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)

Four unlinked fatty acid activation (FAA) genes encoding acyl-CoA synthetases have been identified in Saccharomyces cerevisiae and characterized by noting the phenotypes of isogenic strains containing all possible combinations of faa null alleles. None of these genes is required for vegetative growth when acyl-CoA production by the fatty acid synthetase (Fas) complex is active. When Fas is inhibited by cerulenin, exponentially growing cells are not viable on media containing a fermentable carbon source unless supplemented with fatty acids such as myristate, palmitate, or oleate. The functionally interchangeable FAA1 and FAA4 genes are responsible for activation of these imported fatty acids. Analysis of lysates prepared from isogenic FAA1FAA4 and faa1 delta faa4 delta strains indicated that Faa1p and Faa4p together account for 99% of total cellular myristoyl-CoA and palmitoyl-CoA synthetase activities. Genetic complementation studies revealed that rat liver acyl-CoA synthetase (RLACS) rescues the viability of faa1 delta faa4 delta cells in media containing a fermentable carbon source, myristate or palmitate, plus cerulenin. Rescue is greater at 37 degrees C compared with 24 degrees C, paralleling the temperature-dependent changes in RLACS activity in vitro as well as the enzyme's ability to direct incorporation of tritiated myristate and palmitate into cellular phospholipids in vivo. Complementation by RLACS is blocked by treatment of cells with triacsin C (1-hydroxy-3-(E,E,E,2',4',7'- undecatrienylidine)triazene). Even though Faa1p, Faa4p, and RLACS are all able to activate imported myristate and palmitate in S. cerevisiae, the sensitivity of Faa4p and RLACS, but not Faa1p, to inhibition by triacsin C suggests that the rat liver enzyme is functionally more analogous to Faa4p than to Faa1p. Finally, an assessment of myristate and palmitate import into FAA1FAA4 and faa1 delta faa4 delta strains, with or without episomes that direct overexpression of Faa1p, Faa4p or RLACS, indicated that fatty acid uptake is not coupled to activation in S. cerevisiae.
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PMID:Complementation of Saccharomyces cerevisiae strains containing fatty acid activation gene (FAA) deletions with a mammalian acyl-CoA synthetase. 773 25

The mechanisms of peroxisomal induction and hypolipidaemia caused by treatment with peroxisome proliferators, such as nafenopin and clofibrate, remain to be elucidated. Proposed mechanisms include receptor-mediated processes or adaptations resulting from disruption of hepatic lipid metabolism. The latter mechanism was investigated in a series of in vitro studies. Incubation of primary rat hepatocytes with various carboxyl-containing compounds revealed no clear common factor which imparted potency as a peroxisomal inducer. Inhibitors of fatty acyl-CoA synthetase, norepinephrine and desulpho-CoA, however, decreased the level of peroxisomal induction by nafenopin in rat hepatocytes, suggesting that activation of carboxyl-containing compounds to their CoA thioesters may be a necessary step in initiating peroxisome proliferation. Coenzyme A thioesters of nafenopin, clofibric acid and other carboxyl-containing chemicals were synthesised and found to inhibit the activity of acetyl-CoA carboxylase to varying degrees. The CoA thioester of nafenopin was the most potent inhibitor among this group (Ki = 1.45 x 10(-5) M), but weaker than palmitoyl-CoA (Ki = 2.22 x 10(-6) M), the feedback inhibitor of acetyl-CoA carboxylase. Hypolipidaemia caused by treatment with peroxisome proliferators may, therefore, be related to inhibition of fatty-acid synthesis by the corresponding CoA thioester derivative.
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PMID:In vitro evidence for involvement of CoA thioesters in peroxisome proliferation and hypolipidaemia. 790 45

Ligand-initiated activation of neutrophils triggers O2- generation, degranulation, phospholipid remodeling, and release of fatty acids such as arachidonate, oleate, and palmitate. Long chain acyl-CoA synthetase converts free fatty acids to acyl-CoA esters; a role for acyl-CoA esters as positive modulators of neutrophil functions is proposed. Physiologically relevant concentrations (1-10 microM) of acyl-CoA esters such as palmitoyl-CoA, enhanced O2- generation triggered by fMet-Leu-Phe or guanosine 5'-O-(thiotriphosphate) (GTP gamma S) but did not act as a trigger per se. Triacsin C, an inhibitor of acyl-CoA synthetase, inhibited fMet-Leu-Phe-elicited O2- generation and degranulation in a concentration-dependent manner. Triacsin C inhibited O2- generation elicited by fMet-Leu-Phe and GTP gamma S in electroporated neutrophils, indicating that acyl-CoA acted downstream from the receptor. Palmitoyl-CoA reversed the Triacsin C-induced inhibition of O2- generation. fMet-Leu-Phe elicited a prompt increase in total long chain acyl-CoA esters. Arachidonoyl-CoA and oleoyl-CoA were elevated 5 s after addition of fMet-Leu-Phe, while palmitoyl-CoA was not elevated until 60 s. Triacsin C inhibited fMet-Leu-Phe-initiated increases in arachidonoyl-CoA, oleoyl-CoA, and palmitoyl-CoA. These results suggest a role for acyl-CoA esters in regulating activation of O2- generation and degranulation at the G protein or subsequent step(s).
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PMID:Long chain acyl coenzyme A and signaling in neutrophils. An inhibitor of acyl coenzyme A synthetase, triacsin C, inhibits superoxide anion generation and degranulation by human neutrophils. 798 39

A sensitive and specific GTP-activated Ca2+ translocation process induces rapid Ca2+ movements within cells and appears to reflect G protein-induced membrane fusion or junctional communication between discrete subpopulations of Ca(2+)-pumping organelles (Ghosh, T. K., Mullaney, J. M., Tarazi, F. I., and Gill, D. L. (1989) Nature 340, 236-239). Since fatty acylation can modify G protein action, modification of GTP-induced Ca2+ translocation by fatty acyl-CoA was investigated to throw light on the mechanism underlying Ca2+ transfer. Using permeabilized DDT1MF-2 smooth muscle cells, 2 microM palmitoyl-CoA completely blocked Ca2+ release activated by 20 microM GTP, while having no effect on inositol 1,4,5-trisphosphate-induced Ca2+ release. The IC50 (50% inhibitory concentration) for palmitoyl-CoA was 0.5 microM. Above 3 microM, palmitoyl-CoA inhibited Ca2+ accumulation. Fatty acyl chain length was important, C-13 to C-16 fatty acyl-CoA esters all fully blocking the action of GTP; the IC50 for myristoyl-CoA was also 0.5 microM. C-18 or larger acyl groups had diminished effectiveness as did C-8 or smaller acyl groups. Acetyl-CoA had no blocking effect. In contrast, 10 microM CoA itself blocked GTP-induced Ca2+ release. CoA required a free sulfhydryl group to block, desulfo-CoA having no effect. Removal of ATP by hexokinase and glucose prevented the action of CoA but not palmitoyl-CoA. The free sulfhydryl and ATP requirements indicated CoA was being acylated by endogenous fatty-acyl-CoA synthetase to be effective. The nonhydrolyzable myristoyl-CoA analog, S-(2-oxopentadecyl)-CoA, blocked the GTP effect identically to myristoyl- and palmitoyl-CoA (IC50 = 0.5 microM); thus, fatty acyl transfer is not required, indicating that blockade is due to a direct allosteric modification of a component of the GTP-activated process by acyl-CoA esters. Palmitoyl-CoA not only inhibited but completely reversed GTP-activated Ca2+ release, resulting in the released Ca2+ being taken back up into pools. In the presence of oxalate, GTP-activated Ca2+ transfer results in a substantial increase in Ca2+ accumulation; palmitoyl-CoA also completely reversed this effect resulting in rapid termination of Ca2+ uptake. This reversal provides strong evidence that GTP-activated Ca2+ translocation does not reflect a membrane fusion event. Instead, it likely represents formation of a reversible junction or pore between organelles which may be a required prefusion event.
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PMID:Modification of GTP-activated calcium translocation by fatty acyl-CoA esters. Evidence for a GTP-induced prefusion event. 798 31

Lignoceroyl-coenzyme A (CoA) ligase activity was detected in microsomal fractions from chicken liver in the presence of alpha-cyclodextrin as a solubilizing agent of lignoceric acid. Heptakis(2,6-di-O-methyl)-beta-cyclodextrin (dimethyl-beta-cyclodextrin) and hexakis(2,6-di-O-methyl)-alpha-cyclodextrin (dimethyl-alpha-cyclodextrin), among the cyclodextrins tested, were more effective than alpha-cyclodextrin as solubilizing agents. We have characterized lignoceroyl-CoA ligase activity in comparison with palmitoyl-CoA ligase activity. Lignoceroyl-CoA and palmitoyl-CoA ligase activities showed a similar dependency on CoA concentration. However, lignoceroyl-CoA ligase activity exhibited responses to the Mg2+ ion, adenosine triphosphate (ATP), ATP analogues (adenosine monophosphate (AMP) and adenosine diphosphate (ADP)), and heat treatment, which were distinctly different from the responses of palmitoyl-CoA ligase activity. These results are consistent with the idea that lignoceroyl-CoA and palmitoyl-CoA are synthesized by two different enzymes.
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PMID:Characterization of lignoceroyl-CoA ligase activity in chicken liver microsomes. 828 44

Brain contains high amounts of very-long-chain (VLC) fatty acids (> C22). Since mitochondria from liver and skin fibroblasts lack lignoceroyl-CoA ligase, in liver and skin fibroblasts fatty acids are exclusively oxidized in peroxisomes. Findings by Poulos and associates [9] suggested that contrary to liver and cultured skin fibroblasts brain mitochondria contain lignoceroyl-CoA ligase and can oxidize lignoceric acid. The present study was undertaken to develop a procedure for the isolation of subcellular organelles of higher purity from brain and to get a better understanding of the subcellular localization of the oxidation of VLC fatty acids in brain. The enzyme activities for activation and oxidation of palmitic and lignoceric acids were determined in peroxisomes, mitochondria, microsomes and a myelin fraction from rat brain and peroxisomes, mitochondria and microsomes purified from rat liver. Like in liver, brain lignoceroyl-CoA ligase activity in microsomes and peroxisomes was approx. 9 times higher than in mitochondria. In addition to palmitoyl-CoA ligase the antibodies against palmitoyl-CoA ligase inhibited the residual mitochondrial lignoceroyl-CoA ligase activity, meaning that lignoceroyl-CoA ligase activity in mitochondria was derived from palmitoyl-CoA ligase. Accordingly, in peroxisomes lignoceric acid was oxidized at 7 times higher rate than in mitochondria. Mitochondria were able to oxidize lignoceric acid efficiently when supplemented with lignoceroyl-CoA ligase activity from microsomes or myelin. These results show that in brain lignoceric acid is oxidized in peroxisomes and that lignoceroyl-CoA ligase activity is localized in peroxisomes and microsomes, but not in mitochondria. Peroxisomes and microsomes contain both lignoceroyl-CoA and palmitoyl-CoA ligases. Similar to peroxisomes and microsomes, the antibodies against palmitoyl-CoA ligase inhibited only the palmitoyl-CoA ligase activity in myelin but not the lignoceroyl-CoA ligase activity. These results suggest that in addition to palmitoyl-CoA ligase, myelin also contains lignoceroyl-CoA ligase.
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PMID:Purification of peroxisomes and subcellular distribution of enzyme activities for activation and oxidation of very-long-chain fatty acids in rat brain. 839 26

A system is described for studying protein N-myristoylation, a eukaryotic protein modification, in Escherichia coli strains containing components of eukaryotic metabolic pathways that regulate metabolism of myristoyl-CoA:protein N-myristoyltransferase (Nmt1p) substrates. Three recombinant plasmids were used to simultaneously direct synthesis of Saccharomyces cerevisiae Nmt1p, a substrate protein (S. cerevisiae ADP-ribosylation factor 1, Arf1p), and one of the acyl-CoA synthetases produced by S. cerevisiae (Faa1p) in isogenic strains of bacteria with wild type or mutant alleles of genes comprising the regulon for fatty acid degradation (FadR, FadE, FadL and FadD). Incorporation of exogenous tritiated myristate into Arf1p and bacterial phospholipid biosynthetic pathways was analyzed. Removal of FadL, a 448-residue protein necessary for efficient transport of fatty acids across the outer membrane, had no detectable effect on Nmt1p-dependent N-myristoylation of Arf1p. This finding is consistent with the notion that permeation of C14:0 across the bacterial inner membrane can occur by simple diffusion. Studies of strains that contain a mutation in FadE which inhibits beta-oxidation of exogenous fatty acids, confirm that Nmt1p retains its specificity for myristoyl-CoA over palmitoyl-CoA in E. coli. A mutation that inactivates FadD, a 580-residue protein which is the only acyl-CoA synthetase produced by this bacterium, completely blocks incorporation of exogenous myristate into Arf1p. This failure to be incorporated indicates that myristoyl-acyl carrier protein, generated by inner membrane acyl-acyl carrier protein synthetase, is not a substrate for Nmt1p. S. cerevisiae Faa1p can partially complement this mutant fadD allele. It can fully "restore" N-myristoylation of Arf1p. Faa1p can also rescue growth at 37 degrees C of fadD- strains on minimal media supplemented with C12:0, although this rescue becomes less efficient as the chain length of the supplemental fatty acid increases. In addition, S. cerevisiae Faa1p is better able to direct myristoyl-CoA to the bacteria's phospholipid biosynthetic pathways than FadD, while FadD is more efficient at directing myristoyl-CoA to the genetically engineered protein N-myristoylation pathway. Since cellular acyl-CoA synthetase activity in S. cerevisiae has been distributed to at least two functionally differentiated proteins, this system should be useful for comparing their structure-activity relationships as well as their interactions with Nmt1p in an organelle-free environment.
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PMID:Use of Escherichia coli strains containing fad mutations plus a triple plasmid expression system to study the import of myristate, its activation by Saccharomyces cerevisiae acyl-CoA synthetase, and its utilization by S. cerevisiae myristoyl-CoA:protein N-myristoyltransferase. 844 Jul 12

The dominant position among oxidoreduction processes in peroxisomes is ascribed to catalase, a number of aerobic oxidases, and Cu,Zn-superoxide dismutase. The peroxidase reaction of catalase requires substrates for hydrogen donation, other than H2O2, e.g. alcohols, aldehydes, formic acid. The peroxisomes contain an alternative system of beta-oxidation of higher carboxylic acids which in some types of plant cells is functionally very closely associated with the glyoxylate cycle. Regarding the role of peroxisomes in the metabolism of carboxylic acids, a very important finding has taken place, namely that besides acyl-CoA synthetase which is specific for long chains, the peroxisomes contain still another enzyme which allows the synthesis of CoA esters of fatty acids with very long chains. It is assumed that the entry of acyl-CoA esters or fatty acids into the perxisomes is performed by means of pores in membranes or acyl-carnitine transferases. Peroxisomes oxidize a very wide scale of substrates and contain several types of acyl-CoA oxidases: palmitoyl-CoA oxidase, pristanoyl-CoA oxidase, trihydroxy-coprostanoyl-CoA oxidase. The second and third reactions of peroxisomal beta-oxidation are catalyzed by the so-called three-functional enzyme, the activities of which are identical to those of 2-enoyl-CoA hydratase, beta-hydroxyacyl-CoA dihydrogenase and enoyl-CoA isomerase. The peroxisomes sufficiently oxidize dicarboxylic acids with a higher number of carbons beginning with the adipic acid. The peroxisomal system of beta-oxidation is utilized in metabolism of prostaglandins, pristanic acid-being the product of phytanic acid alpha-oxidation, and cholesterol. Several enzymatic activities needed for the synthesis of cholesterol partially take place in peroxisomes. The peroxisomes represent a decisive compartment for the initial phases of synthesis of plasmalogens. They contain the following enzymes: NAD(+)-glycerol-P-dehydrogenase, dihydroxyacetone-3-P-acyl-transferase, alkyl-dihydroxyacetone-P synthetase and acyl/alkyl-dihydroxyacetone-P reductase. The metabolism of amino acids takes place under the effect of peroxisomal enzymes--oxidase of diamino acids, D-aspartate oxidase, oxidase of L-pipecolic acid and alanine-glyoxylate aminotransferase. Only a few published sources consider it obvious that liver peroxisomes participate in degradation of spermine and spermidine. Polyamine oxidase oxidizes spermine resulting in the origin of spermidine and 3-aminopropionaldehyde, and spermidine is oxidized to putrescine and 3-aminopropionaldehyde. Peroxisomes in many phylogenetically lower animal species enable the break down of purine bases to urea and glyoxylic acid. In phylogenetically higher primates and in man, the activities of urate oxidase in peroxisomes are absent. (Fig. 14, Ref. 166).
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PMID:The role of peroxisomes in intermediary metabolism. 855 58

A long-chain fatty acyl-CoA synthetase that catalyzes the activation of long-chain fatty acids as thioesters of CoA, was described in rat liver nuclei. This is the first step for further metabolization of fatty acids in the cell. Up to now, it has been shown that long-chain fatty acyl-CoA synthetase is located in the endoplasmic reticulum, in plasma membrane, in mitochondria and in peroxisomes. The nuclear long-chain fatty acyl-CoA synthetase was assayed using palmitic (16:0), linoleic (18:2n-6) and 8,11,14-eicosatrienoic (20:3n-6) acids as substrates and was stimulated linearly with nuclear protein concentration and with incubation time The higher enzymatic activity was observed with 18:2n-6 and 20:3n-6 acids as substrates. The synthesis of palmitoyl-CoA, linoleyl-CoA and 8,11,14-eicosatrienoyl-CoA followed normal Michaelis-Menten kinetics with respect to the corresponding substrate concentrations. The acyl-CoA synthetase seems to be saturated at a substrate concentration of 12.8 microM for all the acids tested. The apparent Km values decreased in the following order 20:3n-6 > 18:2n-6 > 16:0. The lowest apparent Km for palmitic acid indicates a preference for acylation of this acid in the cell nucleus.
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PMID:Long-chain fatty Acyl-CoA synthetase enzymatic activity in rat liver cell nuclei. 881 3

Microsomal long-chain acyl-CoA synthetase (EC 6.1.2.3.) has been suggested to be involved in the stereoselective formation of the CoA thioester of ibuprofen. In this study, we demonstrated that the microsomal enzyme from rat liver responsible for palmitoyl-CoA synthesis also catalyzes the formation of R-ibuprofenoyl-CoA in a Mg(2+)- and ATP-dependent process. Long-chain acyl-CoA synthetase from rat liver microsomes was purified to homogeneity as evidenced by SDS-gel electrophoresis. Simultaneous measurements of palmitoyl-CoA and R-ibuprofenoyl-CoA formation with HPLC in various fractions and purification steps during protein isolation revealed a high correlation between both activities. The purification procedure included solubilization of the microsomes obtained from rat livers with Triton X-100 and subsequent chromatography of the 100,000 x g supernatant on blue-sepharose, hydroxyapatite, and phosphocellulose. The purified enzyme exhibited an apparent molecular weight of 72 kDa as estimated by SDS gel electrophoresis, with specific activities of 71 nmol.min-1.mg-1 protein and 901 nmol.min-1.mg-1 protein for formation of R-ibuprofenoyl-CoA and palmitoyl-CoA, respectively. Palmitoyl-CoA formation catalyzed by the purified enzyme exhibited biphasic kinetics indicative of two isoforms, a high-affinity (KM 0.13 +/- 0.11 microM), low-capacity form and a low-affinity (KM 81 +/- 11.5 microM), high-capacity form. In contrast, measurement of R-ibuprofenoyl-CoA synthesis over a concentration range from 5 to 3000 microM showed the participation of a single CoA ligase with a KM of 184 +/- 19 microM, corresponding to the low-affinity isoform of palmitoyl-CoA synthesis with a marked enantioselectivity towards the R-form of ibuprofen. R-ibuprofenoyl-CoA formation of the enzyme preparation was inhibited by palmitic acid (KI 13.5 +/- 0.5 microM) and S-ibuprofen (KI 405 +/- 10 microM). In summary, these data give strong evidence for the identity of R-ibuprofenoyl-CoA and long-chain acyl-CoA synthetase.
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PMID:Isolation and characterization of rat liver microsomal R-ibuprofenoyl-CoA synthetase. 883 19


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