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)

Tissues of fasted animals treated with L-aminocarnitine (L-3-amino-4-trimethylaminobutyrate) showed an accumulation of long-chain acylcarnitines and triacylglycerols. Blood levels of free fatty acids, long-chain acylcarnitines and triacylglycerol-rich lipoproteins were found to be increased, whereas glucose was reduced. The liver mitochondria isolated from rats treated with L-aminocarnitine utilized both pyruvate and succinate normally, but were not able to oxidize palmitoylcarnitine. In vitro oxidation of palmitoylcarnitine by liver mitochondria was inhibited by L-aminocarnitine in a concentration-dependent fashion in contrast to succinate and pyruvate oxidation which was not modified. L-aminocarnitine proved to be a potent and selective inhibitor (IC50 = 805 nM) of the carnitine palmitoyltransferase isoenzyme, located on the inner side of the mitochondrial inner membrane (CPT2). The activity of the carnitine palmitoyltransferase isoenzyme located on the mitochondrial outer membrane inhibitable by malonyl-CoA (IC50 = 19 microM), was not inhibited by 0.8 microM L-aminocarnitine. Both in vitro and in vivo effects of L-aminocarnitine suggest that the substance has a specific and potent inhibitory action on CPT2. Its in vivo inhibition results in a dramatic increase of long-chain acylcarnitines in various organs, that it is why this increase can be considered a very good marker of CPT2 inhibition. A markedly altered lipid metabolism was observed.
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PMID:Tissue lipid accumulation by L-aminocarnitine, an inhibitor of carnitine-palmitoyltransferase-2. Studies in intact rats and isolated mitochondria. 162 37

Treatment of rats with the vitamin B12 analogue hydroxy-cobalamin[c-lactam] (HCCL) impairs methylmalonyl-CoA mutase function and leads to methylmalonic aciduria due to intracellular accumulation of propionyl and methylmalonyl-CoA. Since accumulation of these acyl-CoAs disrupts normal cellular regulation, the present investigation characterized metabolism in hepatocytes and liver mitochondria from rats treated subcutaneously with HCCL or saline (control) by osmotic minipump. Consistent with decreased methylmalonyl-CoA mutase activity, 14CO2 production from 1-14C-propionate (1 mM) was decreased by 76% and 82% after 2-3 wk and 5-6 wk of HCCL treatment, respectively. In contrast, after 5-6 wk of HCCL treatment, 14CO2 production from 1-14C-pyruvate (10 mM) and 1-14C-palmitate (0.8 mM) were increased by 45% and 49%, respectively. In isolated liver mitochondria, state 3 oxidation rates were unchanged or decreased, and activities of the mitochondrial enzymes, citrate synthetase, succinate dehydrogenase, carnitine palmitoyltransferase, and glutamate dehydrogenase (expressed per milligram mitochondrial protein) were unaffected by HCCL treatment. In contrast, activities of the same enzymes were significantly increased in both liver homogenate (expressed per gram liver) and isolated hepatocytes (expressed per 10(6) cells) from HCCL-treated rats. The mitochondrial protein per gram liver, calculated on the basis of the recovery of the mitochondrial enzymes, increased by 39% in 5-6 wk HCCL-treated rats. Activities of lactate dehydrogenase, catalase, cyanide-insensitive palmitoyl-CoA oxidation, and arylsulfatase A in liver were not affected by HCCL treatment. Hepatic levels of mitochondrial mRNAs were elevated up to 10-fold in HCCL-treated animals as assessed by Northern blot analysis. Thus, HCCL treatment is associated with enhanced mitochondrial oxidative capacity and an increased mitochondrial protein content per gram liver. Increased mitochondrial oxidative capacity may be a compensatory mechanism in response to the metabolic insult induced by HCCL administration.
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PMID:Increased hepatic mitochondrial capacity in rats with hydroxy-cobalamin[c-lactam]-induced methylmalonic aciduria. 170 51

The mechanisms by which noradrenaline, lipolytic agents and long-chain fatty acids stimulate glucose transport were investigated in rat brown adipocytes. Glucose transport was evaluated with tracer D-[U-14C]glucose and cell respiration was measured polarographically. Noradrenaline increased basal oxygen consumption (8-10-fold) and glucose transport (4-5-fold) in a dose-dependent manner, with a maximal stimulation at 100 nM. The stimulatory effects of noradrenaline on respiration and glucose transport were selectively mimicked by dibutyryl cyclic AMP (DBcAMP), 3-isobutyl-1-methylxanthine, cholera toxin and physiological concentrations of palmitic acid. Cytochalasin B completely blocked the effects of these agents on glucose transport. The beta-adrenergic antagonist propranolol inhibited noradrenaline-induced glucose transport, but did not affect the action of DBcAMP, palmitic acid or cholera toxin on this process. The specific inhibitor of mitochondrial carnitine palmitoyltransferase, 2-tetradecylglycidic acid (McN 3802) (50 microM), inhibited the stimulatory effects of noradrenaline (100 nM) and palmitic acid (0.5 mM) on both glucose transport and mitochondrial respiration. Significantly, McN 3802 failed to affect insulin (1 nM) action under identical experimental conditions. These results demonstrate that (a) the stimulatory effects of noradrenaline on brown-adipocyte respiration and glucose transport can be dissociated from those induced by insulin, and (b) noradrenaline increases glucose transport indirectly, by activating adenylate cyclase via beta-adrenergic pathways and by stimulating mitochondrial oxidation of fatty acids.
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PMID:Noradrenaline stimulates glucose transport in rat brown adipocytes by activating thermogenesis. Evidence that fatty acid activation of mitochondrial respiration enhances glucose transport. 171 31

The effects of etomoxiryl-CoA on purified carnitine acyltransferases and on carnitine acyl-transferases of rat heart mitochondria and rat liver microsomes were determined. At nanomolar concentrations, the data agreed with that of other investigators who have shown that etomoxiryl-CoA must be binding to a high affinity site with specific inhibition of mitochondrial carnitine palmitoyltransferase (CPTo). Micromolar amounts of etomoxiryl-CoA inhibited both short- and long-chain carnitine acyltransferases. The concentrations of etomoxiryl-CoA required for 50% inhibition of the different carnitine acetyltransferases and microsomal and peroxisomal carnitine octanoyltransferase were in the low micromolar range. Mixed-type and uncompetitive inhibition kinetics were obtained, depending on the source of purified enzyme. When purified rat heart CPT was incubated with etomoxiryl-CoA, it increased the K0.5 and decreased the Hill coefficient for acyl-CoA. Both proteins and phospholipids of mitochondria and microsomes formed covalent adducts of [3H]etomoxir, with the predominant labeling in phospholipids. None of the purified enzymes formed covalent adducts when incubated with [3H]etomoxiryl-CoA, in contrast to intact mitochondria or microsomes. The major 3H-labeled protein for rat heart mitochondria had a molecular weight of 81,000 +/- 4000, and the major proteins from microsomes had a molecular weight of 51,000-57,000. Malonyl-CoA prevented most of the tritum incorporation into the 81,000 Da protein of mitochondria, but it had little effect on incorporation of tritiated etomoxir into the 51,000-57,000 Da proteins of microsomes. When 50 microM etomoxiryl-CoA was added to microsomes and to mitochondria that had been incubated with radioactive etomoxiryl-CoA, much of the radioactive etomoxir disappeared from the major microsomal proteins, but virtually none was displaced from the mitochondrial protein. Thus, at least two different types of covalent etomoxir complexes were formed. This pulse-chase experiment showed that the mitochondrial protein-etomoxir complex was not turned over, consistent with other data showing that etomoxir inhibited carnitine palmitoyltransferase. In contrast, the major protein-etomoxir complex in microsomes was turned over during the pulse-chase experiment.
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PMID:Effect of etomoxiryl-CoA on different carnitine acyltransferases. 173 21

Maximal in vitro activities of key metabolic enzymes were measured in brain and eye heaters of five species of scombroid fishes. Istiophorid billfishes (blue marlin, striped marlin and Mediterranean spearfish), xiphiid billfishes (Pacific and Mediterranean stocks) and a scombrid fish (butterfly mackerel) were included in the analysis. Our main objectives were (1) to assess the maximum possible substrate flux in heater tissue, and (2) to determine what metabolic substrates could fuel heat production. Heater tissue of all scombroids examined showed extremely high oxidative capacity. Activities of citrate synthase, a commonly measured index of oxidative metabolism, included the highest value ever reported for vertebrate tissue. In most billfishes, citrate synthase activities were similar to or higher than those found for mammalian cardiac and avian flight muscle. Marker enzymes for aerobic carbohydrate metabolism (hexokinase) and fatty acid metabolism (carnitine palmitoyltransferase and 3-hydroxyacyl-CoA dehydrogenase) also displayed extraordinarily high activities. Activities of carnitine palmitoyltransferase measured in heater organs were among the highest reported for vertebrates. These results indicate that heat production could be fueled aerobically by either lipid or carbohydrate metabolism. Inter- and intraspecifically, heater organs of fishes from the colder Mediterranean waters had a higher aerobic capacity and, hence, a greater heat-generating potential, than fishes from the warmer waters of the Pacific. This difference may be attributed to different thermal environments or it may result from allometry, since fishes caught in the Mediterranean were considerably smaller than those caught in the Pacific.
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PMID:Activities of key metabolic enzymes in the heater organs of scombroid fishes. 175 72

Carnitine acyltransferase activities in the hearts of normal and dystrophic, sedentary and swim exercised hamsters were studied, in order to analyze the relationship between carnitine metabolism and exercise in cardiomyopathy. After 12 weeks, the mean specific activities of cardiac carnitine acetyltransferase (CAT), carnitine octanoyltransferase (COT) and carnitine palmitoyltransferase (CPT) were significantly higher in the dystrophic sedentary group, relative to the normal sedentary group (p less than 0.05). There was no significant effect of exercise on the mean specific activity of the carnitine acyltransferases, compared to the dystrophic or normal sedentary controls. Thus, the improvements in cardiac histopathology due to exercise noted previously are not associated with altered carnitine acyltransferase activity.
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PMID:Cardiac carnitine acyltransferase activities in exercised normal and dystrophic hamsters. 178 40

Carnitine acyltransferase activities were studied in normal human skeletal muscle and in muscle of three patients with carnitine palmitoyltransferase deficiency. Carnitine acetyltransferase (CAT), carnitine octanoyltransferase (COT), and carnitine palmitoyltransferase (CPT) were differentiated (i) by the use of the substrates acetyl-CoA, octanoyl-CoA, lauroyl-CoA, and palmitoyl-CoA, (ii) by the inhibitors malonyl-CoA, chlorpromazine, and dithio-bis-nitrobenzoic acid (DTNB), and (iii) by the solubilities of the carnitine acyltransferase activities after centrifugation at 48,000 g for 30 min. The results are consistent with the notion of three different carnitine acyltransferases in human skeletal muscle: a membrane-bound malonyl-CoA-sensitive CPT, a soluble malonyl-CoA-insensitive CAT, and a malonyl-CoA-sensitive COT that is not attached to the mitochondrial membrane. The different solubilities of the carnitine acyltransferases allow a clear differentiation of CPT from CAT and COT in homogenates of previously frozen muscle biopsies whereas a separate determination of CAT and COT is only partially possible. In patients with CPT deficiency total CPT activity was within the normal range but was abnormally inhibited by malonyl-CoA and chlorpromazine. Activities of carnitine acyltransferases with the substrates acetyl-CoA and octanoyl-CoA were normal indicating that the biochemical defect in CPT deficiency is confined to CPT without compensatory changes of CAT and COT.
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PMID:Carnitine acyltransferases in normal human skeletal muscle and in muscle of patients with carnitine palmitoyltransferase deficiency. 182 3

The effects of dehydroepiandrosterone (DHEA) and clofibrate on mitochondrial and peroxisomal proliferation and carnitine acyltransferases [mitochondrial carnitine palmitoyltransferase (CPT) and peroxisomal carnitine octanoyltransferase (COT)] were measured in lean and obese female Zucker rats. DHEA increased total hepatic mitochondrial protein twofold; clofibrate increased total hepatic peroxisomal protein more than fivefold. Both DHEA and clofibrate administration increased enzyme activities, immunoreactive protein, messenger RNA levels and transcription rates for the carnitine acyltransferases. Transcription rates and messenger RNA concentration for both carnitine acyltransferases correlated with the increases in activity. These data suggest that the hepatic CPT and COT in female Zucker rats are regulated primarily at the transcriptional level by DHEA and clofibrate.
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PMID:Regulation of carnitine acyltransferase synthesis in lean and obese Zucker rats by dehydroepiandrosterone and clofibrate. 182 32

Humans who lack availability of carbohydrate fuels may provide important models for the study of physiological control mechanisms. We compared seven patients who had unavailability of muscle glycogen and blood glucose as oxidative fuels due to muscle phosphofructokinase deficiency (PFKD) with five patients who had a selective defect in long-chain fatty acid oxidation due to carnitine palmitoyltransferase deficiency (CPTD) and with six healthy subjects. Peak cycle exercise work rate, peak O2 uptake (Vo2), and arteriovenous O2 difference were markedly lower (P less than 0.001) for PFKD patients (23 +/- 6 W, 14 +/- 2 ml.min-1.kg-1, and 7.1 +/- 0.5 ml/dl, respectively) than for CPTD patients (142 +/- 33 W, 31 +/- 4 ml.min-1.kg-1, and 15.0 +/- 0.8 ml/dl, respectively) or healthy subjects (171 +/- 17 W, 36 +/- 1 ml.min-1.kg-1, and 16.4 +/- 0.7 ml/dl, respectively). Peak cardiac output (Q) was similar (P less than 0.05) in all three groups, but the slope of increase in Q (l/min) on Vo2 (l/min) from rest to exercise (delta Q/ delta Vo2) was more than twofold greater (P less than 0.001) for PFKD patients (11.2 +/- 1.2) than for CPTD patients (4.6 +/- 0.6) and healthy subjects (4.6 +/- 0.2). Increasing availability of blood-borne oxidative substrates capable of metabolically bypassing the defect at phosphofructokinase (by fasting plus prolonged moderate exercise to increase plasma free fatty acids or by iv lactate infusion) increased peak work rate, Vo2, and arteriovenous O2 difference, lacked consistent effect on peak Q, and normalized delta Q/ delta Vo2 in PFKD patients. The results extend our previous observations in patients with a block in muscle glycogen but not blood glucose oxidation due to phosphorylase deficiency and imply that specific unavailability of muscle glycogen as an oxidizable fuel is primarily responsible for abnormal muscle oxidative metabolism and associated exercise intolerance and exaggerated delta Q/ delta Vo2 in muscle PFKD. The findings also endorse the concept that factors closely linked with muscle oxidative phosphorylation participate in regulating delta Q/ delta Vo2, likely via activation of metabolically sensitive muscle afferents.
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PMID:Abnormal oxidative metabolism and O2 transport in muscle phosphofructokinase deficiency. 182 93

Epidemiological studies have clearly shown that the so-called metabolic syndrome which is linked to insulin resistance and a reduced glucose utilization of muscle represents an important risk factor for cardiovascular disease. However, only little is known of the intracellular consequences of insulin resistance. An important feature of an altered substrate utilization is related to signal transduction of gene expression. For the example of myosin heavy chain expression, it is shown that metabolic signals exist which reflect the fuel flux and substrate utilization of the heart muscle cell. The signals were characterized in functional states of the heart associated with altered metabolic influences (fasting, diabetes, sucrose feeding, increased calorie intake, carnitine palmitoyltransferase inhibition). In the pressure-overloaded heart, metabolic interventions which are expected to increase glucose utilization (sucrose feeding, captopril treatment) have a pronounced effect. Although a link with gene expression remains to be established, it should be noted that the sarcoplasmic reticulum Ca(2+)-pump activity seems to be affected in a functionally comparable manner. It is concluded that metabolic signals alter the protein phenotype of heart muscle and it is expected that a deranged signal transduction affects, not only the heart, but also vascular muscle.
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PMID:The metabolic syndrome and signal transduction of gene expression. 183 54


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