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 medium-chain acyl-CoA dehydrogenase (MCAD) deficiency of mitochondrial beta oxidation has been identified in two asymptomatic siblings in a family in which two previous deaths had been recorded, one attributed to sudden infant death syndrome and the other to Reye syndrome. Recognition of this disorder in one of the deceased and in the surviving siblings was accomplished by detection of a diagnostic metabolite, octanoylcarnitine, using a new mass spectrometric technique. This resulted in early treatment with L-carnitine supplement in the survivors, which should prevent metabolic deterioration. Further studies suggest that breast-feeding may be protective for infants with MCAD deficiency. Families with children who have had Reye syndrome or in which sudden infant death has occurred are at risk for MCAD deficiency. We suggest that survivors and asymptomatic siblings should be tested for this treatable disorder.
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PMID:Recognition of medium-chain acyl-CoA dehydrogenase deficiency in asymptomatic siblings of children dying of sudden infant death or Reye-like syndromes. 394 76

Short-chain, medium-chain, and long-chain acyl-CoA dehydrogenases were purified to homogeneity from rat liver mitochondria by sequential chromatography on DEAE-Sephadex A-50, hydroxyapatite, Matrex Gel Blue A, agarose-hexane-CoA, and Bio-Gel A-0.5m. Molecular, immunological, and catalytic properties of the pure acyl-CoA dehydrogenases were investigated. The native molecular weights of these three enzymes were 160,000, 180,000, and 180,000, respectively. The subunit molecular weights of the three enzymes were estimated to be 41,000, 45,000, and 45,000, respectively, indicating that these enzymes are each composed of four subunits of equal size. The FAD content was calculated to be 1 mol/mol of subunit. While FAD binding by short-chain acyl-CoA dehydrogenase was very tight, that by medium-chain acyl-CoA and long-chain acyl-CoA dehydrogenases was less tight. The medium- and long-chain acyl-CoA dehydrogenases were also purified to homogeneity as FAD-free apoenzymes. The apoenzymes were converted to the fully active holoenzymes by incubation with FAD. The three acyl-CoA dehydrogenases were immunologically distinct from each other, i.e. the antibodies raised against the individual enzymes were monospecific and did not cross-react with any other acyl-CoA dehydrogenases. Our preparations of the three enzymes exhibited substrate specificities (as defined in Vappmax and Kappmax) significantly more specific than those of the previous preparations isolated from other sources. The substrate specificities were assessed also by measuring the activities in mitochondrial sonicates after selectively precipitating each enzyme with their individual monospecific antibodies. Butyryl-CoA was almost exclusively dehydrogenated by short-chain acyl-CoA dehydrogenase while C6-C10 acyl-CoAs were mainly dehydrogenated by medium-chain acyl-CoA dehydrogenase. C14-C22 acyl-CoAs were exclusively dehydrogenated by long-chain acyl-CoA dehydrogenase. C24 acyl-CoAs were not dehydrogenated by this enzyme. Lauroyl-CoA appeared to be jointly dehydrogenated by the latter two enzymes. Branched-chain acyl-CoAs were not dehydrogenated by short-chain acyl-CoA dehydrogenase. In the presence of electron-transfer flavoprotein or phenazine methosulfate, 2-enoyl-CoAs were identified as products from the corresponding enzyme/acyl-CoA reactions.
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PMID:Purification and characterization of short-chain, medium-chain, and long-chain acyl-CoA dehydrogenases from rat liver mitochondria. Isolation of the holo- and apoenzymes and conversion of the apoenzyme to the holoenzyme. 396 63

A fluorimetric, ETF-linked procedure to determine activities of acyl-CoA dehydrogenase in cultured human fibroblasts is described. The assay readily distinguishes between cell lines deficient in medium-chain acyl-CoA dehydrogenase, long-chain acyl-CoA dehydrogenase, isovaleryl-CoA dehydrogenase, and controls, and may allow for the diagnosis of heterozygous carriers of these disorders. The method has been made feasible with the development of rapid and efficient procedures to isolate ETF, and offers several advantages over procedures that are currently employed.
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PMID:Fluorometric assay of acyl-CoA dehydrogenases in normal and mutant human fibroblasts. 399

Five patients aged 7 to 21 months are described who developed attacks of coma after a short prodromal illness with diarrhea or vomiting or both. Four had concomitant hypoglycemia, and all had hypoketonemia, with excessive urinary excretion of medium-chain dicarboxylic acids, medium-chain (omega-1)-hydroxyacids, suberylglycine, hexanoylglycine, and octanoylcarnitine. All patients accumulated octanoic acid, decanoic acid, and cis-4-decenoic acid in plasma. Fibroblasts from three patients showed a decreased rate of octanoate oxidation (10%, 12%, and 29% of control values, respectively). These findings suggest a deficiency of medium-chain acyl-CoA dehydrogenase, most probably an autosomal recessive inherited metabolic disorder. Two of the patients died during an acute attack, and a third had severe neurologic sequelae; the two remaining patients recovered. Plasma free carnitine levels were low, but total carnitine was normal. The three surviving patients underwent a fasting test, which did not lead to hypoglycemia, although hypoketonemia, dicarboxylic aciduria, and excessive mobilization of fatty acids did occur. The surviving patients were maintained on frequent carbohydrate-enriched meals.
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PMID:Octanoic acidemia and octanoylcarnitine excretion with dicarboxylic aciduria due to defective oxidation of medium-chain fatty acids. 403 35

Octanoyl-beta-D-glucuronide was identified in the urine of five patients with hypoketotic hypoglycemia and dicarboxylic aciduria due to a defective beta-oxidation of medium-chain fatty acids. Two subjects who ingested large amounts of medium-chain triglycerides also excreted large amounts of the glucuronide. The substance was extracted from the urine with ethyl acetate and analyzed by: (1) gas chromatography/mass spectrometry (GC-MS) of the trimethylsilyl derivative and (2) preparative one-dimensional thin-layer chromatography followed by enzymatic hydrolysis with beta-glucuronidase and again GC-MS. A quantitative analysis was performed indirectly by measuring the urinary bound octanoate after the removal of octanoylcarnitine. Octanoylglucuronide represents an additional mechanism for the detoxification of octanoate; its formation may be of help for the maintenance of carnitine homeostasis in patients with medium-chain acyl-CoA dehydrogenase deficiency.
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PMID:Octanoylglucuronide excretion in patients with a defective oxidation of medium-chain fatty acids. 406 33

A new patient with medium-chain dicarboxylic aciduria and suberyl glycinuria during an attack of acute illness is reported. When, inadvertently he was given medium-chain triglycerides for 2 days, the excretion of abnormal metabolites of medium-chain fatty acids increased and hepatomegaly became more pronounced. During remission a low excretion of the metabolites were observed. After 16 h of fasting hypoglycaemia was accompanied by an increase of urinary dicarboxylic acids and psi-hydroxyacids similar to that found on admission. Interestingly this urinary organic acid pattern persisted 8 h after intravenous administration of glucose. In a blood sample obtained after 16 h of fasting there was hypoketonaemia and increased levels of total free fatty acids, octanoic, decanoic and cis-4-decenoic acids. These biochemical data suggest the existence of a deficiency at the level of medium-chain acyl-CoA dehydrogenase.
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PMID:A new patient with dicarboxylic aciduria suggestive of medium-chain Acyl-CoA dehydrogenase deficiency presenting as Reye's syndrome. 643 27

Concentrations of l-carnitine and acylcarnitines have been determined in urine from patients with disorders of organic acid metabolism associated with an intramitochondrial accumulation of acyl-CoA intermediates. These included propionic acidemia, methylmalonic aciduria, isovaleric acidemia, multicarboxylase deficiency, 3-hydroxy-3-methylglutaric aciduria, methylacetoacetyl-CoA thiolase deficiency, and various dicarboxylic acidurias including glutaric aciduria, medium-chain acyl-CoA dehydrogenase deficiency, and multiple acyl-CoA dehydrogenase deficiency. In all cases, concentrations of acylcarnitines were greatly increased above normal with free carnitine concentrations ranging from undetectable to supranormal values. The ratios of acylcarnitine/carnitine were elevated above the normal value of 2.0 +/- 1.1. l-Carnitine was given to three of these patients; in each case, concentrations of plasma and urine carnitines increased accompanied by a marked increase in concentrations of short-chain acylcarnitines. These acylcarnitines have been examined using fast atom bombardment mass spectrometry in some of these diseases and have been shown to be propionylcarnitine in methylmalonic aciduria and propionic acidemia, isovalerylcarnitine in isovaleric acidemia, and hexanoylcarnitine and octanoylcarnitine in medium-chain acyl-CoA dehydrogenase deficiency. The excretion of these acylcarnitines is compatible with the known accumulation of the corresponding acyl-CoA esters in these diseases. In this group of disorders, the increased acylcarnitine/carnitine ratio in urine and plasma indicates an imbalance of mitochondrial mass action homeostasis and, hence, of acyl-CoA/CoA ratios. Despite naturally occurring attempts to increase endogeneous l-carnitine biosynthesis, there is insufficient carnitine available to restore the mass action ratio as demonstrated by the further increase in acylcarnitine excretion when patients were given oral l-carnitine.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Urinary excretion of l-carnitine and acylcarnitines by patients with disorders of organic acid metabolism: evidence for secondary insufficiency of l-carnitine. 644 Nov 43

Three children in two families presented in early childhood with episodes of illness associated with fasting which resembled Reye's syndrome: coma, hypoglycemia, hyperammonemia, and fatty liver. One child died with cerebral edema during an episode. Clinical studies revealed an absence of ketosis on fasting (plasma beta-hydroxybutyrate less than 0.4 mmole/liter) despite elevated levels of free fatty acids (2.6-4.2 mmole/liter) which suggested that hepatic fatty acid oxidation was impaired. Urinary dicarboxylic acids were elevated during illness or fasting. Total carnitine levels were low in plasma (18-25 mumole/liter), liver (200-500 nmole/g), and muscle (500-800 nmole/g); however, treatment with L-carnitine failed to correct the defect in ketogenesis. Studies on ketone production from fatty acid substrates by liver tissue in vitro showed normal rates from short-chain fatty acids, but very low rates from all medium and long-chain fatty acid substrates. These results suggested that the defect was in the mid-portion of the intramitochondrial beta-oxidation pathway at the medium-chain acyl-CoA dehydrogenase step. A new assay for the electron transfer flavoprotein-linked acyl-CoA dehydrogenases was used to test this hypothesis. This assay follows the decrease in electron transfer flavoprotein fluorescence as it is reduced by acyl-CoA-acyl-CoA dehydrogenase complex. Results with octanoyl-CoA as substrate indicated that patients had less than 2.5% normal activity of medium-chain acyl-CoA dehydrogenase. The activities of short-chain and isovaleryl acyl-CoA dehydrogenases were normal; the activity of long-chain acyl-CoA dehydrogenase was one-third normal. These results define a previously unrecognized inherited metabolic disorder of fatty acid oxidation due to deficiency of medium-chain acyl-CoA dehydrogenase.
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PMID:Medium-chain acyl-CoA dehydrogenase deficiency in children with non-ketotic hypoglycemia and low carnitine levels. 664 97

Acylcarnitine profiling from blood or plasma samples by electrospray tandem mass spectrometry (ESI-MS/MS) has been recognized recently as a useful tool in the biochemical diagnosis of propionic acidemia, methylmalonic acidemia together with short-chain and medium-chain acyl-CoA dehydrogenase deficiencies. In the current study, we have investigated the diagnostic capabilities of ESI-MS/MS in other types of organic acidemias and amino acid catabolism disorders. Using multiple scanning functions, we examined the potential for the simultaneous profiling of both acylcarnitines and amino acids, in each of the samples. Our method was found to be specific and accurate; allowing quantification of acylcarnitines and amino acids well below, and significantly above, published normal levels. Complete automation of sample introduction has been achieved, allowing the analysis of up to 200 samples in one injection sequence, at a rate of one sample every 3 min, with excellent separation between successive injections. In our hands, this method permits screening for 20 organic acid and amino acid disorders, using a single sample injection. In our laboratory, more than 2000 blood samples have been analyzed, and 52 new cases were diagnosed by this method. We also confirmed the diagnosis of another 75 previously known cases.
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PMID:Diagnosis of inborn errors of metabolism from blood spots by acylcarnitines and amino acids profiling using automated electrospray tandem mass spectrometry. 749 54

We offer a large scale purification procedure for the recombinant human liver medium-chain acyl-CoA dehydrogenase (HMCAD). This procedure routinely yield 100-150 mg of homogeneous preparation of the enzyme from 80 L of the Escherichia coli host cells. A comparative investigation of kinetic properties of the human liver and pig kidney enzymes revealed that, except for a few minor differences, both of these enzymes are nearly identical. We undertook detailed kinetic and thermodynamic investigations for the interaction of HMCAD-FAD with three C8-CoA molecules (viz., octanoyl-CoA, 2-octenoyl-CoA, and 2-octynoyl-CoA), which differ with respect to the extent of unsaturation of the alpha-beta carbon center; octanoyl-CoA and 2-octenoyl-CoA serve as the substrate and product of the enzyme, respectively, whereas 2-octynoyl-CoA is known to inactivate the enzyme. Our experimental results demonstrate that all three C8-CoA molecules first interact with HMCAD-FAD to form corresponding Michaelis complexes, followed by two subsequent isomerization reactions. The latter accompany either subtle changes in the electronic structures of the individual components (in case of 2-octenoyl-CoA and 2-octynoyl-CoA ligands), or a near-complete reduction of the enzyme-bound flavin (in case of octanoyl-CoA). The rate and equilibrium constants intrinsic to the above microscopic steps exhibit marked similarity with different C8-CoA molecules. However, the electronic structural changes accompanying the 2-octynoyl-CoA-dependent inactivation of enzyme is 3-4 orders of magnitude slower than the above isomerization reactions. Hence, the octanoyl-CoA-dependent reductive half-reaction and the 2-octynoyl-CoA-dependent covalent modification of the enzyme occur during entirely different microscopic steps. Arguments are presented that the origin of the above difference lies in the protein conformation-dependent orientation of Glu-376 in the vicinity of the C8-CoA binding site.
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PMID:Recombinant human liver medium-chain acyl-CoA dehydrogenase: purification, characterization, and the mechanism of interactions with functionally diverse C8-CoA molecules. 757 6


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