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)

The mitochondrial beta-oxidation of 2-methyl fatty acids was studied with coupled rat liver mitochondria and purified enzymes. Measurements of mitochondrial respiration supported by 2-methyl fatty acids, straight chain fatty acids, or their coenzyme A (CoA) thioesters revealed that free short-chain and medium-chain 2-methyl fatty acids are oxidized nearly or as efficiently as are their straight chain analogs. Long-chain 2-methyl hexadecanoyl-CoA is also oxidized, although more slowly than its unbranched counterpart. However, medium-chain 2-methyldecanoyl-CoA, in contrast to its unbranched analog, is not oxidized at all. Of all acyl-CoA dehydrogenases only long-chain acyl-CoA dehydrogenase acts on medium-chain and long-chain 2-methylacyl-CoA thioesters. The resultant 2-methyl-2-enoyl-CoA thioesters are substrates of the mitochondrial trifunctional beta-oxidation complex which catalyzes the sequential hydration, dehydrogenation, and thiolytic cleavage of 2-methyl-substituted substrates to yield chain-shortened acyl-CoA thioesters and propionyl-CoA. The matrix enzymes L-3-hydroxyacyl-CoA dehydrogenase and 3-ketoacyl-CoA thiolase, in contrast to enoyl-CoA hydratase, are inactive with medium-chain and long-chain 2-methyl-substituted chain substrates. The specificity of the beta-oxidation enzymes toward 2-methyl-branched substrates forms the basis for assays of long-chain acyl-CoA dehydrogenase and the trifunctional beta-oxidation complex in the presence of their mitochondrial isozymes. It is concluded that rat liver mitochondria can oxidize 2-methyl fatty acids, but does so most effectively with medium-chain and short-chain ones that can enter mitochondria directly in a carnitine-independent manner.
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PMID:Mitochondrial beta-oxidation of 2-methyl fatty acids in rat liver. 763 25

The Institution's experience with hypoglycemia in different types of organic acidemias, branched chain amino acidemia (MSUD), and disorders of fructose metabolism was reviewed retrospectively. The charts of 144 patients who were followed for 1-5 years were studied for the severity and frequency of hypoglycemia. The patients were mainly Saudi; however, 10-25% were from neighboring countries. Therefore, the observations pertain to the genetic groups in the Arabian peninsula. Organic acidemias which primarily manifest with neurologic signs, such as 4-hydroxybutyric aciduria, infantile onset 3-methylglutaconic aciduria, and glutaric aciduria type 1 never showed hypoglycemia. Patients with beta-ketothiolase deficiency, biotinidase deficiency, or intermittent or intermediate MSUD, also did not have hypoglycemia during metabolic crisis. Hypoglycemia was rare and mild among neonates with classic MSUD, ethylmalonic aciduria, and isovaleric acidemia. Less than 50% of the patients with MSUD older than 8 months, pyruvate carboxylase deficiency, methylmalonic acidemia, or propionic acidemia had hypoglycemia during metabolic crisis. On the other hand, patients with 3-hydroxy-3-methyl glutaryl-CoA lyase deficiency, holocarboxylase synthetase deficiency, medium or long-chain acyl-CoA dehydrogenase deficiency, neonatal onset 3-methylglutaconic aciduria, glutaric aciduria type 2, and disorders of fructose metabolism invariably had moderate-to-severe hypoglycemia associated with metabolic crisis. The purpose of this report is to provide the pediatrician, particularly in the Middle East, with a diagnostic guideline to the identification and management of different types of organic acidemias, based on co-existing hypoglycemia.
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PMID:Comparative frequency and severity of hypoglycemia in selected organic acidemias, branched chain amino acidemia, and disorders of fructose metabolism. 772 85

Studies of effects of 4-thia-substituted fatty acid analogues on rat liver lipid metabolism are described. With isolated hepatocytes tetradecylthiopropionate was shown to divert [1-14C]oleate from beta-oxidation into esterification, the total amount of [1-14C]oleate metabolized remaining unchanged. Tetradecylthiopropionyl-CoA was a good substrate for mitochondrial carnitine palmitoyltransferases I and II (EC 2.3.1.21), acyl-CoA oxidase (EC 1.3.3.6), for the microsomal (but not mitochondrial) glycerophosphate acyltransferase (EC 2.3.1.15), and for long-chain acyl-CoA dehydrogenase (EC 1.3.99.3). In isolated hepatocytes, its 4-thia-trans-2-enoic derivative, tetradecylthioacrylate, inhibits both beta-oxidation of, and incorporation of, [1-14C]oleate into lipids. In rat liver mitochondria tetradecylthiocrylate inhibited beta-oxidation. The degree of inhibition was not markedly increased by preincubation with tetradecylthioacrylate. Tetradecylthioacrylyl-CoA was a poor substrate for carnitine palmitoyltransferase I, and inhibited carnitine palmitoyltransferase II, microsomal glycerophosphate acyltransferase and acyl-CoA oxidase. It is concluded that the inhibitory effects of tetradecylthiopropionyl-CoA are expressed intramitochondrially, whereas primary sites of inhibition by tetradecylthioacrylyl-CoA are extramitochondrial.
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PMID:Effects of tetradecylthiopropionic acid and tetradecylthioacrylic acid on rat liver lipid metabolism. 783 78

We studied the effect of riboflavin treatment on the clinical status and on the activities of beta-oxidation and respiratory chain enzymes in a 69-year-old patient with late-onset myopathy. Before treatment, she was very weak and wasted in the limbs and trunk muscles; also, she could not walk or attend to daily activities. Marked lipid storage was present in the muscle biopsy. The activities of short-chain acyl coenzyme A (acyl-CoA) dehydrogenase (SCAD), medium-chain acyl-CoA dehydrogenase (MCAD), and long-chain acyl-CoA dehydrogenase (LCAD) in isolated muscle mitochondria were reduced to less than 10% of control values. This defect in fatty acid oxidation was associated with a marked deficiency of two flavin-dependent respiratory chain complexes: complex I activity was 20% and complex II activity was 25% of control values. By contrast, the activities of the nonflavin-dependent complex III and complex IV were normal. Western blot analysis of the patient's muscle mitochondrial extracts with antibodies raised against purified SCAD, MCAD, and the alpha- and beta-subunits of the electron transfer flavoprotein (ETF) showed absence of SCAD cross-reacting material (CRM), markedly decreased MCAD-CRM, and normal amounts of both alpha- and beta-ETF-CRM. After riboflavin treatment, the patient's clinical status dramatically improved and morphologic changes in muscle disappeared. SCAD activity increased to 55% of control values, whereas MCAD, LCAD, and complex I and complex II activities normalized. SCAD and MCAD immunoreactivity was restored to normal. On the basis of our experience and the data in the literature, we concluded that some lipid storage myopathies can show dramatic response to riboflavin.
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PMID:Late-onset riboflavin-responsive myopathy with combined multiple acyl coenzyme A dehydrogenase and respiratory chain deficiency. 796 76

At least 12 fatty acid oxidation disorders are known to be responsible for cases of sudden and unexpected death in early childhood. A specific diagnosis of these disorders is essential for genetic counseling and for the screening of siblings potentially at risk for life-threatening episodes of fasting intolerance. Postmortem blood and urine samples often are not available for further biochemical studies, and currently only medium-chain acyl-CoA dehydrogenase (MCAD) deficiency can be diagnosed by the molecular analysis of tissues. We developed a postmortem screening method for fatty acid oxidation disorders by the simultaneous measurement of C8-C20 fatty acids, glucose, lactate, and other metabolites from the methanol wash of a pellet obtained by ultracentrifugation of liver homogenate. Cis-4-decenoic acid was present in five confirmed cases with MCAD deficiency and in one case with glutaric aciduria type II and was absent in 97 of 100 randomly chosen sudden death cases, at least 81 of which were diagnosed as sudden infant death syndrome (SIDS). C14-C18 monounsaturated fatty acids were significantly elevated in the one examined case affected with long-chain acyl-CoA dehydrogenase (LCAD) deficiency. The metabolite profiles in two cases with carnitine uptake deficiency were less informative, but they shared with all the other disease controls a very low glucose concentration, a finding compatible with premortem hypoglycemia. This method is proposed as a simple and practical means of biochemical screening to follow up the postmortem finding of liver fat infiltration.
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PMID:Biochemical diagnosis of fatty acid oxidation disorders by metabolite analysis of postmortem liver. 805 17

Short-chain acyl-CoA dehydrogenase (SCAD) is one of five homologous dehydrogenases that catalyze the first reaction in the beta-oxidation of fatty acids. As the name implies, the substrate for this enzyme is short-chain acyl-CoA (C4-C6). We report here the coding and 3'UT sequence of the cDNA for mouse precursor SCAD. The mouse SCAD cDNA coding sequence covers 1239 bp. This represents a 24-amino-acid leader peptide and a 388-amino-acid mature peptide. Comparison of this sequence with reported rat and human SCAD cDNA sequences reveals a high degree of homology among the three species. Comparison of the amino acid sequence with that of other acyl-CoA dehydrogenases, medium-chain acyl-CoA dehydrogenase and long-chain acyl-CoA dehydrogenase, also shows a high degree of homology.
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PMID:Cloning and characterization of the mouse short-chain acyl-CoA dehydrogenase cDNA. 827 99

Skin fibroblast carnitine uptake studies may identify and differentiate primary and secondary carnitine deficiency disorders. To confirm the specificity of these studies in differentiating primary from secondary carnitine deficiency disorders, we have studied carnitine uptake in the cultured skin fibroblasts from 5 children who have various enzymatic defects in intramitochondrial beta-oxidation including short-chain, medium-chain and long-chain acyl-CoA dehydrogenase and short-chain L-3-hydroxyacyl-CoA dehydrogenase deficiencies, and in 4 children with cytochrome oxidase deficiency. Carnitine uptake was normal in the intramitochondrial beta-oxidation cases, suggesting other mechanisms for their carnitine deficiency. Therefore, intramitochondrial beta-oxidation defects associated with carnitine deficiency can be differentiated from primary carnitine deficiency not only by the presence of an abnormal dicarboxylic aciduria but by normal skin fibroblast carnitine uptake. In contrast to these findings, carnitine uptake in the cultured skin fibroblasts of four children with secondary carnitine deficiency due to cytochrome oxidase deficiency demonstrated a partial decrease in the maximal velocity of uptake (20-47% control Vmax), similar to that observed in the primary carnitine deficiency heterozygotes. We propose that this observation may be due to a generalized decrease in intracellular ATP, thus decreasing the efficiency of the energy- and sodium-dependent carnitine transporter. We conclude that carnitine uptake studies in cultured skin fibroblasts will contribute to an understanding of the mechanisms of carnitine depletion in the primary and secondary carnitine deficiency disorders.
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PMID:Skin fibroblast carnitine uptake in secondary carnitine deficiency disorders. 838 12

Genetic defects in fatty acid oxidation are important, inherited causes of cardiomyopathy, skeletal myopathies, and childhood sudden death. The clinical manifestations and their severity vary widely among affected subjects and different age groups. Although measurement of serum and urinary fatty acid intermediary metabolites and enzymatic assays establish the diagnosis of a defect in fatty acid oxidation, they do not predict the specific clinical manifestations nor their severity in a given subject. To determine whether impaired myocardial fatty acid utilization, indicative of cardiac phenotypic expression of a specific genetic abnormality in fatty acid oxidation, can be detected, cardiac positron emission tomography with the metabolic tracers carbon-11-labeled palmitate and acetate was performed in 6 patients with long-chain acyl-CoA dehydrogenase (ACD) deficiency and in 9 control subjects. The myocardial extraction of both tracers was similar in patients and controls. The rate of clearance of palmitate from myocardium was significantly prolonged in patients compared with that in control subjects (0.022 +/- 0.012 vs 0.061 +/- 0.033 min-1; p < 0.025), indicative of a decreased rate of oxidation of long-chain fatty acids. Furthermore, the extent of diminution of clearance of palmitate, quantified in terms of the rate of clearance for palmitate divided by that for acetate (to correct for individual differences in overall mitochondrial oxidative metabolic flux), correlated with the clinical severity of the long-chain ACD deficiency. Accordingly, noninvasive evaluation with positron emission tomography may not only facilitate diagnosis, but also enable assessment of the pathogenetic impact and effects of therapeutic interventions in the hearts of subjects with specific, inherited defects in fatty acid oxidative metabolism.
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PMID:Detection and assessment by positron emission tomography of a genetically determined defect in myocardial fatty acid utilization (long-chain acyl-CoA dehydrogenase deficiency). 844 75

The cDNA for mouse long-chain acyl-CoA dehydrogenase (Acadl, gene symbol; LCAD, enzyme) was cloned and characterized. The cDNA was obtained by library screening and reverse transcription-polymerase chain reaction (RT-PCR). The deduced amino acid sequence showed a high degree of homology to both the rat and the human LCAD sequence. Northern analysis of multiple tissues using the mouse Acadl cDNA as a probe showed two bands in all tissues examined. We found a total of three distinct mRNAs for Acadl. These three mRNAs were encoded by a single gene that we mapped to mouse chromosome 1. The three transcripts differed in the 3' untranslated region due to use of alternative polyadenylation sites. Quantitative evaluation of a multitissue Northern blot showed a varied ratio of the larger transcript as compared with the smaller transcripts.
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PMID:RNA expression and chromosomal location of the mouse long-chain acyl-CoA dehydrogenase gene. 853 22

Very-long-chain acyl-CoA dehydrogenase (VLCAD) is a major enzyme catalyzing long-chain fatty acids in the first step of mitochondrial beta-oxidation system. Inborn error of this enzyme can cause sudden infant death syndrome and hypertrophic cardiomyopathy is present at a significantly high frequency. To investigate VLCAD deficiency at the genomic DNA level, we cloned the VLCAD gene and analyzed the structure. The gene is about 5.4 kb long and contains 20 exons. We performed mutation analysis in two patients, both having a 105 bp deletion encompassing bases 1078-1182 in cDNA. A point mutation (GT-->AT) at 5' splice site of intron 11 was identified in both patients. This mutation seems to cause skipping of exon 11 corresponding to the 105 bp deletion. This is the first documentation of aberrant splicing in the VLCAD gene.
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PMID:Genomic DNA organization of human mitochondrial very-long-chain acyl-CoA dehydrogenase and mutation analysis. 855 25


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