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)

Di (2-ehtylhexyl) phthalate (DEHP) is a peroxisome proliferator and a drug having a hypolipidemic effect. The body-weight change of rats treated with DEHP was lower than that of rats in an untreated control group. Expressions of long-chain acyl-CoA dehydrogenase and 3-ketoacyl-CoA thiolase, which are involved in fatty acid oxidation and acetate formation in mitochondria, showed an increase in the liver and testes of rats treated with DEHP. The expression of acetyl-CoA synthetase 1 was significantly decreased in the testes and relatively decreased in the liver, while the expression of acetyl-CoA synthetase 2 was significantly increased in the heart. Furthermore, the expressions of acetyl-CoA carboxylase in heart and testes showed a tendency to decrease. From these results, it is suggested that DEHP-treatment increased fatty acid oxidation and acetate formation in liver and testes, and that acetate utilization was increased in peripheral tissues such as the heart.
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PMID:Effect of a hypolipidemic drug, Di (2-ethylhexyl) phthalate, on mRNA-expression associated fatty acid and acetate metabolism in rat tissues. 1728 23

We have initiated clinical selective screening for inborn errors of metabolism in China by analysing amino acids and acylcarnitines in a dried blood filter-paper samples using tandem mass spectrometry. Samples from a total of 3070 children suspected of inborn errors of metabolism were collected through a study network which covered most provinces of China. The diagnoses were further confirmed through clinical symptoms, by gas chromatography-mass spectrometry and other biochemistry studies, and in a few cases by DNA analysis. In all, 212 cases were diagnosed (6.6%) including 92 (43.4%) with amino acids disorders (48 with phenylketonuria, 12 with ornithine carbamoyltransferase deficiency, 7 with tyrosinaemia type I, 9 with maple syrup urine disease, 5 with citrullinaemia type I, 8 with citrullinaemia type II, 2 with homocystinuria, and 1 with argininaemia); 107 (50.5%) with organic acid disorders (including 58 with methylmalonic acidaemia, 13 with propionic acidaemia, 6 with isovaleric acidaemia, 7 with glutaric acidaemia type I, 6 with 3-methylcrotonyl-CoA carboxylase deficiency, 2 with 3-hydroxy-3-methylglutaryl-CoA lyase deficiency, 10 with multiple carboxylase deficiency, and 5 with beta-ketothiolase deficiency); and 13 (6.1%) with fatty acid oxidation disorders (including 1 with carnitine palmitoyltransferase deficiency type I, 1 with carnitine palmitoyltransferase deficiency type II, 1 with short-chain acyl-CoA dehydrogenase deficiency, 5 with medium-chain acyl-CoA dehydrogenase deficiency, 3 with very long-chain acyl-CoA dehydrogenase deficiency, and 2 with multiple acyl-CoA dehydrogenase deficiency). It is suggested that tandem mass spectrometry is useful for selective screening of clinically suspected patients. The majority of diseases (94%) in this study were amino acid disorders and organic acid disorders. Fatty acid oxidation disorders are relatively rare in the Chinese, but medium-chain acyl-CoA dehydrogenase deficiency should be further investigated.
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PMID:Selective screening for inborn errors of metabolism on clinical patients using tandem mass spectrometry in China: a four-year report. 1734 12

Very long-chain acyl-CoA dehydrogenase (VLCAD) catalyzes the first enzymatic step in the mitochondrial beta-oxidation of fatty acids 14-20 carbons in length. More than 100 cases of VLCAD deficiency have been reported with the disease varying from a severe, often fatal neonatal form to a mild adult-onset form. VLCAD is distinguished from matrix-soluble acyl-CoA dehydrogenases by its unique C-terminal domain, homodimeric structure, and localization to the inner mitochondrial membrane. We have for the first time expressed and purified VLCAD using a bacterial system. Recombinant VLCAD had similar biochemical properties to those reported for native VLCAD and the bacterial system was used to study six previously described disease-causing missense mutations including the two most common mild mutations (T220M, V243A), a mutation leading to the severe disease phenotype (R429W), and three mutations in the C-terminal domain (A450P, L462P, and R573W). Of particular interest was the finding that the A450P and L462P bacterial extracts had normal or increased amounts of VLCAD antigen and activity. In the pure form L462P had roughly 30% of wild-type activity while A450P was normal. Using computer modeling both mutations were mapped to a predicted charged surface of VLCAD that we postulate interacts with the mitochondrial membrane. In a membrane pull down assay both mutants showed greatly reduced mitochondrial membrane association, suggesting a mechanism for the disease in these patients. In summary, the bacterial expression system developed here will significantly advance our understanding of both the clinical aspects of VLCAD deficiency and the basic biochemistry of the enzyme.
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PMID:Expression and characterization of mutations in human very long-chain acyl-CoA dehydrogenase using a prokaryotic system. 1737 1

The patient was identified via family screening at the age of 3 years when very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency was diagnosed in his sister by newborn screening. Enzyme and molecular analyses confirmed VLCAD-deficiency (VLCADD). Until the age of 8 years no severe illnesses occurred and the patient was completely asymptomatic without a fat-reduced and fat-modified diet. On regular follow-up, creatine kinase (CK) and liver transaminases were always in the normal range. A long-chain fat load with 1.5 g/kg body weight did not result in clinical symptoms, nor in elevation of CK or liver transaminases. At the age of 8 years, the patient for the first time complained of recurrent muscle pain after exercise. CK concentrations were elevated up to 20,000 U/L during one of these episodes. Medium-chain fat was supplemented. With a medium-chain fat-rich meal directly before exercise, muscle pain after exercise clearly decreased. In asymptomatic mild VLCADD, a fat-reduced diet may not be necessary, whereas in later infancy and adolescence, strenuous physical exercise may require additional energy from medium-chain fat.
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PMID:Effects of a fat load and exercise on asymptomatic VLCAD deficiency. 1745 95

Very long-chain acyl-CoA dehydrogenase (VLCAD) catalyses the initial step of mitochondrial beta-oxidation of long-chain fatty acids with a chain length of 14 to 20 carbons. Deficiency of VLCAD activity has been associated with a range of phenotypes, including a severe lethal form presenting in the infantile period and a milder variant with onset in childhood. Varying rates of residual enzyme activity partly explain the heterogeneity in presentations. Here we report the course of disease in a pair of monozygotic twin sisters who were diagnosed in their late forties during an evaluation for rhabdomyolysis and fatigue. Interestingly, the patients' complaints were most severe during puberty and declined significantly after the menopause. The basis for this observation is uncertain, but may be related to hormonally-mediated changes in lipid metabolism that may occur at these times. As metabolic decompensation can be associated with significant morbidity, timely diagnosis of VLCAD deficiency is important. The introduction of appropriate dietary measures (i.e. avoidance of fasting, long-chain fat restriction and supplementation with medium-chain triglycerides) greatly reduces the likelihood of complications.
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PMID:Very long chain acyl-CoA dehydrogenase deficiency in a pair of mildly affected monozygotic twin sister in their late fifties. 1751 7

Nonalcoholic fatty liver disease (NAFLD) is one of the most frequent causes of abnormal liver dysfunction, and its prevalence has markedly increased. We previously evaluated the expression of fatty acid metabolism-related genes in NAFLD and reported changes in expression that could contribute to increased fatty acid synthesis. In the present study, we evaluated the expression of additional fatty acid metabolism-related genes in larger groups of NAFLD (n=26) and normal liver (n=10) samples. The target genes for real-time PCR analysis were as follows: acetyl-CoA carboxylase (ACC) 1, ACC2, fatty acid synthase (FAS), sterol regulatory element-binding protein 1c (SREBP-1c), and adipose differentiation-related protein (ADRP) for evaluation of de novo synthesis and uptake of fatty acids; carnitine palmitoyltransferase 1a; (CPT1a), long-chain acyl-CoA dehydrogenase (LCAD), long-chain L-3-hydroxyacylcoenzyme A dehydrogenase alpha (HADHalpha), uncoupling protein 2 (UCP2), straight-chain acyl-CoA oxidase (ACOX), branched-chain acyl-CoA oxidase (BOX), cytochrome P450 2E1 (CYP2E1), CYP4A11, and peroxisome proliferator-activated receptor (PPAR)alpha for oxidation in the mitochondria, peroxisomes and microsomes; superoxide dismutase (SOD), catalase, and glutathione synthetase (GSS) for antioxidant pathways; and diacylglycerol O-acyltransferase 1 (DGAT1), PPARgamma, and hormone-sensitive lipase (HSL) for triglyceride synthesis and catalysis. In NAFLD, although fatty acids accumulated in hepatocytes, their de novo synthesis and uptake were up-regulated in association with increased expression of ACC1, FAS, SREBP-1c, and ADRP. Fatty acid oxidation-related genes, LCAD, HADHalpha, UCP2, ACOX, BOX, CYP2E1, and CYP4A11, were all overexpressed, indicating that oxidation was enhanced in NAFLD, whereas the expression of CTP1a and PPARalpha was decreased. Furthermore, SOD and catalase were also overexpressed, indicating that antioxidant pathways are activated to neutralize reactive oxygen species (ROS), which are overproduced during oxidative processes. The expression of DGAT1 was up-regulated without increased PPARgamma expression, whereas the expression of HSL was decreased. Our data indicated the following regarding NAFLD: i) increased de novo synthesis and uptake of fatty acids lead to further fatty acid accumulation in hepatocytes; ii) mitochondrial fatty acid oxidation is decreased or fully activated; iii) in order to complement the function of mitochondria (beta-oxidation), peroxisomal (beta-oxidation) and microsomal (omega-oxidation) oxidation is up-regulated to decrease fatty acid accumulation; iv) antioxidant pathways including SOD and catalase are enhanced to neutralize ROS overproduced during mitochondrial, peroxisomal, and microsomal oxidation; and v) lipid droplet formation is enhanced due to increased DGAT expression and decreased HSL expression. Further studies will be needed to clarify how fatty acid synthesis is increased by SREBP-1c, which is under the control of insulin and AMP-activated protein kinase.
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PMID:Re-evaluation of fatty acid metabolism-related gene expression in nonalcoholic fatty liver disease. 1767 40

Alterations in mitochondrial function have been implicated in the pathogenesis of insulin resistance and type 2 diabetes. However, it is unclear whether the reduced mitochondrial function is a primary or acquired defect in this process. To determine whether primary defects in mitochondrial beta-oxidation can cause insulin resistance, we studied mice with a deficiency of long-chain acyl-CoA dehydrogenase (LCAD), a key enzyme in mitochondrial fatty acid oxidation. Here, we show that LCAD knockout mice develop hepatic steatosis, which is associated with hepatic insulin resistance, as reflected by reduced insulin suppression of hepatic glucose production during a hyperinsulinemic-euglycemic clamp. The defects in insulin action were associated with an approximately 40% reduction in insulin-stimulated insulin receptor substrate-2-associated phosphatidylinositol 3-kinase activity and an approximately 50% decrease in Akt2 activation. These changes were associated with increased PKCepsilon activity and an aberrant 4-fold increase in diacylglycerol content after insulin stimulation. The increase in diacylglycerol concentration was found to be caused by de novo synthesis of diacylglycerol from medium-chain acyl-CoA after insulin stimulation. These data demonstrate that primary defects in mitochondrial fatty acid oxidation capacity can lead to diacylglycerol accumulation, PKCepsilon activation, and hepatic insulin resistance.
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PMID:Mitochondrial dysfunction due to long-chain Acyl-CoA dehydrogenase deficiency causes hepatic steatosis and hepatic insulin resistance. 1794 18

The pathogenesis of hypoketotic hypoglycemia and cardiomyopathy in patients with fatty acid oxidation (FAO) disorders is still poorly understood. In vitro studies are hampered by the lack of natural mutants to asses the effect of FAO inhibition. In addition, only a few inhibitors of FAO are known. Furthermore, most inhibitors of FAO are activating ligands of peroxisome proliferator-activated receptors (PPARs). We show that l-aminocarnitine (L-AC), a carnitine analog, inhibits FAO efficiently, but does not activate PPAR. L-AC inhibits carnitine palmitoyltransferase (CPT) with different sensitivities towards CPT1 and CPT2, as well as carnitine acylcarnitine translocase (CACT). We further characterized L-AC using fibroblasts cell lines from controls and patients with different FAO defects. In these cell lines acylcarnitine profiles were determined in culture medium after loading with [U-(13)C]palmitic acid. In control fibroblasts, L-AC inhibits FAO leading to a reduction of C2-acylcarnitine and elevation of C16-acylcarnitine. In very long-chain acyl-CoA dehydrogenase (VLCAD)-deficient fibroblasts, L-AC decreased the elevated C14-acylcarnitine and increased C16-acylcarnitine. In CACT and CPT2-deficient cell lines, L-AC did not change the already elevated C16-acylcarnitine level, showing that CPT1 is not inhibited. Oxidation of pristanic acid was only partly inhibited at high L-AC concentrations, indicating minimal CACT inhibition. Therefore, we conclude that in intact cells L-AC inhibits CPT2. Combined with our observation that l-AC does not activate PPAR, we suggest that L-AC is useful to simulate a FAO defect in cells from different origin.
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PMID:Characterization of L-aminocarnitine, an inhibitor of fatty acid oxidation. 1807 98

Very-long-chain acyl-CoA dehydrogenase (VLCAD) is a member of the family of acyl-CoA dehydrogenases (ACADs). Unlike the other ACADs, which are soluble homotetramers, VLCAD is a homodimer associated with the mitochondrial membrane. VLCAD also possesses an additional 180 residues in the C terminus that are not present in the other ACADs. We have determined the crystal structure of VLCAD complexed with myristoyl-CoA, obtained by co-crystallization, to 1.91-A resolution. The overall fold of the N-terminal approximately 400 residues of VLCAD is similar to that of the soluble ACADs including medium-chain acyl-CoA dehydrogenase (MCAD). The novel C-terminal domain forms an alpha-helical bundle that is positioned perpendicular to the two N-terminal helical domains. The fatty acyl moiety of the bound substrate/product is deeply imbedded inside the protein; however, the adenosine pyrophosphate portion of the C14-CoA ligand is disordered because of partial hydrolysis of the thioester bond and high mobility of the CoA moiety. The location of Glu-422 with respect to the C2-C3 of the bound ligand and FAD confirms Glu-422 to be the catalytic base. In MCAD, Gln-95 and Glu-99 form the base of the substrate binding cavity. In VLCAD, these residues are glycines (Gly-175 and Gly-178), allowing the binding channel to extend for an additional 12A and permitting substrate acyl chain lengths as long as 24 carbons to bind. VLCAD deficiency is among the more common defects of mitochondrial beta-oxidation and, if left undiagnosed, can be fatal. This structure allows us to gain insight into how a variant VLCAD genotype results in a clinical phenotype.
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PMID:Structural basis for substrate fatty acyl chain specificity: crystal structure of human very-long-chain acyl-CoA dehydrogenase. 1822 65

Deficiency of very long-chain acyl-CoA dehydrogenase (VLCAD) results in accumulation of C14-C18 acylcarnitines and low free carnitine. Carnitine supplementation is still controversial. VLCAD knockout (VLCAD(+/-)) mice exhibit a similar clinical and biochemical phenotype to those observed in humans. VLCAD(+/-) mice were fed with carnitine dissolved in drinking water. Carnitine, acylcarnitines, and gamma-butyrobetaine were measured in blood and tissues. Measurements were performed under resting conditions, after exercise and after 24 h of regeneration. HepG2 cells were incubated with palmitoyl-CoA and palmitoyl-carnitine, respectively, to examine toxicity. With carnitine supplementation, acylcarnitine production was significantly induced. Nevertheless, carnitine was low in skeletal muscle after exercise. Without carnitine supplementation, liver carnitine significantly increased after exercise, and after 24 h of regeneration, carnitine concentrations in skeletal muscle completely replenished to initial values. Incubation of hepatic cells with palmitoyl-CoA and palmitoyl-carnitine revealed a significantly reduced cell viability after incubation with palmitoyl-carnitine. The present study demonstrates that carnitine supplementation results in significant accumulation of potentially toxic acylcarnitines in tissues. The expected prevention of low tissue carnitine was not confirmed. The principle mechanism regulating carnitine homeostasis seems to be endogenous carnitine biosynthesis, also under conditions with increased demand of carnitine such as in VLCAD-deficiency.
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PMID:Carnitine supplementation induces acylcarnitine production in tissues of very long-chain acyl-CoA dehydrogenase-deficient mice, without replenishing low free carnitine. 1831 32


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