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)

We investigated the influence of age on carnitine palmitoyl transferase-I (CPT-I, EC 2.3.1.21) activity in the mouse heart. There was an age-associated decrease in CPT-I activity from 2 to 26 months (P = 0.006). We studied the effect of oxygen-derived radicals on CPT-I activity. Mitochondria from 2-month-old mouse hearts exposed to different concentrations of hydrogen peroxide (H2O2) showed a dose-related decrease in CPT-I activity (P < 0.002). To determine the possible reversibility of the age change in CPT-I activity, we studied the effect of oral administration of propionyl-L-carnitine (PLC). Oral pretreatment of middle-aged (18-month-old) mice with PLC resulted in a 37% increase of basal CPT-I activity (P < 0.05) compared to age-matched untreated animals, and restored it to a level similar to that of 2-month-old mice. Pretreatment of senescent (26-month-old) mice with PLC, however, showed no significant change in basal CPT-I activity. It is possible that the age-related decrease in CPT-I activity may result from an in vivo accumulation of oxygen-derived radical damage. It appears that the age change in CPT-I activity in 18- but not in the 26-month-old mice is reversible with PLC.
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PMID:Carnitine palmitoyl transferase-I activity in the aging mouse heart. 761 63

This study was designed to examine whether the depletion of L-carnitine may induce compensatory mechanisms allowing higher fatty acid oxidative activities in liver, particularly with regard to mitochondrial carnitine palmitoyltransferase I activity and peroxisomal fatty acid oxidation. Wistar rats received D-carnitine for 2 days and 3-(2,2,2,-trimethylhydrazinium)propionate (mildronate), a noncompetitive inhibitor of gamma-butyrobetaine hydroxylase, for 10 days. They were starved for 20 hr before being sacrificed. A dramatic reduction in carnitine concentration was observed in heart, skeletal muscles and kidneys, and to a lesser extent, in liver. Triacylglycerol content was found to be significantly more elevated on a gram liver and whole liver basis as well as per mL of blood (but to a lesser extent), while similar concentrations of ketone bodies were found in the blood of D-carnitine/mildronate-treated and control rats. In liver mitochondria, the specific activities of acyl-CoA synthetase and carnitine palmitoyltransferase I were enhanced by the treatment, while peroxisomal fatty acid oxidation was higher per gram of tissue. It is suggested that there may be an enhancement of cellular acyl-CoA concentration, a signal leading to increased liver fatty acid oxidation in acute carnitine deficiency.
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PMID:Enhancement of activities relative to fatty acid oxidation in the liver of rats depleted of L-carnitine by D-carnitine and a gamma-butyrobetaine hydroxylase inhibitor. 776 83

In newborn-pig hepatocytes, the rate of oleate oxidation is extremely low, despite a very low malonyl-CoA concentration. By contrast, the sensitivity of carnitine palmitoyltransferase (CPT) I to malonyl-CoA inhibition is high, as suggested by the very low concentration of malonyl-CoA required for 50% inhibition of CPT I (IC50). The rates of oleate oxidation and ketogenesis are respectively 70 and 80% lower in mitochondria isolated from newborn-pig liver than from starved-adult-rat liver mitochondria. Using polarographic measurements, we showed that the oxidation of oleoyl-CoA and palmitoyl-L-carnitine is very low when the acetyl-CoA produced is channelled into the hydroxymethylglutaryl-CoA (HMG-CoA) pathway by addition of malonate. In contrast, the oxidation of the same substrates is high when the acetyl-CoA produced is directed towards the citric acid cycle by addition of malate. We demonstrate that the limitation of ketogenesis in newborn-pig liver is due to a very low amount and activity of mitochondrial HMG-CoA synthase as compared with rat liver mitochondria, and suggest that this could promote the accumulation of acetyl-CoA and/or beta-oxidation products that in turn would decrease the overall rate of fatty acid oxidation in newborn- and adult-pig livers.
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PMID:Hepatic ketogenesis in newborn pigs is limited by low mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase activity. 790 71

Carnitine is essential for the metabolism of long-chain fatty acids and has both direct and indirect roles in the metabolism of short-chain and medium-chain acyl-CoAs. The purpose of this study was to quantitate and identify the individual acylcarnitines that occur in human mononuclear phagocytes (MNP) after activating them with phorbol-12-myristate 13-acetate (PMA). Mononuclear phagocytes were isolated from healthy adults and the levels of free carnitine and individual acylcarnitines were determined in unactivated and activated cells. The degree of activation of MNP was assessed by following hydrogen peroxide production. In unactivated cells, acetyl-L-carnitine represented more than 80% of the total acylcarnitine pool. Small amounts of 3-carbon and 4-carbon acylcarnitines were present, with less than 10% of the carnitine pool being long-chain acylcarnitine. Free carnitine in unactivated cells represented 7% of the total carnitine pool, which remained essentially unchanged in unactivated cells when monitored for a period of 60 min. However, free carnitine rose to more than 50% of the total pool in PMA-activated cells. Similarly, after 1 h of activation, the acetylcarnitine level in activated cells decreased by more than 50%. These data suggest that acetylcarnitine plays a key metabolic role as MNP initiate an immune response. It was further shown that MNP contain both carnitine acetyltransferase and malonyl-CoA-sensitive carnitine palmitoyltransferase in mitochondrial-enriched fractions, as well as in post-mitochondrial supernatant fractions.
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PMID:Utilization of intracellular acylcarnitine pools by mononuclear phagocytes. 794 48

Many studies have shown that L-carnitine has a positive effect on ischemic myocardium, probably by reducing accumulation of long-chain acyl coenzyme A (CoA) esters. Previous studies have involved whole-heart extracts and have not assessed changes of CoA ester levels in mitochondria, the site of translocase inhibition. To more precisely assess L-carnitine effects, we measured long-chain acyl CoA ester levels in cytosol and in mitochondria in the ischemic canine heart. Dogs were divided into four groups: a sham-operated control group; an untreated group; and high- and low-dose L-carnitine-treated groups (30 mg/kg and 100 mg/kg). After 60 min of ischemia, the heart was excised, and the cytosolic and mitochondrial fractions were isolated. CoA esters and the activity of carnitine palmitoylcarnitine transferase (CPT) I and II were measured in both compartments. Approximately 89% of cellular free CoA. 90% of cellular acetyl CoA, 97% of cellular shot-chain acyl CoA, and 92% of cellular long-chain acyl CoA were located in the mitochondrial space under the normal condition. Under the ischemic condition, mitochondrial free CoA was significantly decreased. Conversely, mitochondrial acetyl CoA and long-chain acyl CoA were significantly increased. Treatment with L-carnitine significantly decreased acetyl CoA and long-chain acyl CoA in the ischemic mitochondrial space in a dose-dependent manner. These results support the hypothesis that L-carnitine reduces accumulation of long-chain acyl CoA within the ischemic mitochondrial space and thereby improves mitochondrial function and adenine nucleotide translocation.
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PMID:Effect of L-carnitine on mitochondrial acyl CoA esters in the ischemic dog heart. 807 6

The control of fatty acid oxidation in heart is reviewed with special emphasis on the energy-linked regulation of this process. Studies with perfused working hearts and isolated mitochondria have revealed an inverse relationship between the energy-dependent rate of fatty acid oxidation and the intramitochondrial ratio of [acetyl-CoA]:[free CoA] at sufficiently high concentrations of fatty acids. Studies with isolated enzymes demonstrated a strong inhibition of 3-ketoacyl-CoA thiolase by acetyl-CoA at low concentrations of free CoA. Together these observations prompted the proposal that the rate of fatty acid oxidation is tuned to the energy demand of heart via the regulation of 3-ketoacyl-CoA thiolase by the [acetyl-CoA]:[free CoA] ratio. Evidence in support of this regulatory model has been obtained with isolated rat heart mitochondria in which either the activity of 3-ketoacyl-CoA thiolase was decreased by use of mechanism-based inhibitors or the intramitochondrial ratio of [acetyl-CoA]:[free CoA] was adjusted with L-carnitine. Because intermediates of beta-oxidation normally do not accumulate in mitochondria, it remains unclear how the entry of fatty acyl-CoA into the beta-oxidation spiral is tuned to the activity of 3-ketoacyl-CoA thiolase. A control of fatty acid oxidation in heart via the regulation of carnitine palmitoyltransferase I by malonyl-CoA has not been established even though malonyl-CoA is present in this tissue and strongly inhibits myocardial carnitine palmitoyltransferase I.
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PMID:Regulation of fatty acid oxidation in heart. 830 65

The carnitine acyltransferases contribute to the modulation of the acyl-CoA/CoA ratio in various cell compartments with consequent effects on many aspects of fatty acid metabolism. The properties of the enzymes are different in each location. The kinetic mechanisms and kinetic parameters for the carnitine acyltransferases purified from peroxisomes (COT) and from the mitochondrial inner membrane (CPT-II) were determined. Product-inhibition studies established that COT follows a rapid-equilibrium random-order mechanism, but CPT-II follows a strictly ordered mechanism in which acyl-CoA or CoA must bind before the carnitine substrate. Hemipalmitoylcarnitinium [(+)-HPC], a prototype tetrahedral intermediate analogue of the acyltransferase reaction, inhibits CPT-II 100-fold better than COT. (+)-HPC behaves as an analogue of palmitoyl-L-carnitine with COT. In contrast, with CPT-II(+)-HPC binds more tightly to the enzyme than do substrates or products, suggesting that it is a good model for the transition state and, unlike palmitoyl-L-carnitine, (+)-HPC can bind to the free enzyme. The data support the concept of three binding domains for the acyltransferases, a CoA site, an acyl site and a carnitine site. The CoA site is similar in COT and CPT-II, but there are distinct differences between the carnitine-binding site which may dictate the kinetic mechanism.
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PMID:Comparison of the active sites of the purified carnitine acyltransferases from peroxisomes and mitochondria by using a reaction-intermediate analogue. 837 19

To better understand the role of the liver in the hypertriglyceridemia observed in a tumor-bearing state, we have examined tumor-induced alterations in hepatic lipogenesis and fatty acid oxidation. The effects of differing tumor burden as well as tumor excision on the activity and mRNA levels of malic enzyme and carnitine palmitoyltransferase were studied in Fisher 344 rats bearing a methylcholanthrene-induced sarcoma. Serum triacylglycerols and plasma nonesterified fatty acids (NEFA) levels were both elevated with increasing tumor burden (P < 0.05 vs control). The elevation disappeared with tumor removal. Malic enzyme activity of tumor bearers, compared with control rats, declined with an increase in tumor burden. These two variables were negatively correlated (r = -0.90, P < 0.01). The changes in activity were accompanied by positively correlated changes in mRNA levels (r = 0.73, P < 0.01). Carnitine palmitoyltransferase activity was not altered, even in the presence of a large tumor burden. Hepatic lipogenesis, reflected by malic enzyme activity, was tumor-dependent and was significantly reduced during the period of circulating hypertriglyceridemia. Fatty acid oxidation, reflected by carnitine palmitoyltransferase activity, was not enhanced in spite of an ample supply of NEFAs to the liver from the peripheral tissues. The data suggest that neither hepatic lipogenesis nor fatty acid oxidation contribute to hypertriglyceridemia in the tumor-bearing state.
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PMID:Tumor-induced alterations in hepatic malic enzyme and carnitine palmitoyltransferase activity. 841 23

Carnitine octanoyltransferase (COT) purified from rat liver microsomes has K0.5 values between 1.0 and 4.0 microM for saturated 6-carbon to 16-carbon length acyl-CoAs, with little differences in Vmax values. The reaction rate is linear with time in the forward direction (acyl-CoA-->acylcarnitine), but it increases with time when assayed in the reverse direction (acylcarnitine-->acyl-CoA). The K0.5 for decanoylcarnitine and CoASH are 0.3 mM for CoASH and between 1.0 and 4.0 mM for decanoylcarnitine. The kinetic data indicate that the enzyme functions in the direction of acyl-carnitine formation. It is moderately inhibited by aminocarnitine, and D-carnitine and etomoxiryl-CoA are weak inhibitors; malonyl-CoA does not inhibit the enzyme. The enzyme has little, if any, capacity to use valproylcarnitine, 3-methylglutarylcarnitine, or pivaloylcarnitine as a substrate. Polyclonal antibodies prepared against COT give a positive Western blot against the purified enzyme and against a protein in microsomes having the molecular mass of COT (53 kDA). Antimitochondrial CPT and antiperoxisomal CAT did not show appreciable cross-reactivity with purified microsomal COT. The inhibitor data, the kinetic data, the molecular masses, and the Western blotting profiles all show that the enzyme purified from rat liver microsomes is a different carnitine acyltransferase than those previously purified from other organelles.
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PMID:Properties of the medium chain/long chain carnitine acyltransferase purified from rat liver microsomes. 844 Jul 34

Many authors agree that alteration of the energy substrate from glucose to free fatty acid occurs during the early stage after partial hepatectomy. An accelerative effect of carnitine on the early phase of liver regeneration was suggested in several reports, but much controversy prevails. Using male Wistar rats weighing about 200 g as subjects, we undertook partial hepatectomy with resection of the median and left lateral lobes (67%). Another group of rats undergoing a sham operation was compared. Rats were killed at 6, 24, 48, or 72 hr after the operation. The rate of synthesis of DNA and content of DNA in remnant liver were chosen as regenerative indicators. Serum carnitine, free fatty acid and its metabolites, remnant liver carnitine palmitoyltransferase I (CPT-I) activity, high-energy phosphate (HEP), including adenosine triphosphate (ATP), and creatine phosphate (CP) were measured. The results showed a marked decrease of HEP, ATP, and CP with suddenly increased free fatty acid and total ketone body in serum that occurred during the early regenerating phase after partial hepatectomy. Serum L-carnitine also increased markedly in this early stage. The mitochondrial CPT-I activity in the remnant liver decreased significantly 24 hr after partial hepatectomy. Our data show that regenerating liver utilizes free fatty acids as an immediate main substrate. Mitochondrial respiration with a CPT-I effect could be an important reaction in this utilization.
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PMID:Alterations of remnant liver carnitine palmitoyltransferase I activity and serum carnitine concentration after partial hepatectomy in rats. 853 77


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