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)

Plasma free fatty acid profiles from patients suffering from various mitochondrial beta-oxidation deficiencies were analyzed by gas chromatography-mass spectrometry. cis-4-Decenoic acid (10:1n-6) in medium-chain acyl-CoA dehydrogenase deficiency and cis-5-tetradecenoic acid (14:1n-9) in very-long-chain and 3-hydroxy-long chain acyl-CoA dehydrogenase deficiencies are characteristic of these diseases. In addition, patients with 3-hydroxy-long chain acyl-CoA dehydrogenase deficiency showed a specific increase of 3-hydroxy-long chain fatty acids. The study of plasma free fatty acids is an easy and useful methodology for the diagnostic approach of some mitochondrial beta-oxidation deficiencies, allowing us to establish a quick differentiation between medium- and long-chain defects.
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PMID:Plasma free fatty acids in mitochondrial fatty acid oxidation defects. 946 49

The acyl-CoA dehydrogenases are a family of mitochondrial flavoenzymes involved in fatty acid and branched chain amino-acid metabolism. Long chain acyl-CoA dehydrogenase (LCAD) and short/branched chain acyl-CoA dehydrogenase (SBCAD) have been shown to have activity towards 2-methyl branched chain acyl-CoA substrates of varying chain lengths. In humans, long chain 2-branched chain fatty acids such as pristanic acid are largely thought to be metabolized in peroxisomes through desaturation of their CoA esters by branched chain acyl-CoA oxidase, but LCAD is also capable of utilizing 2-methyldecanoyl- and 2-methylpalmitoyl-CoA as substrate [1]. Since the acyl-CoA oxidase reaction is specific for the S-enantiomer of the branched chain substrates, we investigated the stereo specificity of mitochondrial LCAD. Purified LCAD had a specific activity of 390 and 340 mU/mg of purified LCAD protein using palmitoyl-CoA and S-2-methylpentadecanoyl-CoA, respectively, as substrate. No activity was measurable with R-2-methylpentadecanoyl-CoA. Purified medium chain acyl-CoA dehydrogenase (MCAD) could also utilize S-2-methylpentadecanoyl-CoA as a substrate, but not R-2-methylpentadecanoyl-CoA. These results indicate that LCAD and MCAD are specific for the S-enantiomers of methylbranched chain substrates. Crude mitochondrial extracts showed no activity when dehydrogenating activity was measured with R/S-2-methylpalmitoyl-CoA or S-2-methylpentadecanoyl-CoA after inactivation of the extract with antibodies to very long chain acyl-CoA dehydrogenase and MCAD, suggesting that this substrate is not useful in identifyig clinical deficiencies of LCAD.
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PMID:Human long chain, very long chain and medium chain acyl-CoA dehydrogenases are specific for the S-enantiomer of 2- methylpentadecanoyl-CoA. 948 54

A gene from Mycobacterium tuberculosis coding for acyl-CoA dehydrogenase was cloned, overexpressed and characterized on the basis of enzyme activity with various chain length substrates. The results show that the protein is a medium chain acyl-CoA dehydrogenase (MCADH). The mycobacterium protein expressed appears to be unique, since by comparison, the active site glutamic acid of the protein does not lie in the same position as other well characterized MCADH, but in a position present in long chain and isovaleryl acyl-CoA dehydrogenases (LCADH and IVDH).
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PMID:Cloning and expression of an acyl-CoA dehydrogenase from Mycobacterium tuberculosis. 953 63

When placed in the cold (4 degreesC), BALB/cByJ mice of both genders rapidly lose body temperature as compared with the control strain, C57BL/6J. This sensitivity to cold resembles that previously described for mice with a defect in nonshivering thermogenesis due to the targeted inactivation of the brown adipocyte-specific mitochondrial uncoupling protein gene, Ucp1. Genetic mapping of the trait placed the gene on chromosome 5 near Acads, a gene encoding the short chain acyl CoA dehydrogenase, which is mutated in BALB/cByJ mice. The analysis of candidate genes in the region indicated a defect only in the expression of Acads. Confirmation of the importance of fatty acid oxidation to thermogenesis came from our finding that mice carrying the targeted inactivation of the long chain acyl CoA dehydrogenase gene (Acadl) are also sensitive to the cold. Both of these mutations attenuate the induction of genes normally responsive to adrenergic signaling in brown adipocytes. These results suggest that the action of fatty acids as regulators of gene expression has been perturbed in the mutant mice. From a clinical perspective, it is important to determine whether defects in thermogenesis may be a phenotype in human neonates with inherited deficiencies in fatty acid beta-oxidation.
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PMID:Abnormal nonshivering thermogenesis in mice with inherited defects of fatty acid oxidation. 980 86

A 5-month-old Korean boy who presented with lethargy and cardiomyopathy was diagnosed with very long chain acyl coenzyme A dehydrogenase (VLCAD) deficiency by organic acid, fatty acid, acylcarnitine, and molecular genetic analysis. The patient was a compound heterozygote for mutations in the VLCAD gene. One allele contains a 3-bp deletion in exon 6, deleting glutamic acid in codon 130 (E130del ); this allele is of paternal origin. The patient's maternally derived allele is a novel mutation, C1843T in exon 20, which creates a premature termination codon (R615stop ). Although molecular genetic characterization of VLCAD deficiency is limited to a few patients, heterogeneity of mutations is already apparent. However, the E130del is a relatively frequent mutant allele, which has been noted in 2 previously identified patients. The 2 mutant alleles in our patient appear to be responsible for his severe and fatal clinical manifestations.
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PMID:Very long chain acyl coenzyme A dehydrogenase deficiency in a 5-month-old Korean boy: identification of a novel mutation. 1043 Nov 22

Very long chain acyl-CoA dehydrogenase (VLCAD) catalyzes the initial step of long chain fatty acid oxidation in the mitochondria. Patients with VLCAD deficiency have recently been observed with two clinical phenotypes. The cardiac form presents with an early onset cardiomyopathy and a high incidence of infant death, while the hypoglycemic form resembles medium chain acyl-CoA dehydrogenase (MCAD) manifesting with hypoketotic hypoglycemia. In our investigation on the molecular basis for these phenotypes, we identified two novel mutations in one VLCAD patient with the hypoglycemic form, a C953T (Pro318Leu) mutation in exon 10 resulting in a substitution of proline 318 by leucine on one allele, and a C1194A (Tyr398Stop) mutation in exon 12 which created a premature stop codon TAA on another allele. The Tyr398Stop mutation may result in a truncated protein or instable messenger RNA.
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PMID:Identification of two novel mutations in the hypoglycemic phenotype of very long chain acyl-CoA dehydrogenase deficiency. 1052 89

Ketonuria accompanying hypoglycaemia is conventionally thought to exclude fat oxidation defects. We describe a 2 year old girl with hypoglycaemic encephalopathy in whom a diagnosis of very long chain acyl CoA dehydrogenase deficiency was suggested on the basis of acylcarnitine analysis despite massive ketonuria.
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PMID:Fat oxidation defect presenting with overwhelming ketonuria. 1239 Sep 22

Long chain acyl-CoA dehydrogenase (LCAD) has recently been shown to be the mitochondrial enzyme responsible for the beta-oxidation of branched chain and unsaturated fatty acids [Biochim. Biophys. Acta 1393 (1998) 35; Biochim. Biophys. Acta 1485 (2000) 121]. Whilst disorders of short, medium and very long chain acyl dehydrogenases are known, there is no known disorder of LCAD deficiency in humans. Experimental LCAD deficiency in mice shows an acyl-carnitine profile with prominent elevations of unsaturated fatty acid metabolites C14:1 and C14:2 [Hum. Mol. Genet. 10 (2001) 2069]. A child with autism whose acyl-carnitine profile also shows these abnormalities is presented, and it is hypothesized that the child may have LCAD deficiency. Additional metabolic abnormalities seen in this patient include alterations of TCA energy production, ammonia detoxification, reduced synthesis of omega-3 DHA, and abnormal cholesterol metabolism. These metabolic changes are also seen as secondary abnormalities in dysfunction of fatty acid beta-oxidation, and have also been reported in autism. It is hypothesized that LCAD deficiency may be a cause of autism. Similarities between metabolic disturbances in autism, and those of disorders of fatty acid beta-oxidation are discussed.
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PMID:Is autism a disorder of fatty acid metabolism? Possible dysfunction of mitochondrial beta-oxidation by long chain acyl-CoA dehydrogenase. 1514 59

The main purpose of this study was to identify mitochondrial proteins that exhibit post-translational oxidative modifications during the aging process and to determine the resulting functional alterations. Proteins forming adducts with malondialdehyde (MDA), a product of lipid peroxidation, were identified by immunodetection in mitochondria isolated from heart and hind leg skeletal muscle of 6-, 16-, and 24-month-old mice. Aconitase, very long chain acyl coenzyme A dehydrogenase, ATP synthase, and alpha-ketoglutarate dehydrogenase were detected as putative targets of oxidative modification by MDA. Aconitase and ATP synthase from heart exhibited significant decreases in activity with age. Very long chain acyl coenzyme A dehydrogenase and alpha-ketoglutarate dehydrogenase activities were unaffected during aging in both heart and skeletal muscle. This suggests that the presence of a post-translational oxidative modification in a protein does not a priori reflect an alteration in activity. The biological consequences of an age-related decrease in aconitase and ATP synthase activities may contribute to the decline in mitochondrial bioenergetics evident during aging.
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PMID:Aconitase and ATP synthase are targets of malondialdehyde modification and undergo an age-related decrease in activity in mouse heart mitochondria. 1578 Dec 44

A loss-of-function mutation of the mitochondrial beta-oxidation enzyme l-3-hydroxyacyl-CoA dehydrogenase, short chain (HADHSC), has been associated with hyperinsulinemic hypoglycemia in man. It is still unclear whether loss of glucose homeostasis in these patients (partly) results from a dysregulation of beta cells. This study examines HADHSC expression in purified rat beta cells and investigates whether its selective suppression elevates insulin release. Beta cells expressed the highest levels of HADHSC mRNA and protein of all examined tissues, including those with high rates of mitochondrial beta-oxidation. On the other hand, beta cells expressed relatively low levels of other beta-oxidation enzymes (acyl-CoA dehydrogenase short, medium, and long chain and acetyl-coenzyme A acyltransferase 2). HADHSC expression was sequence-specifically silenced by RNA interference, and the effects were examined on glucose-stimulated insulin secretion following 48-72 h of suppression. In both rat beta cells and in the beta cell line INS1 832-13, HADHSC silencing resulted in elevated insulin release at low and at high glucose concentrations, which appeared not to be caused by increased rates of glucose metabolism or an inhibition in fatty acid oxidation. These data indicate that the normal beta cell phenotype is characterized by a high expression of HADHSC and a low expression of other beta-oxidation enzymes. Down-regulation of HADHSC causes an elevated secretory activity suggesting that this enzyme protects against inappropriately high insulin levels and hypoglycemia.
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PMID:Specificity in beta cell expression of L-3-hydroxyacyl-CoA dehydrogenase, short chain, and potential role in down-regulating insulin release. 1749 Oct 19


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