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:2.3.1.21 (CPT)
4,580 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Fatty acids are known to increase the severity of injury during acute myocardial ischemia. In this study, we determined the effects of a carnitine palmitoyltransferase I inhibitor, ethyl 2-[6-(4-chlorophenoxy)hexyl]oxirane-2-carboxylate (Etomoxir) on reperfusion recovery of fatty acid perfused hearts. Following a 25-minute period of global ischemia, isolated working hearts reperfused with 1.2 mM palmitate, 11 mM glucose exhibited depressed function compared to hearts perfused with 11 mM glucose alone. A low dose of Etomoxir (10(-9) M) decreased long chain acylcarnitine and long chain acyl-coenzyme A (CoA) levels but did not prevent depressed function. In contrast, a high dose of Etomoxir (10(-6) M) prevented the palmitate-induced depression of function but did not decrease myocardial long chain acylcarnitine or long chain acyl-CoA levels. At this high dose of Etomoxir, oxygen consumption per unit work was decreased during reperfusion recovery, and ATP and creatine-phosphate levels were significantly higher after reperfusion. In aerobic hearts not subjected to ischemia, Etomoxir (10(-6) M) increased glucose oxidation both in the presence and absence of palmitate, while 10(-9) M Etomoxir had no effect. In these aerobic hearts, only the low dose of Etomoxir decreased long chain acylcarnitine and long chain acyl-CoA levels. These data demonstrate that Etomoxir (10(-6) M) increases functional recovery of fatty acid perfused ischemic hearts. This protection is unrelated to changes in levels of long chain acylcarnitines but may be due to increased glucose use by the reperfused heart, resulting in decreased oxygen consumption per unit work.
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PMID:Etomoxir, a carnitine palmitoyltransferase I inhibitor, protects hearts from fatty acid-induced ischemic injury independent of changes in long chain acylcarnitine. 319 71

1. Carnitine and carnitine palmitoyltransferase are active in the transfer of fatty acids into the mitochondria for oxidation. Very long chain fatty acids (C22) are poorly oxidized by mitochondria. Lack of carnitine or overloading with C22 fatty acids leads to lipidosis in heart and other tissues. 2. The oxidation of fatty acids (including C22 fatty acids) in the peroxisomes is not dependent on carnitine. However, carnitine acetyltransferase and carnitine medium chain acyltransferase are presumably auxiliary enzymes in the oxidation of acetyl-CoA and shortened fatty acids formed in the peroxisomes. 3. Branched-chain acylcarnitines may be formed in the mitochondria from branched-chain amino acids. They are also metabolized in the mitochondria. When formed in large amounts, they are released into the circulation and urine by the liver and kidney. 4. The mechanisms leading to secondary carnitine deficiency because of branched-chain acylcarnitine formation in metabolic disturbances are discussed.
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PMID:Role of carnitine-dependent metabolic pathways in heart disease without primary ischemia. 332 30

The peroxisomal beta-oxidation of omega-phenyl fatty acids (PFAs) as model compounds for xenobiotic acyl compounds was investigated. In isolated hepatocytes, omega-phenyllauric acid (PFA12) was chain-shortened to PFAs having an even number of carbon atoms in the acyl side chain. Associated with this reaction, H2O2 generation was observed, the rate of which was markedly enhanced by clofibrate treatment of rats. Also when using isolated peroxisomes, such a chain-shortening of PFA12 occurred, associated with stoichiometrical production of NADH and acetyl-CoA. The CoA-ester form of PFA12 as a substrate and NAD as a cofactor were required in this reaction, indicating the participation of peroxisomal beta-oxidation in the chain-shortening of PFA12. When using PFAs with various chain lengths, the rates of H2O2 generation measured as the peroxisomal beta-oxidation in isolated hepatocytes were similar to those with the corresponding fatty acids, whereas the rates of ketone body production measured as the mitochondrial beta-oxidation were much lower than that with any fatty acid examined. From the study with isolated mitochondria and purified enzymes, it was found that the mitochondrial beta-oxidation of PFAs was carnitine-dependent, and that the activities of carnitine palmitoyltransferase for PFA-CoAs are low. Moreover, the activities of acyl-CoA dehydrogenase for PFA-CoAs were lower than those for fatty acyl-CoAs, while the activities of acyl-CoA oxidase for PFA-CoAs were comparable to those for fatty acyl-CoAs. As a result, relatively long chain PFAs were hardly subjected to mitochondrial beta-oxidation. Based on the maximum enzyme activities of the beta-oxidation, which were measured by following acyl-CoA-dependent NAD reduction in isolated peroxisomes and O2 consumption in isolated mitochondria, about 60% of the beta-oxidation of PFA12 in the rat liver was peroxisomal. In clofibrate-treated rats, the value reached about 85%. From these results it is concluded that the peroxisome is one of the important sites of degradation of xenobiotic acyl compounds.
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PMID:Participation of peroxisomes in the metabolism of xenobiotic acyl compounds: comparison between peroxisomal and mitochondrial beta-oxidation of omega-phenyl fatty acids in rat liver. 365 89

Emeriamine [(R)-3-amino-4-trimethylaminobutyric acid], derived from a novel fungal metabolite "emericedin" [(R)-3-acetylamino-4-trimethylaminobutyric acid], was proved to be a strong and specific inhibitor of carnitine-dependent oxidation of long chain fatty acid (IC50; 3.2 X 10(-6)M) and its main inhibition site was shown to be carnitine palmitoyltransferase I located on the outer-surface of the mitochondrial inner membrane. Emeriamine also showed hypoglycemic and antiketogenic activities in a dose-dependent manner (1 - 10 mg/kg) when administered orally to fasted normal and diabetic animals.
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PMID:Emeriamine, an antidiabetic beta-aminobetaine derived from a novel fungal metabolite. 383 82

Carnitine levels in the embryonic chick heart were measured. The amount of total carnitine, free plus short chain acyl carnitine (acid-soluble fraction), and long chain acyl carnitine (acid-insoluble fraction) were examined at days 7, 11, 17, and 21 of incubation. These concentrations were found to correspond favorably with data from previous investigators with regard to variations in palmitoylcarnitine transferase enzyme activity, mitochondrial chain elongation activity, and palmitic acid oxidation.
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PMID:Changes in carnitine levels in the embryonic chick heart during development. 408 13

Interrelationships between propionate, palmitate, and butyrate metabolism were investigated in vitro with [1-carbon-14] carboxyl substrates. Production of labeled glucose, ketone bodies, and carbon dioxide was used to estimate rates of bovine hepatic gluconeogenesis and ketogenesis. Incubations were with liver slices from eight lactating Holstein cows fed either a control or high concentrate-low fiber diet. Liver samples were acquired by trochar biopsy at 30, 60, 90, and 180 days postpartum. Ketone production from both palmitate and butyrate was highest in liver slices obtained at 30 days. Glucose production from labeled propionate was also highest in early lactation. The higher rates of gluconeogenesis and ketogenesis in early lactation were associated with higher hepatic carnitine palmitoyltransferase (EC 2.3.1.21) activity. Feeding the high concentrate enhanced gluconeogenesis from propionate and decreased ketogenesis from palmitate. Propionate addition (10 mM) to incubation media also decreased the total amount of palmitate oxidized [( carbon-14] dioxide plus [carbon-14] ketones). Diet had no effect on hepatic butyrate metabolism. Results indicated that ketogenesis is regulated via rate of long chain fatty acid transport into the mitochondria. Stage of lactation has a greater influence on long and short chain fatty acid metabolism than does diet composition.
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PMID:Hepatic gluconeogenic and ketogenic interrelationships in the lactating cow. 648 Sep 60

The requirement for carnitine and the malonyl-CoA sensitivity of carnitine palmitoyl-transferase I (EC 2.3.1.21) were measured in isolated mitochondria from eight tissues of animal or human origin using fixed concentrations of palmitoyl-CoA (50 microM) and albumin (147 microM). The Km for carnitine spanned a 20-fold range, rising from about 35 microM in adult rat and human foetal liver to 700 microM in dog heart. Intermediate values of increasing magnitude were found for rat heart, guinea pig liver and skeletal muscle of rat, dog and man. Conversely, the concentration of malonyl-CoA required for 50% suppression of enzyme activity fell from the region of 2-3 microM in human and rat liver to only 20 nM in tissues displaying the highest Km for carnitine. Thus, the requirement for carnitine and sensitivity to malonyl-CoA appeared to be inversely related. The Km of carnitine palmitoyltransferase I for palmitoyl-CoA was similar in tissues showing large differences in requirement for carnitine. Other experiments established that, in addition to liver, heart and skeletal muscle of fed rats contain significant quantities of malonyl-CoA and that in all three tissues the level falls with starvation. Although its intracellular location in heart and skeletal muscle is not known, the possibility is raised that malonyl-CoA (or a related compound) could, under certain circumstances, interact with carnitine palmitoyltransferase I in non-hepatic tissues and thereby exert control over long chain fatty acid oxidation.
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PMID:Observations on the affinity for carnitine, and malonyl-CoA sensitivity, of carnitine palmitoyltransferase I in animal and human tissues. Demonstration of the presence of malonyl-CoA in non-hepatic tissues of the rat. 661 66

An understanding of the mechanism of malonyl-CoA interaction with carnitine palmitoyltransferase (CPT-I) in isolated mitochondria is complicated by membrane fragmentation and CPT-II exposure. Using cultured neonatal rat cardiac myocytes, as in situ model was developed to measure CPT-I. In the cardiac cells treated with 5 microM digitonin, CPT-II contamination of CPT activity is 0.62% as quantitated by citrate synthase activity present in damaged myocytes under assay conditions. Moreover, the sensitivity of myocyte CPT-I to malonyl-CoA, its substrate preference for decanoyl-CoA and the affinity of CPT-I for l-carnitine (0.19 mM) are comparable with similar measurements published for isolated cardiac mitochondrial membranes. There is no evidence in the cells for contamination of CPT-I activities by extramitochondrial sources, in particular, the sarcoplasmic reticulum (SR). The presence of carnitine octanoyltransferase (COT) is not detected either in the cells or in preparations of adult SR from which COT is subsequently isolated. With these control measurements, the inhibition kinetics of CPT-I in the cardiac cells in situ maintains a partial competitive pattern which is more pronounced with decanoyl-CoA than with palmitoyl-CoA as substrate. The presence of a malonyl-CoA/long chain acyl-CoA binding site on CPT-I, distinct from the inhibitory site, has previously been proposed. Existence of this binding region is consistent with partial inhibition kinetics so that malonyl-CoA at this site could modify the CPT-high-affinity malonyl-CoA inhibitory interaction, producing acylcarnitine even at high malonyl-CoA concentrations in the cell. These findings may help to explain, in part, the inability to suppress completely beta-oxidation in the heart where malonyl-CoA may be 50 to 100 times the estimated values of its Ki.
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PMID:Kinetic properties of carnitine palmitoyltransferase I in cultured neonatal rat cardiac myocytes. 791 95

A microsomal protein having N-terminal amino acid sequence SDVLELTDEN, was initially described as a phosphatidyl inositol-specific phospholipase C alpha when its cDNA was cloned (Bennett et al., Nature, 334, 268, 1988). Later, this protein, with an estimated molecular mass of 54 to 60 kDa, was shown to lack the phospholipase activity and instead a protein disulfide oxidoreductase and a thiol protease activities were ascribed to it. Following evidences indicated that the protein in question is the carnitine medium/long chain acyltransferase (CPT) of microsomes that was recently purified as a approximately 54 kDa protein (Murthy and Bieber, Protein Exp. Purif. 3, 75, 1992). First, the N-terminal amino acids of the microsomal CPT showed 100% homology to the sequence described above. Second, during purification of this CPT, the oxidoreductase and the thiol protease activities of the microsomes became separated from the CPT and these other activities were not found in the approximately 900 fold enriched CPT preparations. Third, an antibody to this protein did not immunoprecipitate oxidoreductase of the solubilized microsomal extract but precipitated the CPT. This same protein has been studied by others as the ERp61 (endoplasmic reticulum protein), GRP58 (glucose regulated protein), and HIP-70 (hormone induced protein) but its function was not identified.
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PMID:Carnitine medium/long chain acyltransferase of microsomes seems to be the previously cloned approximately 54 kDa protein of unknown function. 823 44

The effects of mono(2-ethyl-5-oxohexyl)phthalate [ME(O)HP], a di(2-ethylhexyl)phthalate (DEHP) metabolite and a potent peroxisomal inducer, on the mitochondrial beta-oxidation were investigated. In isolated rat hepatocytes, ME(O)HP inhibited long chain fatty acid oxidation and had no effect on the ketogenesis of short chain fatty acids, suggesting that the inhibition occurred at the site of carnitine-dependent transport across the mitochondrial inner membrane. In rat liver mitochondria, ME(O)HP inhibited carnitine acyltransferase I (CAT I; EC 2.3.1.21) competitively with the substrates palmitoyl-CoA and octanoyl-CoA. An analogous treatment of mouse mitochondria produced a similar competitive inhibition of palmitoyl-CoA transport whereas ME(O)HP exposure with guinea pig and human liver mitochondria revealed little or no effect. The addition of clofibric acid, nafenopin or methylclofenopate revealed no direct effects upon CAT I activity. Inhibition of transferase activity by ME(O)HP was reversed in mitochondria which had been solubilized with octyl glucoside to expose the latent form of carnitine acyltransferase (CAT II), suggesting that the inhibition was specific for CAT I. Our results demonstrate that in vitro ME(O)HP inhibits fatty acid oxidation in rat liver at the site of transport across the mitochondrial inner membrane with a marked species difference and support the idea that induction of peroxisome proliferation could be due to an initial biochemical lesion of the fatty acid metabolism.
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PMID:In vitro inhibition of carnitine acyltransferase activity in mitochondria from rat and mouse liver by a diethylhexylphthalate metabolite. 845 57


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