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 have synthesized (2S,6R:2R,6S)-6-carboxymethyl-2-hydroxy-2-pentadecyl-4,4-dimethylmorp holinium bromide (hemipalmitoylcarnitinium, HPC) which is a conformationally restricted analog inhibitor of carnitine palmitoyltransferase (CPT; EC 2.3.1.21). rac-HPC inhibits catalytic activity in purified rat liver CPT. In the forward reaction, HPC competes with both (R)-carnitine (Ki(app) = 5.1 +/- 0.7 microM) and palmitoyl-CoA (Ki(app) = 21.5 +/- 4.9 microM). In the reverse reaction, inhibition by HPC is competitive with palmitoyl-(R)-carnitine (Ki(app) = 1.6 +/- 0.6 microM), but inhibition is uncompetitive with CoA. The forward reaction is also competitively inhibited by its product, palmitoyl-(R)-carnitine, Ki(app)'s 14.2 +/- 2.1 microM relative to (R)-carnitine and 8.7 +/- 2.6 microM relative to palmitoyl-CoA. rac-HPC is the most potent synthetic reversible inhibitor of purified CPT. HPC fails to inhibit carnitine acetyltransferase (CAT; EC 2.3.1.7). Palmitoylcholine also inhibits CPT in the forward reaction, competing with (R)-carnitine (Ki(app) = 18.6 +/- 4.5 microM) and with palmitoyl CoA (Ki(app) = 10.4 +/- 2.5 microM). Choline is not an effective CPT inhibitor. We have shown [R.D. Gandour et al. (1986) Biochem. Biophys. Res. Commun. 138, 735-741] that hemiacetylcarnitinium inhibits CAT but not CPT. The combined data demonstrate further differences between the carnitine recognition sites in CPT and CAT.
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PMID:Hemipalmitoylcarnitinium, a strong competitive inhibitor of purified hepatic carnitine palmitoyltransferase. 321 66

The activities and amounts of enzyme proteins of peroxisomal beta-oxidation in Japanese children with Zellweger syndrome were investigated. Cyanide-insensitive fatty acid oxidation, peroxisomal enoyl-CoA hydratase and 3-oxoacyl-CoA thiolase activities were not detectable in liver tissue at autopsy, whereas the activities of mitochondrial enoyl-CoA hydratase, 3-oxoacyl-CoA thiolase and carnitine palmitoyltransferase were similar to those in the healthy controls. On immunoblot analysis, immunoreactive proteins of peroxisomal acyl-CoA oxidase, bifunctional protein and 3-oxoacyl-CoA thiolase were not detected in the livers, kidneys and fibroblasts from the patients. Proteins of catalase and some enzymes of mitochondrial fatty acid oxidation were similar as in normal controls. These data indicate that increased levels of very-long-chain fatty acids in Zellweger syndrome are due to the lack of the enzyme proteins of peroxisomal beta-oxidation.
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PMID:Deficient activities and proteins of peroxisomal beta-oxidation enzymes in infants with Zellweger syndrome. 351 3

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

The effect of some hypolipidemic agents, which are commercially available and those being developed, on certain biochemical values and on hepatic peroxisomal enzyme activities of rats were examined. Clofibrate (0.25% (w/w) in the diet), p-chlorophenoxy-isobutyryl-glycinamide (CGA) (0.25%), clinofibrate (0.1%), KCD-232 (0.1%) and MLM-160 (0.1%) increased the activities of peroxisomal fatty acyl-CoA oxidizing system, carnitine acetyltransferase, and mitochondrial carnitine palmitoyltransferase. Of peroxisomal enzymes, catalase activity was increased by the above agents, whereas the activities of D-amino acid oxidase and urate oxidase were decreased by clofibrate and CGA, and but were increased by KCD-232 and MLM-160 which are structurally unrelated to clofibrate. No influence on these enzyme activities by AL-369 and probucol treatments were observed. Hepatomegaly was induced by clofibrate, CGA, KCD-232 and MLM-160. Concerning serum lipid levels, clofibrate, CGA, clinofibrate, KCD-232 and MLM-160 decreased both cholesterol and triglyceride levels, whereas probucol decreased only cholesterol level. AL-369 had no influence on serum lipid levels under this condition using normolipemic rat. From these results, it was concluded that differing clofibrate and CGA, clinofibrate, MLM-160 and KCD-232 might not induce peroxisome proliferation in hepatic cells, although these have an influence on the enzyme composition of hepatic peroxisomes.
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PMID:Effects of some hypolipidemic agents on biochemical values and hepatic peroxisomal enzymes in rats: comparison of probucol, CGA, KCD-232, MLM-160, AL-369 and clinofibrate with clofibrate. 362 48

A new carnitine palmitoyltransferase (CPT) was purified to homogeneity from bovine liver mitochondria which were 96% free of peroxisomal contamination, as judged by catalase and glutamate dehydrogenase activities. The enzyme is easily removed from mitochondria, without the use of detergent. It is monomeric (Mr 63,500), unlike other preparations of CPT from mitochondria, and is most active with myristoyl-CoA and palmitoyl-CoA. The Km values are between 0.8 and 4 microM for a range of substrates from hexanoyl-CoA to stearoyl-CoA; these are much lower than values reported for other purified CPT preparations. The Km for L-carnitine is 185 microM measured with palmitoyl-CoA, and does not vary greatly with the chain length. This is also lower than the values reported for other CPT preparations, but higher than those cited for the medium-chain transferases. Kinetic and inhibitor studies were consistent with a rapid-equilibrium random-order mechanism. 2-Bromopalmitoyl-CoA, which is an inhibitor of the outer CPT, inhibited the enzyme competitively with palmitoyl-CoA as the variable substrate, when added without preincubation. If the enzyme was preincubated with 2-bromopalmitoyl-CoA and carnitine, the activity did not reappear after gel filtration of the protein. The inhibitor was bound in a 1:1 stoichiometry per subunit of enzyme.
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PMID:Purification and properties of the soluble carnitine palmitoyltransferase from bovine liver mitochondria. 366 21

Obese Zucker rats were dosed orally for one week with fenofibrate (100 mg/kg). Liver weights of treated rats as expressed as percent of body weight were slightly increased, while protein, DNA and lipid contents were unaffected per g of liver or increased when expressed in whole liver. Compared with the control animals, activities of fatty acid oxidase, of the peroxisomal fatty acid-oxidizing system and of catalase were markedly increased by fenofibrate both per g of liver and per total liver, while urate oxidase activity was unchanged when expressed per g of liver. The activity of monoamine oxidase and that of cytochrome c oxidase used as marker enzymes for mitochondria were increased only when expressed per total liver. However, fenofibrate treatment induced a pronounced increase in the activities of mitochondrial palmitoyl-CoA dehydrogenase and carnitine acyltransferases, particularly carnitine acetyltransferase. Fenofibrate also caused a significant increase of carnitine content in liver and hepatic mitochondria. The greatest observed increases were in free carnitine and in the rate of carnitine-dependent oleate oxidation, which might be favoured in vivo by a lesser sensitivity of CPT-I to a malonyl-CoA inhibitory effect. The present results suggest that fenofibrate treatment induces increased hepatic mitochondrial beta-oxidation in obese Zucker rats.
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PMID:Effects of fenofibrate treatment on fatty acid oxidation in liver mitochondria of obese Zucker rats. 366 37

Methylglyoxal bis(guanylhydrazone) (MGBG) is an antileukemic agent and a structural polyamine analogue which inhibits S-adenosyl methionine decarboxylase. However, MGBG also produces profound mitochondrial structural damage and inhibition of fatty acid oxidation. Carnitine palmitoyltransferase-A (CPT-A) is located on the outer surface of the inner mitochondrial membrane and is the putative rate-controlling enzyme for mitochondrial long-chain fatty acid oxidation. The present experiments were designed to determine if MGBG inhibits CPT-A. Liver, heart and skeletal muscle mitochondria were isolated from rats following 24 hr of starvation. Measuring the reaction in the direction of palmitoylcarnitine plus CoA formation from palmitoyl-CoA plus carnitine ("forward reaction"), MGBG was competitive with l-carnitine. The MGBG CPT-A Ki values were (mM): liver, 5.0 +/- 0.6 (N = 15); heart 3.2 +/- 1.2 (N = 3); and skeletal muscle, 2.8 +/- 1.0 (N = 3). Lysis of hepatic mitochondria with Triton X-100 yielded a Ki of 4.0 +/- 2.0, which was not significantly different from intact mitochondria or inverted vesicles (4.9 mM). Purified hepatic CPT had a Ki of 4.2 mM. MGBG did not inhibit purified CPT in the "reverse reaction" (palmitoyl-CoA plus carnitine formation from palmitoylcarnitine plus CoA). Spermine and spermidine, which are structurally similar to MGBG, did not inhibit either CPT activity or acid-soluble product formation from 1-[14C]palmitoyl-CoA. MGBG inhibited mitochondrial state 3 oxidation rates of palmitoyl-CoA and palmitoylcarnitine, as well as of glutamate. However, the fatty acid substrates were considerably more sensitive than glutamate to MGBG inhibition. MGBG also increased hepatic mitochondrial aggregation which was reversed by l-carnitine. Fluorescence polarization, using 1,6-diphenyl-1,3,5-hexatriene (DPH) as a probe, indicated that MGBG increased membrane rigidity in a dose-dependent manner. This effect was not altered by l-carnitine. MGBG also inhibited purified pigeon breast carnitine acetyltransferase (CAT; Ki = 1.6 mM). While MGBG appeared to be competitive with l-carnitine for both CPT and CAT, MGBG also exhibits a number of effects which may be mediated through membrane interaction and which are not reversed by carnitine.
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PMID:Effect of methylglyoxal bis(guanylhydrazone) on hepatic, heart and skeletal muscle mitochondrial carnitine palmitoyltransferase and beta-oxidation of fatty acids. 382 37

Effects of tolmetin, diclofenac Na, fenbufen, alclofenac, aminopyrine, mepirizole, thiaramide and aspirin as a positive control, which are widely used in this country as anti-inflammatory drugs, and on body and liver weights, triglyceride and cholesterol level and hepatic peroxisomal enzymes of normolipemic rats were examined. All of these drugs except diclofenac Na affected the enzyme composition of hepatic peroxisomes. Tolmetin (100 mg/kg) and fenbufen (50 mg/kg) increased carnitine acetyltransferase (CAT) and fatty acyl-coenzyme A oxidizing system (FAOS) activities, which participate in hepatic lipid metabolism. The latter also increased the activity of D-amino acid oxidase slightly. Alclofenac (300 mg/kg) increased the activities of FAOS, CAT and carnitine palmitoyltransferase which has been known as the rate-limiting enzyme of fatty acid oxidation in mitochondria, and decreased those of catalase and urate oxidase. Aminopyrine (300 mg/kg) increased the activities of catalase and FAOS. However, none of the above drugs influenced liver weight, serum or liver lipid levels. Mepirizole (300 mg/kg) increased the activities of FAOS and CAT about 2-fold, whereas the activities of catalase and urate oxidase and serum triglyceride level were decreased. Furthermore, these drugs showed no enhancement of the biosynthesis of peroxisome proliferation associated polypeptide having a molecular weight of 80000. From these results, it is concluded that although these drugs have an influence on the enzyme composition of hepatic peroxisomes, they may not induce the peroxisome population in hepatic cells. Thus, the possibility of hepatocarinogenicity and lipid lowering effect through the peroxisome-proliferation would be excluded.
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PMID:Effects of some anti-inflammatory drugs on biochemical values and on hepatic peroxisomal enzymes of rat. 383 60

Interaction between the natural ceolite clinoptilolite and cell suspensions has been investigated using rat peritoneal macrophages and erythrocytes. The ceolite under study has been demonstrated to exhibit a high hemolytic activity and cytotoxicity. The viability of macrophages was evaluated from the incorporation of trypane blue. The ability of macrophages to phagocytosis was measured by chemiluminescence with luminol. The modification of clinoptilolite surface by ammonia ions led to a decrease in its cytotoxic properties. Ethanol, mannit and sodium azide did not affect whereas catalase appreciably reduced the ability of CPT to damage the membranes of macrophages and red cells. The role of hydrogen peroxide in the mechanism of cell membrane damage is discussed.
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PMID:[Mechanism of the cytotoxic action of the natural zeolite clinoptilolite]. 609 37

Effects of fat content in the diet on rat liver peroxisomes was examined. In the livers of rats fed for one week on the high-fat diet containing 30% fat, the cyanide-insensitive palmitoyl-CoA oxidation was accelerated to eight times that of control and the enzymic activities of catalase, carnitine acetyltransferase and carnitine palmitoyltransferase were elevated by the factors of 1.3, 5 and 2, respectively. In contrast, the activities of D-amino acid oxidase in addition to the three enzymes mentioned above were all lowered by 20% when the animals were maintained on a fat-free diet for the same period of time. It appears that the high-fat diet-induced increase in the activity of carnitine palmitoyltransferase is a result of the raised activity of this enzyme in mitochondria only while the apparent high activity reflects stimulation of carnitine acetyltransferase in all the subcellular fractions. Another notable effect of the high-fat diet was a remarkable increase in the quantity of a peroxisome-associated polypeptide which was separable by sodium dodecyl sulfate polyacrylamide gel electrophoresis. It is noteworthy that this effect of the high-fat diet resemble that of clofibrate. If the diet was deprived of fat, however, this polypeptide species, with an estimated molecular weight of 80 000, decreased to a level slightly lower than normal. On the basis of the electron micrographic criteria, the high-fat diet provoked a marked proliferation of hepatic peroxisomes.
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PMID:Effects of fat content in the diet on hepatic peroxisomes of the rat. 610 40


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