 2004 Sep
PMID:Cloning and characterization of a human cDNA ACAD10 mapped to chromosome 12q24.1. 1556 Mar 74

Unsaturated fatty acids play an important role in the prevention of human diseases such as diabetes, obesity, cancer, and neurodegeneration. However, their oxidation in vivo by acyl-CoA dehydrogenases (ACADs) that catalyze the first step of each cycle of mitochondrial fatty acid beta-oxidation is not entirely understood. Recently, a novel ACAD (ACAD-9) of unknown function that is highly homologous to human very-long-chain acyl-CoA dehydrogenase was identified by large-scale random sequencing. To characterize its enzymatic role, we have expressed ACAD-9 in Escherichia coli, purified it, and determined its pattern of substrate utilization. The N terminus of the mature form of the enzyme was identified by in vitro mitochondrial import studies of precursor protein. A 37-amino acid leader peptide was cleaved sequentially by two mitochondrial peptidases to yield a predicted molecular mass of 65 kDa for the mature subunit. Submitochondrial fractionation studies found native ACAD-9 to be associated with the mitochondrial membrane. Gel filtration analysis indicated that, like very-long-chain acyl-CoA dehydrogenase, ACAD-9 is a dimer, in contrast to the other known ACADs, which are tetramers. Purified mature ACAD-9 had maximal activity with long-chain unsaturated acyl-CoAs as substrates (C16:1-, C18:1-, C18:2-, C22:6-CoA). These results suggest a previously unrecognized role for ACAD-9 in the mitochondrial beta-oxidation of long-chain unsaturated fatty acids. Because of the substrate specificity and abundance of ACAD-9 in brain, we speculate that it may play a role in the turnover of lipid membrane unsaturated fatty acids that are essential for membrane integrity and structure.
J Biol Chem 2005 Sep 16
PMID:Human acyl-CoA dehydrogenase-9 plays a novel role in the mitochondrial beta-oxidation of unsaturated fatty acids. 1602 May 46

A gene (PP2216) that codes for an acyl-CoA dehydrogenase was cloned from Pseudomonas putida strain KT2240 and over-expressed in Escherichia coli, and the recombinant enzyme purified and characterised. The enzyme is tetrameric with one FAD per subunit of molecular mass 40,500 Da. An anaerobic titration with sodium dithionite showed that the enzyme accepts two electrons. A similar titration with butyryl-CoA showed that reduction by this substrate was incomplete with 4.5 mol butyryl-CoA added per mol enzyme FAD; the equilibrium was used to calculate that the oxidation-reduction potential of the enzyme at pH 7 and 25 degrees C is 5+/-5 mV versus the standard hydrogen electrode. The enzyme shows catalytic activity with butyryl-CoA, valeryl-CoA and hexanoyl-CoA, and very low activity with heptanoyl-CoA and octanoyl-CoA; it fails to oxidise propionyl-CoA. These properties resemble those of short-chain acyl-CoA dehydrogenases from other sources. The enzyme is inactive with the CoA derivatives of all phenylalkanoates that were tested (side chains 3-8 carbon atoms) indicating that in contrast to an earlier suggestion, the enzyme is not involved in the beta-oxidation of aromatic compounds.
FEMS Microbiol Lett 2005 Sep 01
PMID:The protein coded by the PP2216 gene of Pseudomonas putida KT2440 is an acyl-CoA dehydrogenase that oxidises only short-chain aliphatic substrates. 1602 85

Short-chain acyl-CoA dehydrogenase (SCAD) is a mitochondrial enzyme that catalyzes the dehydrogenation of short chain fatty acids (4 to 6 carbons in length) thereby initiating the cycle of beta-oxidation. This process generates acetyl-CoA, the key substrate for hepatic ketogenesis or ATP production by the Kreb's cycle. A deficiency of SCAD results in the build-up of potentially cytotoxic metabolites including ethylmalonic acid, methylsuccinyl CoA and butyryl-carnitine. The end-organ involvement is heterogeneous, but most commonly includes hypotonia with possible lipid myopathy and developmental delay. Other reported complications include dysmorphic craniofacial features, hypoglycemia, seizures, scoliosis, hypertonia and hyperreflexia, cyclic vomiting and myocardial dysfunction. We present a 23-month-old girl with SCAD deficiency, who required posterior fossa decompression for type 1 Chiari malformation. The potential perioperative implications of SCAD deficiency are reviewed.
Paediatr Anaesth 2005 Sep
PMID:Perioperative management of a child with short-chain acyl-CoA dehydrogenase deficiency. 1610 9

Two novel rare mutations, MCAD approximately 842G-->C (R256T) and MCAD approximately 1166A-->G (K364R), have been investigated to assess how far the biochemical properties of the mutant proteins correlate with the clinical phenotype of medium chain acyl-CoA dehydrogenase (MCAD) deficiency. When the gene for K364R was overexpressed in Escherichia coli, the synthesized mutant protein only exhibited activity when the gene for chaperonin GroELS was co-overexpressed. Levels of activity correlated with the amounts of native MCAD protein visible in western blots. The R256T mutant, by contrast, displayed no activity either with or without chaperonin, but in this case a strong MCAD protein band was seen in the western blots throughout. The proteins were also purified, and the enzyme function and thermostability investigated. The K364R protein showed only moderate kinetic impairment, whereas the R256T protein was again totally inactive. Neither mutant showed marked depletion of FAD. The pure K364R protein was considerably less thermostable than wild-type MCAD. Western blots indicated that, although the R256T mutant protein is less thermostable than normal MCAD, it is much more stable than K364R. Though clinically asymptomatic thus far, both mutations have a severe impact on the biochemical phenotype of the protein. K364R, like several previously described MCAD mutant proteins, appears to be defective in folding. R256T, by contrast, is a well-folded protein that is nevertheless devoid of catalytic activity. How the mutations specifically affect the catalytic activity and the folding is further discussed.
FEBS J 2005 Sep
PMID:Two novel variants of human medium chain acyl-CoA dehydrogenase (MCAD). K364R, a folding mutation, and R256T, a catalytic-site mutation resulting in a well-folded but totally inactive protein. 1612 23

The isobutyryl-CoA dehydrogenase (IBD) enzyme is involved in the degradation of valine. IBD deficiency was first reported in 1998 and subsequent genetic investigations identified acyl-CoA dehydrogenase (ACAD) 8, now IBD, as the gene responsible for IBD deficiency. Only three individuals homozygous or compound heterozygous for variations in the IBD gene have been reported. We present IBD deficiency in an additional four newborns with elevated C(4)-carnitine identified by tandem mass spectrometry (MS/MS) screening in Denmark and the United States. Three showed urinary excretions of isobutyryl-glycine, and in vitro probe analysis of fibroblasts from two newborns indicated enzymatic IBD defect. Molecular genetic analysis revealed seven new rare variations in the IBD gene (c.348C>A, c.400G>T, c.409G>A, c.455T>C, c.958G>A, c.1000C>T and c.1154G>A). Furthermore, sequence analysis of the short-chain acyl-CoA dehydrogenase (SCAD) gene revealed heterozygosity for the prevalent c.625G>A susceptibility variation in all newborns and in the first reported IBD patient. Functional studies in isolated mitochondria demonstrated that the IBD variations present in the Danish newborn (c.409G>A and c.958G>A) together with a previously published IBD variation (c.905G>A) disturbed protein folding and reduced the levels of correctly folded IBD tetramers. Accordingly, low/no IBD residual enzyme activity was detectable when the variant IBD proteins were overexpressed in Chang cells.
Pediatr Res 2006 Sep
PMID:Variations in IBD (ACAD8) in children with elevated C4-carnitine detected by tandem mass spectrometry newborn screening. 1685 60

The sigma(54)-dependent transcriptional regulator SfnR is essential for the use of dimethyl sulfone (DMSO(2)) as a sulfur source by Pseudomonas putida DS1. SfnR binds three SfnR-binding sites (sites 1, 2 and 3) within an intergenic region of the divergently transcribed sfnAB and sfnFG gene clusters. The site 1 region, proximal to the sfnF gene, is indispensable for the expression of the sfnFG operon, which encodes components of DMSO(2) monooxygenase. We investigated the transcriptional regulation of the sfnAB operon and possible functions of the sfnA gene. RT-PCR analysis revealed that the sfnAB gene cluster, which is similar to homologues of the acyl-CoA dehydrogenase family, was transcribed as an operon, and its expression was regulated by SfnR under conditions of sulfate starvation. Deletion analyses using lacZ as a reporter demonstrated that the region up to at least -138 bp from the transcription start point of sfnA (containing sites 2 and 3) was necessary for the expression of the sfnAB operon. A growth test of the sfnA-disrupted mutant revealed the possibility that sfnA may be involved in the use of methanethiol as a sulfur source.
Microbiology (Reading) 2007 Sep
PMID:Transcriptional regulation of the sulfate-starvation-induced gene sfnA by a sigma54-dependent activator of Pseudomonas putida. 1776 52

Growth of Pseudomonas aeruginosa on acyclic terpene alcohols (citronellol) and on other methyl-branched compounds such as leucine or isovalerate requires a functional leucine/isovalerate utilization (Liu) pathway. In this study, we investigated the liuABCDE gene cluster by insertion mutant analysis, heterologous expression of liuA in Escherichia coli and by biochemical characterization of purified LiuA protein. Mutants with insertion in any of the liu genes were unable to utilize acyclic terpenes or leucine/isovalerate and confirmed the importance of the liu genes for catabolism of methyl-branched compounds. An insertion mutant in liuA was complemented by a liuA copy in trans, indicating that possible polar downstream effects of the insertion are not essential for growth. LiuA purified from recombinant E. coli revealed acyl-CoA dehydrogenase activity with isovaleryl-CoA (KM 2.3 microM) and butyryl-CoA as substrates. Other acyl-CoA compounds such as isobutyryl-CoA, 3-hydroxybutyryl-CoA, octanoyl-CoA, citronellyl-CoA or 5-methyl-hex-4-enoyl-CoA were not utilized. Experimental evidence for expression and essential functions of other Liu proteins in metabolism of methyl-branched compounds is provided.
FEMS Microbiol Lett 2008 Sep
PMID:Biochemical characterization of isovaleryl-CoA dehydrogenase (LiuA) of Pseudomonas aeruginosa and the importance of liu genes fora functional catabolic pathway of methyl-branched compounds. 1862 20

Pressure overload (PO) first causes cardiac hypertrophy and then heart failure (HF), which are associated with sex differences in cardiac morphology and function. We aimed to identify genes that may cause HF-related sex differences. We used a transverse aortic constriction (TAC) mouse model leading to hypertrophy without sex differences in cardiac function after 2 weeks, but with sex differences in hypertrophy 6 and 9 weeks after TAC. Cardiac gene expression was analyzed 2 weeks after surgery. Deregulated genes were classified into functional gene ontology (GO) categories and used for pathway analysis. Classical marker genes of hypertrophy were similarly upregulated in both sexes (alpha-actin, ANP, BNP, CTGF). Thirty-five genes controlling mitochondrial function (PGC-1, cytochrome oxidase, carnitine palmitoyl transferase, acyl-CoA dehydrogenase, pyruvate dehydrogenase kinase) had lower expression in males compared to females after TAC. Genes encoding ribosomal proteins and genes associated with extracellular matrix remodeling exhibited relative higher expression in males (collagen 3, matrix metalloproteinase 2, TIMP2, and TGFbeta2, all about twofold) after TAC. We confirmed 87% of the gene expression by real-time polymerase chain reaction. By GO classification, female-specific genes were related to mitochondria and metabolism and males to matrix and biosynthesis. Promoter studies confirmed the upregulation of PGC-1 by E2. Less downregulation of metabolic genes in female hearts and increased protein synthesis capacity and deregulation of matrix remodeling in male hearts characterize the sex-specific early response to PO. These differences could contribute to subsequent sex differences in cardiac function and HF.
J Mol Med (Berl) 2008 Sep
PMID:Sex-specific pathways in early cardiac response to pressure overload in mice. 1866 44

In our previous studies, AveI was identified as a negative regulator for avermectin biosynthesis in Streptomyces avermitilis NRRL8165, and the aveI-null mutant of NRRL8165 could produce at least 10-fold more avermectin B1a than its wild-type strain. In order to explore the regulatory mechanism by which aveI affects avermectin biosynthesis, in this study, we performed a global comparative gene expression analysis between aveI deletion mutant 8165DeltaI and its wild-type strain using NimbleGen microarrays in combination with real-time reverse transcriptase-PCR. The results showed the aveI deletion has caused global changes beyond the avermectin biosynthetic gene cluster. The aveI gene not only negatively affected expression of the avermectin biosynthetic gene cluster but also affected expression of oligomycin and filipin biosynthetic clusters. In addition, the genes involved in precursor biosyntheses for avermectin or other antibiotics, such as crotonyl-CoA reductase and methylmalonyl-CoA decarboxylase, were also upregulated in aveI mutant. Furthermore, genes in several key primary metabolic pathways, such as protein synthesis and fatty acid metabolism, were found downregulated in the mutant. These results suggested that the aveI gene may be functioning as a global regulator involved in directing carbon flux from primary to secondary metabolism.
FEMS Microbiol Lett 2009 Sep
PMID:Transcriptomics analyses reveal global roles of the regulator AveI in Streptomyces avermitilis. 1965 97


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