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)

Hemiacetylcarnitinium (2S,6R:2R,65)-6-carboxymethyl-2-hydroxy-2,4,4- trimethylmorpholinium) chloride is a relatively potent competitive inhibitor (Ki = 0.89 mM) of pigeon breast carnitine acetyltransferase (CAT) and of the crude rat liver CAT (Ki = 4.72 mM) but is neither an inhibitor nor an effective substrate for purified rat liver carnitine palmitoyltransferase (CPT). It does not inhibit state 3 oxygen consumption in isolated hepatic mitochondria using palmitoyl-CoA or palmitoylcarnitine as substrates. This compound is a reaction intermediate analogue of the proposed tetrahedral intermediate for acetyl transfer between acetylcarnitine and CoASH. Because the hemiketal carbon is chiral, a suggestion is made that one of the enantiomers has the same relative configuration as the proposed tetrahedral intermediate.
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PMID:Active-site probes of carnitine acyltransferases. Inhibition of carnitine acetyltransferase by hemiacetylcarnitinium, a reaction intermediate analogue. 374 30

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

DL-Aminocarnitine (3-amino-4-trimethylaminobutyric acid) and acetyl-DL-aminocarnitine (3-acetamido-4-trimethylaminobutyric acid) have been synthesized and the interactions of these compounds with carnitine acetyltransferase and carnitine palmitoyltransferase investigated. As anticipated from the low group transfer potential of amides, carnitine acetyltransferase catalyzes the transfer of acetyl groups from CoASAc to aminocarnitine (Km = 3.8 mM) but does not catalyze detectable transfer from acetylaminocarnitine to CoASH. Acetyl-DL-aminocarnitine is, however, a potent competitive inhibitor of carnitine acetyltransferase (Ki = 24 microM) and is bound to carnitine acetyltransferase about 13-fold more tightly than is acetylcarnitine, with which it is isosteric. DL-Aminocarnitine and, to a lesser extent, acetyl-DL-aminocarnitine are also inhibitors of the carnitine palmitoyltransferase activity of detergent-lysed rat liver mitochondria; in the presence of 1 mM L-carnitine, 5 microM aminocarnitine inhibits palmitoyl transfer by 64%. Significant acylation of aminocarnitine by palmitoyl-CoA was not observed. Neither aminocarnitine nor acetylaminocarnitine is significantly catabolized by mice; aminocarnitine is converted to acetylaminocarnitine in vivo. Both compounds are excreted in the urine. Mice given acetylaminocarnitine catabolize [14C]acetyl-L-carnitine and [14C]palmitate to 14CO2 more slowly than do control animals. Mice given acetylaminocarnitine and then starved are found to reversibly accumulate triglycerides in their livers; mice given the inhibitor but not starved do not show this effect.
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PMID:DL-aminocarnitine and acetyl-DL-aminocarnitine. Potent inhibitors of carnitine acyltransferases and hepatic triglyceride catabolism. 384 Apr 86

The activities of peroxisomal and mitochondrial beta-oxidation and carnitine acyltransferases changed during the process of development from embryo to adult chicken, and the highest activities of peroxisomal beta-oxidation, palmitoyl-CoA oxidase, and carnitine acetyltransferase were found at the hatching stage of the embryo. The profiles of these alterations were in agreement with those of the contents of triglycerides and free fatty acids in the liver. The highest activities of mitochondrial beta-oxidation and palmitoyl-CoA dehydrogenase were observed at the earlier stages of the embryo; then the activities decreased gradually from embryo to adult chicken. The ratio of activities of carnitine acetyltransferase in peroxisomes and mitochondria (peroxisomes/mitochondria) increased from 0.54 to 0.82 during the development from embryo to adult chicken. The ratio of activities of carnitine palmitoyltransferase decreased from 0.82 to 0.25 during the development. The affinity of fatty acyl-CoA dehydrogenase toward the medium-chain acyl-CoAs (C6 and C8) was high in the embryo and decreased with development, whereas the substrate specificity of fatty acyl-CoA oxidase did not change. The substrate specificity of mitochondrial carnitine acyltransferases did not change with development. The affinity of peroxisomal carnitine acyltransferases toward the long-chain acyl-CoAs (C10 to C16) was high in the embryo, but low in adult chicken.
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PMID:Developmental changes in the activities of peroxisomal and mitochondrial beta-oxidation in chicken liver. 397 May 42

The effect of a 0.25% clofibrate diet for 2 weeks on peroxisomal and mitochondrial beta-oxidation in chicken liver was studied. The activities of antimycin antimycin A-insensitive palmitoyl-CoA oxidation (peroxisomal beta-oxidation) and carnitine acetyltransferase increased about two-fold. The activities of palmitoyl-CoA-dependent O2 consumption (mitochondrial beta-oxidation) and carnitine palmitoyltransferase were also slightly activated by the administration of clofibrate, but not significant. Thus, clofibrate may be a typical drug which activates the peroxisomal beta-oxidation more than the mitochondrial one in various species. The effect of clofibrate on peroxisomal carnitine acetyltransferase was the same as that on the mitochondrial one in chicken liver. Serum lipids were not lowered, but hepatomegaly was observed in the present experiment with chicken.
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PMID:Effect of clofibrate on peroxisomal and mitochondrial beta-oxidation in chicken liver. 401 36

Previous studies have demonstrated that certain high fat diets can induce peroxisomal fatty acid beta-oxidation in rodent liver and that this may be due to their content of trans 22:1 fatty acids. In this study we have examined the effects of cis and trans 22:1 fatty acids (erucic and brassidic) and oleic acid (18:1) on palmitoyl-CoA oxidation, carnitine acetyltransferase and carnitine palmitoyltransferase activities in primary rat hepatocyte cultures. Brassidic and erucic acid and, to a lesser extent, oleic acid were cytotoxic to rat hepatocytes. However, at a concentration of 0.1 mM, brassidic acid produced small increases in palmitoyl-CoA oxidation and carnitine acetyltransferase activities in hepatocytes cultured 70 hr. Treatment of cells with 0.1 and 0.3 mM of either erucic or oleic acid had no effect on any of the enzymes measured.
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PMID:Effect of very long chain fatty acids on peroxisomal beta-oxidation in primary rat hepatocyte cultures. 409 23

1. The content of carnitine, acylcarnitine and total acid soluble carnitine in brown adipose tissue of rats increases rapidly after birth, attaining a peak on about day 10 and then decreases. Similar changes with age were found for carnitine acetyltransferase activity in mitochondria from brown adipose tissue and heart. The activity of this enzyme in brain and in liver is much smaller, but also increases postnatally. 2. The activity of carnitine palmitoyltransferase in brown adipose tissue, however, decreases after birth then increases later in life. 3. Exposure of 18-day-old rats to the cold for 20 days leads to an increase in carnitine content in brown adipose tissue and raises the activity of carnitine acetyltransferase. The activity of carnitine palmitoyltransferase is not affected by cold adaptation.
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PMID:Carnitine and brown adipose tissue metabolism in the rat during development. 507 35

1. Carnitine acetyltransferase is very rapidly inhibited in the presence of bromoacetyl-(-)-carnitine plus CoA or of bromoacetyl-CoA plus (-)-carnitine. 2. Under appropriate conditions, the enzyme may be titrated with either bromoacetyl substrate analogue; in each case about 1mole of inhibitor is required to inactivate completely 1mole of enzyme of molecular weight 58000+/-3000. 3. Inhibition by bromoacetyl-CoA plus (-)-carnitine results in the formation of an inactive enzyme species, containing stoicheiometric amounts of bound adenine nucleotide and (-)-carnitine in a form that is not removed by gel filtration. This is shown to be S-carboxymethyl-CoA (-)-carnitine ester. 4. The inhibited enzyme recovers activity slowly on prolonged standing at 4 degrees . 5. Incubation with S-carboxymethyl-CoA (-)-carnitine ester causes a slow inhibition of carnitine acetyltransferase. 6. The formation of bound S-carboxymethyl-CoA (-)-carnitine ester by the enzyme is discussed. Presumably the resulting inhibition reflects binding of the ester to both the CoA- and carnitine-binding sites on the enzyme and its consequent very slow dissociation. These observations confirm that carnitine acetyltransferase can form ternary enzyme-substrate complexes; this also appears to be the case with carnitine palmitoyltransferase and choline acetyltransferase.
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PMID:Conditions for the self-catalysed inactivation of carnitine acetyltransferase. A novel form of enzyme inhibition. 576 88

We have studied a 17-year-old girl with lactic acidosis (3-18 mEq/liter) and progressive muscle weakness since 9 years of age. Morphological findings in muscle were of a typical ragged red myopathy with multiple collections of bizarre mitochondria, some containing paracrystalline inclusions. The carnitine content of serum and muscle was normal, as were the activities of carnitine palmitoyltransferase, carnitine octanoyltransferase, and carnitine acetyltransferase in the patient's muscle. Measurement of the enzymes of oxidative phosphorylation in both crude muscle homogenates and mitochondrial fractions showed close to normal activities of cytochrome c oxidase, succinate dehydrogenase, and ATPase. In contrast, succinate cytochrome c reductase activity was greatly reduced in the patient, being 0.035 mumol/min/g tissue in whole muscle (controls 1.16 +/- 0.47 mumol/min/g tissue) and 8 nmol/min/mg protein in the mitochondria (control, 340 nmol/min/mg protein). Rotenonesensitive NADH-cytochrome c reductase was also undetectable in the patient's mitochondria. Spectral analysis of cytochromes showed decrease of reducible cytochrome b to 16% of the control. These results indicate a defect of ubiquinol-cytochrome c reductase or the cytochrome bc1 segment (complex III) of the electron transport chain. Antibody-binding studies of the individual components of complex III showed additional deficiencies of core proteins I and II and peptide VI, indicating a more widespread defect of complex III than was evident from spectral analysis and enzyme activity measurements alone. Urine organic acid analysis after fasting and following a medium chain triglyceride load showed unusually high levels of lactate and 3-hydroxybutyrate, lower than expected levels of acetoacetate and dicarboxylic acids, and the presence of several other metabolites suggesting a disturbed citric acid cycle and redox state.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Lactic acidosis and mitochondrial myopathy associated with deficiency of several components of complex III of the respiratory chain. 609 35


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