acyl-CoA Dehydrogenase (acyl-coa + dehydrogenase)

Distribution by Scientific Domains
Distribution within Medical Sciences

Terms modified by acyl-CoA Dehydrogenase

  • acyl-coa dehydrogenase deficiency

  • Selected Abstracts


    Purification, crystallization and preliminary crystallographic analysis of very-long-chain acyl-CoA dehydrogenase from Caenorhabditis elegans

    ACTA CRYSTALLOGRAPHICA SECTION F (ELECTRONIC), Issue 4 2010
    Zhijie Li
    Acyl-CoA dehydrogenase [acyl-CoA:(acceptor) 2,3-oxidoreductase; EC 1.3.99.3] catalyzes the first reaction step in mitochondrial fatty-acid ,-oxidation. Here, the very-long-chain acyl-CoA dehydrogenase from Caenorhabditis elegans (cVLCAD) has been cloned and overexpressed in Escherichia coli strain BL21 (DE3). Interestingly, unlike other very-long-chain acyl-CoA dehydrogenases, cVLCAD was found to form a tetramer by size-exclusion chromatography coupled with in-line static light-scattering, refractive-index and ultraviolet measurements. Purified cVLCAD (12,mg,ml,1) was successfully crystallized by the hanging-drop vapour-diffusion method under conditions containing 100,mM Tris,HCl pH 8.0, 150,mM sodium chloride, 200,mM magnesium formate and 13% PEG 3350. The crystal has a tetragonal form and a complete diffraction data set was collected and processed to 1.8, resolution. The crystal belonged to space group C2, with unit-cell parameters a = 138.6, b = 116.7, c = 115.3,, , = , = 90.0, , = 124.0. A self-rotation function indicated the existence of one noncrystallographic twofold axis. A preliminary molecular-replacement solution further confirmed the presence of two molecules in one asymmetric unit, which yields a Matthews coefficient VM of 2.76,3,Da,1 and a solvent content of 55%. [source]


    Decreased activities of mitochondrial respiratory chain complexes in non-mitochondrial respiratory chain diseases

    DEVELOPMENTAL MEDICINE & CHILD NEUROLOGY, Issue 2 2006
    Joannie Hui MBBS
    The aim of this study was to illustrate the difficulties in establishing a diagnosis of mitochondrial respiratory chain (MRC) disorders based on clinical grounds in combination with intermediate activities of the MRC enzyme complexes. We reviewed retrospectively all medical and laboratory records of patients initially considered likely to have MRC disorders on clinical grounds, and subsequently diagnosed with other disorders (n=20; 11 males, 9 females). Data were retrieved from hospital records, referral letters, and results of enzymatic analysis at a reference laboratory. Clinical symptoms included developmental delay, epilepsy, hypotonia, movement disorder, spastic quadriplegia, tetany, microcephaly, visual problems, carpopedal spasms, dysmorphism, hearing loss, muscle weakness and rhabdomyolysis, and fulminant hepatitis. Blood and cerebrospinal fluid lactate levels were elevated in 13/20 and 9/20 respectively. One or more MRC complex activities (expressed as ratios relative to citrate synthase and/or complex II activity) were less than 50% of control mean activity in 11/20 patients (including patients with deficiencies of pyruvate dehydrogenase complex, pantothenate kinase, holocarboxylase synthetase, long-chain hydroxy acyl-CoA dehydrogenase, molybdenum co-factor, and neonatal haemochromatosis). One patient had a pattern suggestive of mitochondrial proliferation. We conclude that intermediate results of MRC enzymes should be interpreted with caution and clinicians should be actively looking for other underlying diagnoses. [source]


    The Y42H mutation in medium-chain acyl-CoA dehydrogenase, which is prevalent in babies identified by MS/MS-based newborn screening, is temperature sensitive

    FEBS JOURNAL, Issue 20 2004
    Linda O'Reilly
    Medium-chain acyl-CoA dehydrogenase (MCAD) is a homotetrameric flavoprotein which catalyses the initial step of the ,-oxidation of medium-chain fatty acids. Mutations in MCAD may cause disease in humans. A Y42H mutation is frequently found in babies identified by newborn screening with MS/MS, yet there are no reports of patients presenting clinically with this mutation. As a basis for judging its potential consequences we have examined the protein phenotype of the Y42H mutation and the common disease-associated K304E mutation. Our studies of the intracellular biogenesis of the variant proteins at different temperatures in isolated mitochondria after in vitro translation, together with studies of cultured patient cells, indicated that steady-state levels of the Y42H variant in comparison to wild-type were decreased at higher temperature though to a lesser extent than for the K304E variant. To distinguish between effects of temperature on folding/assembly and the stability of the native enzyme, the thermal stability of the variant proteins was studied after expression and purification by dye affinity chromatography. This showed that, compared with the wild-type enzyme, the thermostability of the Y42H variant was decreased, but not to the same degree as that of the K304E variant. Substrate binding, interaction with the natural electron acceptor, and the binding of the prosthetic group, FAD, were only slightly affected by the Y42H mutation. Our study suggests that Y42H is a temperature sensitive mutation, which is mild at low temperatures, but may have deleterious effects at increased temperatures. [source]


    Inactivation of oxidized and S -nitrosylated mitochondrial proteins in alcoholic fatty liver of rats,

    HEPATOLOGY, Issue 5 2006
    Kwan-Hoon Moon
    Increased oxidative/nitrosative stress is a major contributing factor to alcohol-mediated mitochondrial dysfunction. However, which mitochondrial proteins are oxidatively modified under alcohol-induced oxidative/nitrosative stress is poorly understood. The aim of this study was to systematically investigate oxidized and/or S -nitrosylated mitochondrial proteins and to use a biotin- N -maleimide probe to evaluate their inactivation in alcoholic fatty livers of rats. Binge or chronic alcohol exposure significantly elevated nitric oxide, inducible nitric oxide synthase, and ethanol-inducible CYP2E1. The biotin- N -maleimide-labeled oxidized and/or S -nitrosylated mitochondrial proteins from pair-fed controls or alcohol-fed rat livers were subsequently purified with streptavidin-agarose. The overall patterns of oxidized and/or S -nitrosylated proteins resolved by 2-dimensional polyacrylamide gel electrophoresis were very similar in the chronic and binge alcohol treatment groups. Seventy-nine proteins that displayed differential spot intensities from those of control rats were identified by mass spectrometry. These include mitochondrial aldehyde dehydrogenase 2 (ALDH2), ATP synthase, acyl-CoA dehydrogenase, 3-ketoacyl-CoA thiolase, and many proteins involved in chaperone activity, mitochondrial electron transfer, and ion transport. The activity of 3-ketoacyl-CoA thiolase involved in mitochondrial ,-oxidation of fatty acids was significantly inhibited in alcohol-exposed rat livers, consistent with hepatic fat accumulation, as determined by biochemical and histological analyses. Measurement of activity and immunoblot results showed that ALDH2 and ATP synthase were also inhibited through oxidative modification of their cysteine or tyrosine residues in alcoholic fatty livers of rats. In conclusion, our results help to explain the underlying mechanism for mitochondrial dysfunction and increased susceptibility to alcohol-mediated liver damage. (HEPATOLOGY 2006;44:1218,1230.) [source]


    Mutation analysis in mitochondrial fatty acid oxidation defects: Exemplified by acyl-CoA dehydrogenase deficiencies, with special focus on genotype,phenotype relationship

    HUMAN MUTATION, Issue 3 2001
    Niels Gregersen
    Abstract Mutation analysis of metabolic disorders, such as the fatty acid oxidation defects, offers an additional, and often superior, tool for specific diagnosis compared to traditional enzymatic assays. With the advancement of the structural part of the Human Genome Project and the creation of mutation databases, procedures for convenient and reliable genetic analyses are being developed. The most straightforward application of mutation analysis is to specific diagnoses in suspected patients, particularly in the context of family studies and for prenatal/preimplantation analysis. In addition, from these practical uses emerges the possibility to study genotype,phenotype relationships and investigate the molecular pathogenesis resulting from specific mutations or groups of mutations. In the present review we summarize current knowledge regarding genotype,phenotype relationships in three disorders of mitochondrial fatty acid oxidation: very-long chain acyl-CoA dehydrogenase (VLCAD, also ACADVL), medium-chain acyl-CoA dehydrogenase (MCAD, also ACADM), and short-chain acyl-CoA dehydrogenase (SCAD, also ACADS) deficiencies. On the basis of this knowledge we discuss current understanding of the structural implications of mutation type, as well as the modulating effect of the mitochondrial protein quality control systems, composed of molecular chaperones and intracellular proteases. We propose that the unraveling of the genetic and cellular determinants of the modulating effects of protein quality control systems may help to assess the balance between genetic and environmental factors in the clinical expression of a given mutation. The realization that the effect of the monogene, such as disease-causing mutations in the VLCAD, MCAD, and SCAD genes, may be modified by variations in other genes presages the need for profile analyses of additional genetic variations. The rapid development of mutation detection systems, such as the chip technologies, makes such profile analyses feasible. However, it remains to be seen to what extent mutation analysis will be used for diagnosis of fatty acid oxidation defects and other metabolic disorders. Hum Mutat 18:169,189, 2001. 2001 Wiley-Liss, Inc. [source]


    Gene expression profile analysis of regenerating liver after portal vein ligation in rats by a cDNA microarray system

    LIVER INTERNATIONAL, Issue 3 2004
    Y Nagano
    Abstract: Aims: We assessed changes in gene expression of hypertrophied liver after portal vein ligation (PL) in a test group of rats compared to a control group, which had the same size liver but no PL. Methods: The portal veins of the left and median lobes in the test group were ligated in an initial operation. Four days after the PL, the liver volume of the posterior caudate lobe (5%) increased two-fold and comprised 10% of the liver. A 90% hepatectomy was then performed, leaving only the hypertrophied posterior caudate lobe, and leaving the normal anterior and posterior caudate lobes (10%) in the control (sham) group. A comparison of the expression profiles between two groups was performed using cDNA microarrays and the hepatic ATP level was measured. Results: The survival rate for the PL group was significantly higher than for the sham group at 4 days after the hepatectomy (56.3% and 26.7%, P<0.05). Gene expression of cyclin D1, proliferating cell nuclear antigen, cyclin A and B was upregulated, and the cyclin-dependent kinase inhibitor was downregulated. Increases were observed in: (i) pyruvate dehydrogenase, the tricarboxylic acid cycle cycle regulator, (ii) acyl-CoA dehydrogenase, the oxidation regulator, and (iii) cytochrome oxidases, the oxidative phosphorylation regulator. Hepatic ATP concentration after hepatectomy was better maintained in the PL group than in the sham group (0.480.01 ,mol/ml vs. 0.330.01 ,mol/ml, P<0.05). Conclusion: The regenerating liver increased tolerance for extended hepatectomy compared to normal liver. It is believed that this is because the induced rapid regeneration of the remaining liver after hepatectomy increases ATP metabolism. [source]


    Atypical presentation of VLCAD deficiency associated with a novel ACADVL splicing mutation

    MUSCLE AND NERVE, Issue 3 2009
    Oleg Shchelochkov MD
    Abstract Very long chain acyl-CoA dehydrogenase (VLCAD) deficiency is an autosomal recessive inborn error of metabolism characterized by impaired mitochondrial ,-oxidation of fatty acids with a chain length between 14 and 18 carbons. While expansion of newborn screening has improved our ability to detect VLCAD deficiency in early childhood, the late-onset form of the disease still presents a significant diagnostic challenge. We report a 20-year-old female with VLCAD deficiency who first presented in infancy with hypoketotic hypoglycemia. In childhood the patient developed complex partial seizures that were aggravated by Lamotrigine treatment. The clinical course in early adulthood was complicated by recurrent, often unprovoked, episodes of rhabdomyolysis and myoglobinuria. In addition, she suffered from chronic myalgia, muscle weakness, and diffuse abdominal tenderness. A muscle biopsy revealed accumulation of fat droplets. Her acylcarnitine profile showed significantly elevated C14, C14:1, C16, and C18-carnitines. Sequence analysis of ACADVL revealed a heterozygous recurrent mutation c.848T>C (p.V283A) and a heterozygous novel splice mutation c.879-8T>A that results in the inclusion of six nucleotides from intron 9 into the transcript sequence. The molecular characterization of this novel mutation and its correlation with the clinical phenotype are discussed. Muscle Nerve 39: 374,382, 2009 [source]


    Perioperative management of a child with short-chain acyl-CoA dehydrogenase deficiency

    PEDIATRIC ANESTHESIA, Issue 9 2005
    BRIAN TURPIN BS
    Summary 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 , -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. [source]


    Gene expression of fatty acid-binding proteins, fatty acid transport proteins (cd36 and FATP) and ,-oxidation-related genes in Atlantic salmon (Salmo salar L.) fed fish oil or vegetable oil

    AQUACULTURE NUTRITION, Issue 4 2009
    B.E. TORSTENSEN
    Abstract Relative gene expression pattern of fatty acid transport proteins (FATP and cd36), intracellular fatty acid-binding proteins (FABP3, FABP10 and FABP11), ,-oxidation-related genes [carnitine palmitoyl transferase II (CPTII), peroxisome proliferator-activated receptor , (PPAR,), acyl-CoA oxidase (AOX), long-chain fatty acyl-CoA synthetase (FACS), acyl-CoA dehydrogenase (dehydrogenase)] and uncoupling protein 2 (UCP2) was assessed by RT-qPCR in Atlantic salmon muscle (red and white), liver, heart, myosepta and visceral fat. FABP11, a FABP isoform not previously described in Atlantic salmon, was highly expressed in visceral fat and myosepta and at the lower level in red muscle, white muscle, myosepta and heart. Furthermore, Atlantic salmon were fed either a diet containing fish oil (FO) or a complete replacement of FO with a vegetable oil blend (55% rapeseed oil, 30% palm oil and 15% linseed oil; VO) for the production cycle (27 months from start of feeding and until ,4.5 kg mean weight). The expression of genes related to ,-oxidation, fatty acid uptake and transport in the white muscle indicate (n = 3) significant down-regulation in VO fed Atlantic salmon and correlated with previously reported white muscle triacylglycerol stores and ,-oxidation. FABP11 in visceral fat and myosepta was also down-regulated in VO fed fish. [source]


    Purification, crystallization and preliminary crystallographic analysis of very-long-chain acyl-CoA dehydrogenase from Caenorhabditis elegans

    ACTA CRYSTALLOGRAPHICA SECTION F (ELECTRONIC), Issue 4 2010
    Zhijie Li
    Acyl-CoA dehydrogenase [acyl-CoA:(acceptor) 2,3-oxidoreductase; EC 1.3.99.3] catalyzes the first reaction step in mitochondrial fatty-acid ,-oxidation. Here, the very-long-chain acyl-CoA dehydrogenase from Caenorhabditis elegans (cVLCAD) has been cloned and overexpressed in Escherichia coli strain BL21 (DE3). Interestingly, unlike other very-long-chain acyl-CoA dehydrogenases, cVLCAD was found to form a tetramer by size-exclusion chromatography coupled with in-line static light-scattering, refractive-index and ultraviolet measurements. Purified cVLCAD (12,mg,ml,1) was successfully crystallized by the hanging-drop vapour-diffusion method under conditions containing 100,mM Tris,HCl pH 8.0, 150,mM sodium chloride, 200,mM magnesium formate and 13% PEG 3350. The crystal has a tetragonal form and a complete diffraction data set was collected and processed to 1.8, resolution. The crystal belonged to space group C2, with unit-cell parameters a = 138.6, b = 116.7, c = 115.3,, , = , = 90.0, , = 124.0. A self-rotation function indicated the existence of one noncrystallographic twofold axis. A preliminary molecular-replacement solution further confirmed the presence of two molecules in one asymmetric unit, which yields a Matthews coefficient VM of 2.76,3,Da,1 and a solvent content of 55%. [source]


    MOUSE STRAIN-SPECIFIC DIFFERENCES IN CARDIAC METABOLIC ENZYME ACTIVITIES OBSERVED IN A MODEL OF ISOPROTERENOL-INDUCED CARDIAC HYPERTROPHY

    CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 1-2 2007
    Michael D Faulx
    SUMMARY 1Alterations in myocardial energy metabolism accompany pressure overload-induced hypertrophy. We previously described a novel model of catecholamine-induced hypertrophy in which A/J mice exhibit more robust cardiac hypertrophy than B6 mice. Accordingly, we assessed the influence of mouse strain on the activities of key myocardial metabolic enzymes and whether there are strain-related metabolic adaptations to short-term, high-dose isoproterenol (ISO) administration. 2Thirty-nine male mice (19 A/J mice, 20 B6 mice), aged 12,15 weeks, were randomly assigned to receive either ISO (100 mg/kg, s.c.) or vehicle (sterile water) daily for 5 days. On Day 6, all hearts were excised, weighed, freeze clamped and assayed for pyruvate dehydrogenase (PDH), medium chain acyl-CoA dehydrogenase, carnitine palmitoyl transferase I and citrate synthase activities. Plasma fatty acids (FA) were also measured. 3The ISO-treated A/J mice demonstrated greater percentage increases in gravimetric heart weight/bodyweight ratio than ISO-treated B6 mice (24 vs 3%, respectively; P < 0.001). All enzyme activities were significantly greater in vehicle-treated B6 mice than in A/J mice, illustrating a greater capacity for aerobic metabolism in B6 mice. Administration of ISO reduced PDHa (active form) activity in B6 mice by 47% (P < 0.001), with no significant change seen in A/J mice. Free FA levels were not significantly different between groups; thus, the differences in PDHa were not due to changes in FA. 4The basal activity of myocardial metabolic enzymes is greater in B6 mice than in A/J mice and ISO alters myocardial PDH activity in a mouse strain-dependent manner. Compared with A/J mice, B6 mice demonstrate less ISO-induced cardiac hypertrophy, but greater activity of key enzymes regulating FA and carbohydrate oxidation, which may protect against the development of hypertrophy. The metabolic adaptations associated with ISO-induced hypertrophy differ from those reported with pressure overload hypertrophy. [source]


    Purification, crystallization and preliminary crystallographic analysis of very-long-chain acyl-CoA dehydrogenase from Caenorhabditis elegans

    ACTA CRYSTALLOGRAPHICA SECTION F (ELECTRONIC), Issue 4 2010
    Zhijie Li
    Acyl-CoA dehydrogenase [acyl-CoA:(acceptor) 2,3-oxidoreductase; EC 1.3.99.3] catalyzes the first reaction step in mitochondrial fatty-acid ,-oxidation. Here, the very-long-chain acyl-CoA dehydrogenase from Caenorhabditis elegans (cVLCAD) has been cloned and overexpressed in Escherichia coli strain BL21 (DE3). Interestingly, unlike other very-long-chain acyl-CoA dehydrogenases, cVLCAD was found to form a tetramer by size-exclusion chromatography coupled with in-line static light-scattering, refractive-index and ultraviolet measurements. Purified cVLCAD (12,mg,ml,1) was successfully crystallized by the hanging-drop vapour-diffusion method under conditions containing 100,mM Tris,HCl pH 8.0, 150,mM sodium chloride, 200,mM magnesium formate and 13% PEG 3350. The crystal has a tetragonal form and a complete diffraction data set was collected and processed to 1.8, resolution. The crystal belonged to space group C2, with unit-cell parameters a = 138.6, b = 116.7, c = 115.3,, , = , = 90.0, , = 124.0. A self-rotation function indicated the existence of one noncrystallographic twofold axis. A preliminary molecular-replacement solution further confirmed the presence of two molecules in one asymmetric unit, which yields a Matthews coefficient VM of 2.76,3,Da,1 and a solvent content of 55%. [source]