Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: CAS:1763-10-6 (palmitoyl-CoA)
 1,624 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. Long-chain acid: CoA ligase (AMP-forming) (trivial name acyl-CoA synthetase; EC 6.2.1.3) is located at the membranes of the endoplasmic reticulum and the outer membrane of the mitochondria. The latter membrane has by far the highest specific activity. 2. GTP-dependent synthesis of acyl-CoA has a very low activity in liver mitochondria (about 5% of the activity measured with ATP). CTP, ITP, UTP and GTP may all provide energy for fatty acid activation in sonicated mitochondria by formation of ATP from endogenous ADP and AMP. 3. In rat liver palmitoyl-CoA: L-carnitine O-palmitoyltransferase (trivial name carnitine palmitoyltransferase; EC 2.3.1.21) is located at the microsomal membranes and in the inner membrane of the mitochondria. Its activity is increased, in both membranes, during fasting and in thyroxine-treated rats. The extramitochondrial carnitine palmitoyltransferase may capture part of the acyl CoA formed at the endoplasmic reticulum as acyl-carnitine, especially during fasting and other metabolic conditions of high fatty acid turnover. This transport form of activated fatty acid can penetrate the inner mitochondrial membrane (the acyl-CoA barrier) where it can be reconverted to acyl-CoA, providing the substrate for beta-oxidation in the inner membrane-matrix compartment. The small part of the mitochondrial carnitine palmitoyltransferase, described to be present at the external surface of the mitochondrial inner membrane, may have the same function in the transport of acyl-CoA formed at the mitochondrial outer membrane. 4. Isolated rat liver mitochondria can oxidize high concentrations of palmitate or oleate in the absence of carnitine. In this case the fatty acids are activated in the inner membrane-matrix compartment of the mitochondria, probably by a medium-chain acyl-CoA synthetase with wide substrate specificity. Because this enzyme is less active in heart and absent in skeletal muscle, these tissues oxidize long-chain fatty acids in an obligatory carnitine-dependent fashion. Also the liver oxidizes long-chain fatty acids in a carnitine-dependent way if lower fatty acid concentrations are used. In this tissue carnitine stimulates specifically the partial oxidation of fatty acids to beta-hydroxybutyrate and acetoacetate. 5. The activities of acyl-CoA: sn-glycerol-3-phosphate O-acyltransferase (trivial name glycerophosphate acyltransferase; EC 2.3.1.15) and carnitine palmitoyltransferase change in opposite directions during fasting. These activity changes, together with the measured kinetic properties of the enzymes in mitochondria and microsomes, allow a switch (relatively) from lipid synthesis to ketogenesis during fasting. This switch may occur at the level of long-chain acyl-CoA both in the endoplasmic reticulum and in the mitochondria.
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PMID:Aspects of long-chain acyl-COA metabolism. 113 97

We examined stereoselectivities of enzymes related to bile acid formation in hepatic peroxisomes using two stereoisomers of 3 alpha,7 alpha,12 alpha-trihydroxy-5 beta-cholestanoic acid (THCA) and its coenzyme A (CoA) derivatives. The activity of acyl-CoA synthetase for 25 S-THCA was 1.4-times higher than that for 25 R-THCA. The difference was also observed after clofibrate-treatment. This activity was located in microsomes, differing from palmitoyl-CoA synthetase located in mitochondria, peroxisomes and microsomes. There was no stereoselectivity in the reaction of peroxisomal fatty acyl-CoA oxidase for THCA isomers, and the activity was one tenth of that for acyl-CoA synthetase. Considering the overall reaction of peroxisomal bile acid formation, the stereoselective difference observed in THCA-CoA synthesis should be denied. Thus, the previous finding that the overall formation of bile acid from THCA was not stereoselective was further confirmed. Furthermore, the activity for THCA oxidation was not induced by clofibric acid, suggesting that there would be different isozymes of peroxisomal acyl-CoA oxidase against THCA-CoA and palmitoyl-CoA.
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PMID:Study on stereospecificity of enzyme reaction related to peroxisomal bile acid synthesis in rat liver. 135 23

The mechanism by which enoximone, a reported phosphodiesterase inhibitor, inhibits the oxidation of long-chain fatty acids was studied in isolated rat heart mitochondria using a series of 14C-labeled substrates. Enoximone decreased palmitate oxidation in a time- and concentration-dependent manner. Fifty percent inhibition of palmitate oxidation was achieved with 250 microM of enoximone. In contrast to its effect on palmitate, enoximone (250 microM) increased octanoate oxidation by 30%, whereas pyruvate oxidation was unaffected by enoximone. At that dose there was no effect on the oxidation of palmitoyl-CoA and palmitoyl carnitine. The degree of palmitate oxidation inhibited by enoximone was parallel to the inhibition of acyl-CoA synthetase in both rat heart mitochondria and microsomes. These results suggest that enoximone is a reversible inhibitor of long-chain fatty acyl-CoA synthetase. Moreover, the reaction, which is catalyzed by this enzyme, is a rate-limiting step in the pathway of fatty acid oxidation in rat heart mitochondria.
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PMID:The inhibition of long-chain fatty acyl-CoA synthetase by enoximone in rat heart mitochondria. 137 10

ATP-dependent coenzyme A (CoA) ligases catalyse the formation of the acyl-CoA thioesters of xenobiotic carboxylic acids and the formation of xenobiotic-CoAs has been implicated as being a causative factor in peroxisomal proliferation. In this study we have demonstrated using rat liver peroxisomes that the formation of palmitoyl-CoA is inhibited by a variety of xenobiotic carboxylic acids. Palmitoyl-CoA formation exhibited biphasic kinetics indicative of two isoforms, a high affinity (Km1 2.3 microM) low capacity form and a low affinity (Km2 831 microM) high capacity form. These forms were differentially inhibited by a range of xenobiotics. However, it would appear that the low affinity component may not contribute to any major extent to the formation of xenobiotic-CoAs in vivo. At a concentration of 1 mM, greater than 20% inhibition of the high affinity form was observed with the 2-arylpropionates, ibuprofen, naproxen, benoxaprofen, fenoprofen, indoprofen, ketoprofen, tiaprofenic acid and cicloprofen, the hypolipidaemics, nafenopin and ciprofibrate, and the herbicides, silvex and 2,4,5-trichlorophenoxyacetate. Valproic acid, clofibric acid, salicylic acid and 2,4-dichlorophenoxy-acetate were non-inhibitory at all concentrations studied (0.1-2.5 mM). Analysis of the type of inhibition established that only nafenopin (Ki 430 microM) and ciprofibrate (Ki 97 microM) were competitive inhibitors of palmitoyl-CoA formation suggesting that they bind at the active site and thus potentially function as alternative substrates for the peroxisomal ligase. Notably, clofibric acid which has previously been shown to form clofibroyl-CoA in peroxisomes did not interact with the palmitoyl-CoA ligase thereby suggesting that activation is mediated via an alternative peroxisomal CoA ligase. In addition, the xenobiotic inhibitors of the peroxisomal palmitoyl-CoA ligase differed from those previously reported for the equivalent microsomal enzyme suggesting that the organellar forms may be functionally distinct. This study establishes that numerous xenobiotic carboxylic acids interact with the peroxisomal palmitoyl-CoA ligase; however, it would appear that relatively few function as alternative substrates. The toxicological ramifications of peroxisomally mediated xenobiotic-CoA formation and the identification of other peroxisomal xenobiotic-CoA ligase(s) remain to be elucidated.
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PMID:Inhibition of rat peroxisomal palmitoyl-CoA ligase by xenobiotic carboxylic acids. 138 10

Investigations have been carried out on the alterations of membrane lipids and some enzyme activities during liver regeneration. The results indicated that 32 h after partial hepatectomy the membrane phospholipids per mg protein were augmented. The cholesterol esters were also increased in both microsomal and plasma membranes. The specific radioactivity of the separate phospholipid fractions, estimated by incorporation of 14C-palmitate into the phospholipid molecules, was higher in membranes from partially hepatectomized rats, compared to sham-operated ones, indicating an enhanced phospholipid synthesis. The content and specific radioactivity of diacylglycerols and triacylglycerols was enhanced in both types of membranes from regenerating liver. Moreover, we observed a fluidization of these membranes, which is illustrated by the decrease of the structural order parameter (SDPH) of the lipid bilayer as well as by the elevation of the excimer to monomer fluorescent ratio (IE/IM). 1,6-Diphenyl-1,3,5-hexatriene and pyrene were used as fluorescent probes for determination of the membranes physical state. Palmitoyl-CoA and oleoyl-CoA synthetase, acyl-CoA: lysophosphocholine and acyl-CoA:lysophosphoethanolamine acyltransferase as well as phospholipase C activities were augmented in membranes from partially hepatectomized rats. The biological significance of these alterations in the process of liver regeneration is discussed.
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PMID:Alterations in microsomal and plasma membranes during liver regeneration. 147 42

Microsomal long chain fatty acid CoA ligase (EC 6.2.1.3) has been implicated in the formation of CoA thioesters of xenobiotics containing a carboxylic acid moiety. In this study we have demonstrated that the microsomal enzyme from rat liver exhibits biphasic kinetics for the formation of palmitoyl-CoA, i.e. there are high affinity low capacity Kmhigh, 1.6 microM, Vmaxhigh, 12.9 nmol/mg/min) and low affinity high capacity (Kmlow, 506 microM, Vmaxlow, 58.3 nmol/mg/min) components. Inhibition of the high affinity isoform was studied using the R and S enantiomers of ibuprofen, fenoprofen, ketoprofen and naproxen. The high affinity component of palmitoyl-CoA formation was competitively inhibited by R-fenoprofen (Ki 15.4 microM) while R-ibuprofen exhibited mixed inhibition kinetics. In contrast the R and S enantiomers of ketoprofen and naproxen were non-competitive inhibitors. This diversity of inhibition kinetics observed argues in favour of a binding site in addition to the catalytic site. A competitive interaction with the high affinity form correlated with literature evidence of enantiospecific chiral inversion and "hybrid" triglyceride formation for the R enantiomers of fenoprofen and ibuprofen. Paradoxically, R-ketoprofen which is extensively inverted in rats was a non-competitive inhibitor of palmitoyl-CoA formation by the high affinity isoform suggesting that it may not act as an alternate substrate. The results of this study clearly indicate that formation of R-2-arylpropionate-CoAs is not fully explained by interaction with the high affinity isoform of a microsomal long chain (palmitoyl) CoA ligase and therefore the involvement of other isoforms cannot be discounted.
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PMID:Inhibition kinetics of hepatic microsomal long chain fatty acid-CoA ligase by 2-arylpropionic acid non-steroidal anti-inflammatory drugs. 156 71

2-Bromopalmitate and 2-bromopalmitoyl-CoA have been shown to inhibit a variety of enzymes and proteins associated with lipid metabolism. We found that both of the brominated compounds were non-competitive inhibitors of two microsomal activities of triacylglycerol biosynthesis, the mono- and diacylglycerol acyltransferases. With both compounds, the calculated Ki values were lower than the Km value for the palmitoyl-CoA substrate. In addition to inhibiting two other lipid synthetic activities, fatty acid CoA ligase and glycerol-3-P acyltransferase, 2-bromopalmitate and 2-bromopalmitoyl-CoA also inhibited two microsomal enzyme activities that are not related to lipid metabolism, NADPH cytochrome-c reductase and glucose-6-phosphatase. Inhibition of the three acyltransferases and fatty acid CoA ligase could be overcome by the addition of phospholipid vesicles, and 2-bromo[14C]palmitate readily labeled a large number of membrane-bound proteins as well as cytosolic proteins that had been solubilized in SDS. Thus, it appears likely that the inhibitory properties of the brominated compounds strongly depend on the effective concentration of the inhibitor within membranes rather than on any specific affinity for an acyl-chain binding region of the enzyme.
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PMID:2-Bromopalmitoyl-CoA and 2-bromopalmitate: promiscuous inhibitors of membrane-bound enzymes. 157 64

The different topology of palmitoyl-CoA ligase (on the cytoplasmic surface) and of lignoceroyl-CoA ligase (on the luminal surface) in peroxisomal membranes suggests that these fatty acids may be transported in different form through the peroxisomal membrane (Lazo, O., Contreras, M., and Singh, I. (1990) Biochemistry 29, 3981-3986), and this differential transport may account for deficient oxidation of lignoceric acid in X-adrenoleukodystrophy (X-ALD) (Singh, I., Moser, A. B., Goldfisher, S., and Moser, H. W. (1984) Proc. Natl. Acad. Sci. U.S.A. 81, 4203-4207). To define the transport mechanism for these fatty acids through the peroxisomal membrane and its possible implication to lignoceric acid metabolism in X-ALD, we examined cofactors and energy requirements for the transport of palmitic and lignoceric acids in isolated peroxisomes from rat liver and peroxisomes isolated from X-ALD and control fibroblasts. The similar rates of transport of palmitoyl-CoA (87.6 +/- 6.3 nmol/h/mg protein) and palmitic acid in the fatty acid activating conditions (83.4 +/- 5.1 nmol/h/mg protein) and lack of transport of palmitic acid (4% of palmitoyl-CoA transport) when ATP and/or CoASH were removed or substituted by alpha,beta-methyleneadenosine-5'-triphosphate (AMPCPOP) and/or desulfoCoA-agarose from assay medium clearly demonstrate that transport of palmitic acid requires prior synthesis of palmitoyl-CoA by palmitoyl-CoA ligase on the cytoplasmic surface of peroxisomes. The 10-fold higher rate of transport of lignoceric acid (5.3 +/- 0.6 nmol/h/mg protein) as compared with lignoceroyl-CoA (0.41 +/- 0.11 nmol/h/mg protein) and lack of inhibition of transport of lignoceric acid when ATP and/or CoASH were removed or substituted with AMPCPOP or desulfoCoA-agarose suggest that lignoceric acid is transported through the peroxisomal membrane as such. Moreover, the lack of effect of removal of ATP or substitution with AMPOPCP (a nonhydrolyzable substrate) demonstrates that the translocation of palmitoyl-CoA and lignoceric acid across peroxisomal membrane does not require energy. The transport, activation, and oxidation of palmitic acid are normal in peroxisomes from X-ALD. The deficient lignoceroyl-CoA ligase (13% of control) and oxidation of lignoceric acid (10% of control) as compared with normal transport of lignoceric acid into peroxisomes from X-ALD clearly demonstrates that pathogenomonic accumulation of very long chain fatty acids (greater than C22) in X-ALD is due to the deficiency of peroxisomal lignoceroyl-CoA ligase activity.
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PMID:Transport of fatty acids into human and rat peroxisomes. Differential transport of palmitic and lignoceric acids and its implication to X-adrenoleukodystrophy. 161 32

Investigations were performed on the influence of the phospholipid composition and physicochemical properties of the rat liver microsomal membranes on acyl-CoA synthetase and acyl-CoA:1-acyl-sn-glycero-3-phosphocholine O-acyltransferase activities. The phospholipid composition of the membranes was modified by incubation with different phospholipids in the presence of lipid transfer proteins or by partial delipidation with exogenous phospholipase C and subsequent enrichment with phospholipids. The results indicated that the incorporation of phosphatidylglycerol, phosphatidylserine and phosphatidylethanolamine induced a marked activation of acyl-CoA synthetase for both substrates used--palmitic and oleic acids. Sphingomyelin occurred as specific inhibitor for this activity especially for palmitic acid. Palmitoyl-CoA: and oleoyl-CoA: 1-acyl-sn-glycero-3-phosphocholine acyltransferase activities were found to depend on the physical state of the membrane lipids. The alterations in the membrane physical state were estimated using two different fluorescent probes--1,6-diphenyl-1,3,5-hexatriene and pyrene. In all cases of membrane fluidization this activity was elevated. On the contrary, in more rigid membranes obtained by incorporation of sphingomyelin and dipalmitoylphosphatidylcholine, acyltransferase activity was reduced for both palmitoyl-CoA and oleoyl-CoA. We suggest a certain similarity in the way of regulation of membrane-bound acyltransferase and phospholipase A2 which both participate in the deacylation-reacylation cycle.
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PMID:Phospholipid dependence of rat liver microsomal acyl:CoA synthetase and acyl-CoA:1-acyl-sn-glycero-3-phosphocholine O-acyltransferase. 162 22

We have investigated the localization of palmitoyl-CoA (hexadecanoyl-CoA) synthetase (EC 6.2.1.3) and cerotoyl-CoA (hexacosanoyl-CoA) synthetase in peroxisomes isolated from rat liver. Palmitoyl-CoA and cerotoyl-CoA synthetases, like acyl-CoA: dihydroxyacetone phosphate acyltransferase (EC 2.3.1.42), are present in the peroxisomal membrane. Trypsin treatment of intact peroxisomes led to the disappearance of both palmitoyl-CoA and cerotoyl-CoA synthetase activities but had little, if any, effect on L-alpha-hydroxy-acid oxidase (EC 1.1.3.15), D-amino acid oxidase (EC 1.4.3.3) or acyl-CoA:dihydroxyacetone phosphate acyltransferase. The latter three enzymes were inactivated if the trypsin treatment was preceeded by disruption of the peroxisomes by sonication. These results show that the active site, or at least domains essential for the activity of cerotoyl-CoA synthetase, like that of palmitoyl-CoA synthetase, is located on the cytosolic face of the peroxisomal membrane.
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PMID:Topography of very-long-chain-fatty-acid-activating activity in peroxisomes from rat liver. 182 48


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