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)

1. Carnitine esters of erucic acid (22:1 n-9 cis), cetoleic acid (22:1 n-11 cis), brassidic acid (22:1 n-9 trans), gadoleic acid (20:1 n-9 cis) and oleic acid (18:1 n-9 cis) have been compared as mitochondrial substrates and as inhibitors of palmitoylcarnitine oxidation in heart and liver mitochondria. 2. Both the rate of intramitochondrial-CoA acylation and the rate of beta-oxidation decreases as the chain length increases from C18 to C22. There are no significant differences among the three C22 isomers as oxidizable substrates. 3. All the tested acylcarnitines inhibit palmitoylcarnitine oxidation. The C18 and C20 acylcarnitines inhibit by virtue of being competing substrates; i.e. the respiration is not inhibited. The C22-isomers inhibit also respiration; this shows that the inhibition of palmitolycarnitine oxidation is not compensated for by oxidation of C22-acylcarnitines. Brassidoylcarnitine inhibits the oxidation of palmitoylcarnitine and respiration less than erucoyl-and cetoleoylcarnitine. The different behaviour of the C22-isomers is probably due to the difference in their competitive properties with respect to long-chain acyl-CoA dehydrogenase. 4. All C22 acylcarnitines seem to be relatively better oxidized in the liver than in the heart mitochondria while their inhibitory effect on the usage of the radioactive palmitoylcarnitine is very similar. 5. Palmitoylcarnitine inhibits almost completely the "endogenous" formation of acetyl-CoA presumably from malate via pyruvate in the liver mitochondria while the C22-acylcarnitines cause only a partial inhibiton of this acetyl-CaO formation.
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PMID:Monoethlenic C20 and C22 fatty acids in marine oil and rapeseed oil. Studies on their oxidation and on their relative ability to inhibit palmitate oxidation in heart and liver mitochondria. 87 57

Long-chain fatty acids (LCFA) are oxidized by muscle mitochondria after transport in the cytosol by fatty-acid-binding protein(s) and their activation by a thiokinase. Carnitine, two forms of carnitine palmitoyltransferase(s) and carnitine acylcarnitine translocase are involved in LCFA gating. A primary genetic carnitine deficiency occurs in children with dilated cardiomyopathy, hypoglycaemia and low carnitine content in plasma, liver and muscle, owing to a defect in a common high-affinity transport system. This high-affinity transport in muscle differs from a low-affinity transport that has modifications during muscle maturation. The genetic enzyme defects of beta-oxidation (long-chain acyl-CoA dehydrogenase, medium- and short-chain acyl-CoA-dehydrogenase) present with Reye-like attacks that may lead to non-ketotic hypoglycaemia, coma and sudden infant death syndrome. There is elevated urinary excretion of dicarboxylic acids, acylcarnitines and acylglycines. Secondary carnitine deficiency may occur. ETF and ETF dehydrogenase deficiencies may present in a neonatal form with congenital anomalies, or in a later-onset form with ethylmalonic adipic aciduria. A still-unidentified defect leads to LCFA accumulation in fibroblasts, bone marrow, liver and muscle cells in a multisystem triglyceride disorder.
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PMID:Defects of fatty-acid oxidation in muscle. 226 28

Medium-chain acyl-CoA dehydrogenase deficiency is a recently described inborn error of metabolism characterized by episodes of coma and hypoketotic hypoglycaemia in response to prolonged fasting. Secondary carnitine deficiency has been documented in these patients as well as the excretion in the urine of medium-chain-length acyl carnitine esters, such as octanoylcarnitine. Based on the potential toxicity of medium-chain fatty acid metabolites and the beneficial responses of patients with other inborn errors of metabolism and secondary carnitine deficiency, oral carnitine has been proposed as treatment for children with medium-chain acyl-CoA dehydrogenase deficiency. We report the results of carefully monitored fasting challenges of an infant with this deficiency both before and after 3 months of oral carnitine therapy. Carnitine supplementation failed to prevent lethargy, vomiting, hypoglycaemia and accumulation of free fatty acids in response to fasting despite normalization of plasma carnitine levels and a marked increase in urinary excretion of acyl-carnitine esters. Potentially toxic medium-chain fatty acids accumulated in the plasma in spite of therapy. Based on this study of one patient, we stress that avoidance of fasting and prompt institution of glucose supplementation in situations when oral intake is interrupted remain the mainstays of therapy for medium-chain acyl-CoA dehydrogenase deficient patients.
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PMID:Medium-chain acyl-CoA dehydrogenase deficiency: metabolic effects and therapeutic efficacy of long-term L-carnitine supplementation. 250 71

The activities of antimycin A-insensitive palmitoyl-CoA oxidation and of palmitoyl-CoA oxidase in peroxisomes from chicken liver were similar to those of rat liver. Catalase and D-amino acid oxidase activities in peroxisomes from chicken liver were lower than those of rat liver, and urate oxidase was not detected. Carnitine acetyl-transferase and palmitoyltransferase levels in chicken liver were 18- and 2-fold higher, respectively, than those of rat liver. Peroxisomal palmitoyl-CoA oxidation of chicken liver was inhibited by cyanide, in contrast to that of rat liver, although it was insensitive to antimycin A. Subcellular distribution of this enzyme was similar to that of rat liver; i.e., it was located only in the peroxisomes. The fatty acyl-CoA oxidase had a higher affinity toward medium- to long-chain fatty acyl-CoAs (C8 to C16) than shorter-chain analogs. The fatty acyl-CoA dehydrogenase had a broad affinity toward fatty acyl-CoAs (C4 to C18). Carnitine acetyltransferase was distributed equally in both peroxisomes and mitochondria. Carnitine palmitoyltransferase was distributed in the proportion of 20 and 80% in peroxisomes and mitochondria, respectively.
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PMID:Peroxisomal fatty acyl-coenzyme A oxidation in chicken liver. 613 87

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

Rats treated with six to eight doses (80 mg/kg, i.p.) of 4-pentenoic acid, an inhibitor of mitochondrial fatty acid oxidation in vitro, during a 48-hr starvation period developed microvesicular fatty infiltration of the liver similar to that observed in Reye's Syndrome. Hepatic triglycerides were elevated an average of 5-fold, although considerable variability was found between individual rats. Fed rats did not develop fatty liver upon similar treatment with pentenoic acid. Liver mitochondria isolated from rats with pentenoic acid-induced fatty liver showed a persistent inhibition of fatty acid oxidation. Rates of oxidation of palmitoylcarnitine and decanoylcarnitine were decreased about 70%, while that of octanoylcarnitine was decreased 50%. Carnitine-independent oxidation of octanoate was also inhibited. Oxidation rates for substrates other than fatty acids, including glutamate, succinate, pyruvate, and alpha-ketoglutarate, were unaffected. Measurements of flavoprotein reduction in intact mitochondria indicated that neither palmitoylcarnitine nor palmitoyl CoA plus L-carnitine could elicit reduction of acyl-CoA dehydrogenase and electron transferring flavoprotein in mitochondria from rats with pentenoic acid-induced fatty liver. These results support a site of inhibition of mitochondrial beta-oxidation at the level of acyl-CoA dehydrogenase for pentenoic acid treatment in vivo, and they suggest a role for nutritional or hormonal factors in the metabolic disposition of pentenoic acid in vivo and in the development of fatty liver.
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PMID:Inhibition of mitochondrial fatty acid oxidation in pentenoic acid-induced fatty liver. A possible model for Reye's syndrome. 671 30

Linoleate monohydroperoxide (L-HPO), methyl linoleate monohydroperoxide (ML-HPO), and methyl hydroperoxy-epoxy-octadecenoate (ML-X) inhibited state 3 respiration of mitochondria when palmitate, palmitoyl CoA, or L-palmitoylcarnitine was used as a substrate. L-HPO was the most effective, and 50% inhibition of palmitate-supported respiration was observed with 2, 3.3, and 6.5 nmol/mg protein of L-HPO, ML-X, and ML-HPO, respectively. Almost the same values were obtained when palmitoyl CoA or L-palmitoylcarnitine was used in place of palmitate. L-HPO inhibited the reaction of beta-oxidation in mitochondria in a similar concentration range (4 nmol/mg protein for 50% inhibition) when L-palmitoylcarnitine was used as a substrate. L-HPO also inhibited the formation of 3-hydroxypalmitoylcarnitine from the same substrate. Carnitine palmitoyltransferase activity of mitochondria was inhibited by L-HPO, 50% inhibition occurring at 12 nmol/mg protein. These inhibitory effects of L-HPO were weaker when ATP was removed by hexokinase and glucose. ATP-dependent formation of carnitine ester of L-HPO was also suggested. It was deduced that L-HPO (and ML-X and ML-HPO after hydrolysis) was converted to carnitine ester and inhibited the palmitate metabolism at the site(s) of intramitochondrial carnitine palmitoyltransferase (and possibly acyl CoA dehydrogenase).
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PMID:Inhibition of palmitate oxidation in mitochondria by lipid hydroperoxides. 672 34

This paper describes a method for the quantitative determination of free carnitine, acetylcarnitine, propionylcarnitine, hexanoylcarnitine, octanoylcarnitine, and total carnitine in plasma. Carnitine and acylcarnitines were extracted from 100 microliters of plasma with acetonitrile/methanol and isolated using 0.5-ml columns of silica gel. Samples were then derivatized with 4'-bromophenacyl trifluoromethanesulfonate and quantified by high-performance liquid chromatography with detection at 260 nm. Carnitine and acylcarnitines were quantified in normal human plasma and the plasma of patients diagnosed with methylmalonic aciduria, propionic acidemia, and medium-chain acyl-CoA dehydrogenase deficiency.
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PMID:Quantification of free carnitine, individual short- and medium-chain acylcarnitines, and total carnitine in plasma by high-performance liquid chromatography. 821 94

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

This paper describes the development of a high-performance liquid chromatographic method for the quantitation of free carnitine, total carnitine, acetylcarnitine, propionylcarnitine, isovalerylcarnitine, hexanoylcarnitine and octanoylcarnitine in human urine. Carnitine and acylcarnitines were isolated from 10 or 25 microliters of urine using 0.5-ml columns of silica gel, derivatized with 4'-bromophenacyl trifluoromethanesulfonate and separated by high-performance liquid chromatography. Using 4-(N,N-dimethyl-N-ethylammonio)-3-hydroxybutanoate ("e-carnitine") as the internal standard, standard curves (10-300 nmol/ml) were generated. Carnitine and acylcarnitines were quantified (when they were present) in normal human urine and the urine of patients diagnosed with one of three different disorders of organic acid metabolism: methylmalonic aciduria, isovaleric aciduria, isovaleric acidemia, and medium-chain acyl-CoA dehydrogenase deficiency.
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PMID:Quantification of carnitine and specific acylcarnitines by high-performance liquid chromatography: application to normal human urine and urine from patients with methylmalonic aciduria, isovaleric acidemia or medium-chain acyl-CoA dehydrogenase deficiency. 849 7


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