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)

Changes of enzymes involved in the hepatic metabolism of long-chain fatty acids (palmitoyl-CoA synthetase (EC 6.2.1.3), carnitine palmitoyltransferase (EC 6.2.1.3), glycerophosphate acyltransferase (EC 2.3.1.15)) in the liver of male rats were examined after ethionine exposure. Ethionine administration resulted in a dose- and time-dependent enhancement of the palmitoyl-CoA synthetase activity both in the mitochondrial, peroxisomal and microsomal fractions. The total carnitine palmitoyltransferase activity in the mitochondrial fraction was enhanced. Ethionine administration was also associated with dose- and time-dependent changes of the microsomal glycerophosphate acyltransferase activity, whereas the mitochondrial enzyme activity was marginally affected. The hepatic triacylglycerol content of the ethionine-treated animals was increased. Hepatic lipids were accumulated in large droplets. Serum triacylglycerol and cholesterol were decreased. In particular, the serum HDL-cholesterol level was lowered. The concentration of ATP in the liver decreased. Accumulation of the metabolic product S-adenosylethionine (AdoEth) was observed for the first 2 days of exposure followed by a fall in S-adenosylmethionine (Ado-Met) during the next 10 days. Linear regression analysis of ATP content versus AdoEth and AdoMet showed highly significant correlations. A significant correlation between the hepatic triacylglycerol and AdoEth content was also observed upon ethionine treatment. The data show that ethionine perturbs the hepatic lipid metabolism. Enhanced esterification of long-chain fatty acids, but not a simple reduction of their oxidation, might contribute to ethionine-induced fatty liver in addition to a block in secretion of lipoproteins and decreased protein synthesis.
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PMID:Ethionine-induced alterations of enzymes involved in lipid metabolism and their possible relationship to induction of fatty liver. 297 12

The enzyme targets for chlorpromazine inhibition of rat liver peroxisomal and mitochondrial oxidations of fatty acids were studied. Effects of chlorpromazine on total fatty acyl-CoA synthetase activity, on both the first and the third steps of peroxisomal beta-oxidation, on the entry of fatty acyl-CoA esters into the peroxisome and on catalase activity, which allows breakdown of the H2O2 generated during the acyl-CoA oxidase step, were analysed. On all these metabolic processes, chlorpromazine was found to have no inhibitory action. Conversely, peroxisomal carnitine octanoyltransferase activity was depressed by 0.2-1 mM-chlorpromazine, which also inhibits mitochondrial carnitine palmitoyltransferase activity in all conditions in which these enzyme reactions are assayed. Different patterns of inhibition by the drug were, however, demonstrated for both these enzyme activities. Inhibitory effects of chlorpromazine on mitochondrial cytochrome c oxidase activity were also described. Inhibitions of both cytochrome c oxidase and carnitine palmitoyltransferase are proposed to explain the decreased mitochondrial fatty acid oxidation with 0.4-1.0 mM-chlorpromazine reported by Leighton, Persico & Necochea [(1984) Biochem. Biophys. Res. Commun. 120, 505-511], whereas depression by the drug of carnitine octanoyltransferase activity is presented as the factor responsible for the decreased peroxisomal beta-oxidizing activity described by the above workers.
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PMID:Chlorpromazine and carnitine-dependency of rat liver peroxisomal beta-oxidation of long-chain fatty acids. 359 22

In an attempt to clarify why the brain oxidizes fatty acids poorly or not at all, the activities of beta-oxidation enzymes present in rat brain and rat heart mitochondria were measured and compared with each other. Although the apparent Km values and chain-length specificities of the brain and heart enzymes are similar, the specific activities of all but one brain enzyme are between 4 and 50% of those observed in heart mitochondria. The exception is 3-ketoacyl-CoA thiolase (EC 2.3.1.16) whose specific activity in brain mitochondria is 125 times lower than in heart mitochondria. The partially purified brain 3-ketoacyl-CoA thiolase was shown to be catalytically and immunologically identical with the heart enzyme. The low rate of fatty acid oxidation in brain mitochondria, estimated on the basis of palmitoylcarnitine-supported respiration and [1-14C]palmitoylcarnitine degradation to be less than 0.5 nmol/min/mg of protein, may be the consequence of the low activity of 3-ketoacyl-CoA thiolase. Inhibition of [1-14C]palmitoylcarnitine oxidation by 4-bromocrotonic acid proves the observed oxidation of fatty acids in brain to be dependent on 3-ketoacyl-CoA thiolase and thus to occur via beta-oxidation. Since the reactions catalyzed by carnitine palmitoyltransferase (EC 2.3.1.21) and acyl-CoA synthetase (EC 6.2.1.3) do not seem to restrict fatty acid oxidation in brain, it is concluded that the oxidation of fatty acids in rat brain is limited by the activity of the mitochondrial 3-keto-acyl-CoA thiolase.
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PMID:Fatty acid oxidation in rat brain is limited by the low activity of 3-ketoacyl-coenzyme A thiolase. 365 1

The oral hypoglycemic agent, methyl 2-tetradecylglycidate (Me-TDGA), which inhibits in vitro mitochondrial carnitine palmitoyl transferase A (CPT-A) was used to study the relationship of CPT inhibition to changes in ketonemia and glycemia in normal and diabetic rats. After oral administration of Me-TDGA, the CPT activity of isolated rat liver mitochondria was substantially reduced with only the presumed outer enzyme fraction CPT-A released by digitonin treatment showing reduced activity. Mitochondrial fatty acyl-CoA synthetase was not inhibited. Oral doses of 0.1-2.5 mg/kg Me-TDGA produced both a dose-dependent lowering of plasma ketones and an inhibition of liver CPT. With single doses in excess of 2.5 mg/kg, po, heart and skeletal muscle CPT were also consistently inhibited. The effect on the liver enzyme persisted for at least 48 hr following 1 mg/kg, po, while the effect on ketones disappeared by 36 hr. The degree of inhibition of liver CPT produced by Me-TDGA was not altered by diabetes or the dietary state. At low doses (0.05-0.25 mg/kg, po), the most sensitive parameter was inhibition of hepatic CPT. Both plasma ketones and CPT were lowered with doses 10-fold less (0.1 mg/kg) than were required for blood glucose lowering, thus making Me-TDGA the most potent hypoketonemic compound known. In conclusion, inhibition of liver beta-oxidation at the stage of CPT-A by Me-TDGA can explain the potent hypoketonemic effects of this compound in fasted normal and diabetic rats. Higher acute doses are needed for both inhibition of muscle CPT and lowering of blood glucose.
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PMID:Inhibition of mitochondrial carnitine palmitoyl transferase A in vivo with methyl 2-tetradecylglycidate (methyl palmoxirate) and its relationship to ketonemia and glycemia. 396 83

1. Deca-2,4,6,8-tetraenoic acid is a substrate for both ATP-specific (EC 6.2.1.2 or 3) and GTP-specific (EC 6.2.1.-) acyl-CoA synthetases of rat liver mitochondria. The enzymic synthesis of decatetraenoyl-CoA results in new spectral characteristics. The difference spectrum for the acyl-CoA minus free acid has a maximum at 376nm with epsilon(mM) 34. Isosbestic points are at 345nm and 440nm. 2. The acylation of CoA by decatetraenoate in mitochondrial suspensions can be continuously measured with a dual-wavelength spectrophotometer. 3. By using this technique, three distinct types of acyl-CoA synthetase activity were demonstrated in rat liver mitochondria. One of these utilized added CoA and ATP, required added Mg(2+) and corresponded to a previously described ;external' acyl-CoA synthetase. The other two acyl-CoA synthetase activities utilized intramitochondrial CoA and did not require added Mg(2+). Of these two ;internal' acyl-CoA synthetases, one was insensitive to uncoupling agents, was inhibited by phosphate or arsenate, and corresponded to the GTP-specific enzyme. The other corresponded to the ATP-specific enzyme. 4. Atractylate inhibited the activity of the two internal acyl-CoA synthetases only when the energy source was added ATP. 5. The amount of intramitochondrial CoA acylated by decatetraenoate was independent of whether the internal ATP-specific or GTP-specific acyl-CoA synthetase was active. It is concluded that these two internal acyl-CoA synthetases have access to the same intramitochondrial pool of CoA. 6. The amount of intramitochondrial CoA that could be acylated with decatetraenoate was decreased by the addition of palmitoyl-dl-carnitine, 2-oxoglutarate, or pyruvate. These observations indicated that pyruvate dehydrogenase (EC 1.2.4.1), oxoglutarate dehydrogenase (EC 1.2.4.2), carnitine palmitoyltransferase (EC 2.3.1.-), citrate synthase (EC 4.1.3.7), and succinyl-CoA synthetase (EC 6.2.1.4) all have access to the same intramitochondrial pool of CoA as do the two internal acyl-CoA synthetases.
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PMID:Spectrophotometric studies of acyl-coenzyme A synthetases of rat liver mitochondria. 550 Mar 16

Mitochondria isolated from the flight muscle of the southern armyworm moth, Prodenia eridania, can oxidize palmitate+malate very rapidly. Added carnitine had no effect on the rate of oxidation of palmitate+malate by flight-muscle mitochondria from two species of moths, and carnitine palmitoyltransferase could not be detected in Prodenia by direct assay. Palmitoylcarnitine was not oxidized by moth mitochondria, but when added in low concentrations it reversibly suppressed the oxidation of palmitate. The evidence indicates that carnitine is not involved in fatty acid degradation by moth flight muscle. Added thiols, including CoA, also suppressed palmitate+malate oxidation. An ATP-dependent fatty acyl-CoA synthetase is present in moth mitochondria.
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PMID:The carnitine-independent oxidation of palmitate plus malate by moth flight-muscle mitochondria. 572 81

The acyl-CoA synthetase (acid: CoA ligase (AMP-forming), EC 6.2.1.3) activity of rat heart has been measured in fatty acid-depleted fractions of mitochondria, microperoxisomes and microsomes. The assay was based on (i) the measurement of the reaction product AMP by high-performance liquid chromatography or (ii) a coupled reaction in which the intramitochondrial (matrix) CoASH is the final acyl acceptor and the redox state of the flavoproteins in the acyl-CoA dehydrogenase pathway is used to determine the intramitochondrial level of acyl-CoA. This spectrophotometric method was also used to estimate the 'outer' carnitine long-chain acyltransferase (palmitoyl-CoA:L-carnitine O-palmitoyltransferase, EC 2.3.1.21) activity. Comparison of the distribution of long-chain acyl-CoA synthetase activity and marker enzymes in the various subcellular fractions revealed that the synthetase activity is exclusively localized in the mitochondrial fraction. Experimental evidence is presented in support of the conclusion that the chain-length specificity of saturated and monounsaturated fatty acids (16:1-22:1) for the acyl-CoA synthetase is mainly determined by the availability of the fatty acid at the active site, which is largely determined by the affinity of binding of fatty acids to the bulk phase of the mitochondrial phospholipids. Among the 22:1 isomers, 22:1(11) (cis) (cetoleic acid) revealed a slightly higher activity (1.4-fold) than 22:1(13) (cis) (erucic acid). The polyunsaturated fatty acids tested were rather poor substrates. Using isolated intact mitochondria and 16:0 or 22:1(13) (cis) as the substrates, it was found that the initial rate of the 'outer' long-chain acyltransferase activity was approximately four times higher than that of the long-chain acyl-CoA synthetase. The data support the hypothesis that the long-chain acyl-CoA synthetase reaction is rate-limiting in the sequence of coupled reactions leading to beta-oxidation in the mitochondrial matrix.
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PMID:Acyl-CoA synthetase activity of rat heart mitochondria. Substrate specificity with special reference to very-long-chain and isomeric fatty acids. 640 51

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

The effects of troglitazone and pioglitazone on glucose and fatty acid metabolism were studied in hepatocytes isolated from 24-h-starved rats. These thiazolidinediones inhibited long-chain fatty acid (oleate) oxidation and produced a very oxidized mitochondrial redox state. By contrast, thiazolidinediones did not affect the rate of medium-chain fatty acid (octanoate) oxidation or the activity of mitochondrial carnitine palmitoyltransferase (CPT) I. Thiazolidinediones inhibited selectively triglyceride synthesis but not phospholipid synthesis. The combined inhibition of oleate oxidation and esterification by troglitazone was due to a noncompetitive inhibition of mitochondrial and microsomal long-chain acyl-CoA synthetase (ACS) activities. It was suggested that troglitazone must be metabolized into its sulfo-conjugate derivative in liver cells to inhibit mitochondrial and microsomal ACS activities. Thiazolidinediones inhibited glucose production from lactate/pyruvate or from alanine. Analysis of gluconeogenic metabolite concentrations suggested that troglitazone would inhibit gluconeogenesis at the level of pyruvate carboxylase and glyceraldehyde-3-phosphate dehydrogenase reactions. It was concluded that 1) at a similar concentration, troglitazone was more efficient than pioglitazone to inhibit fatty acid metabolism and gluconeogenesis and 2) the inhibition of gluconeogenesis by troglitazone could be the result of the inhibition of long-chain fatty acid oxidation (decrease in acetyl-CoA, NADH-to-NAD+, and ATP-to-ADP ratios).
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PMID:Troglitazone inhibits fatty acid oxidation and esterification, and gluconeogenesis in isolated hepatocytes from starved rats. 886 61

In this work, an attempt was made to identify the reasons of impaired long-chain fatty acid utilization that was previously described in volume-overloaded rat hearts. The most significant data are the following: (1) The slowing down of long-chain fatty acid oxidation in severely hypertrophied hearts cannot be related to a feedback inhibition of carnitine palmitoyltransferase I from an excessive stimulation of glucose oxidation since, because of decreased tissue levels of L-carnitine, glucose oxidation also declines in volume-overloaded hearts. (2) While, in control hearts, the estimated intracellular concentrations of free carnitine are in the range of the respective Km of mitochondrial CPT I, a kinetic limitation of this enzyme could occur in hypertrophied hearts due to a 40% decrease in free carnitine. (3) The impaired palmitate oxidation persists upon the isolation of the mitochondria from these hearts even in presence of saturating concentrations of L-carnitine. In contrast, the rates of the conversion of both palmitoyl-CoA and palmitoylcarnitine into acetyl-CoA are unchanged. (4) The kinetic analyses of palmitoyl-CoA synthase and carnitine palmitoyltransferase I reactions do not reveal any differences between the two mitochondrial populations studied. On the other hand, the conversion of palmitate into palmitoylcarnitine proves to be substrate inhibited already at physiological concentrations of exogenous palmitate. The data presented in this work demonstrate that, during the development of severe cardiac hypertrophy, a fragilization of the mitochondrial outer membrane may occur. The functional integrity of this membrane seems to be further deteriorated by increasing concentrations of free fatty acids which gives rise to an impaired cooperation between palmitoyl-CoA synthase and carnitine palmitoyltransferase I. In intact myocardium, the utilization of the in situ generated palmitoyl-CoA can be further slowed down by decreased intracellular concentrations of free carnitine.
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PMID:Palmitate oxidation by the mitochondria from volume-overloaded rat hearts. 954 38


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