Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.3.3.1 (citrate synthase)
 4,488 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Three fibric acid derivatives, clofibric acid (CFB), bezafibrate (BFB), and gemfibrozil (GFB), mainly used in the treatment of hypertriglyceridaemic or mixed hyperlipidaemic states, have been tested for their ability to modify fatty acid chain elongation and desaturation in vitro. Both endogenous and exogenous (saturated, monounsaturated and polyunsaturated) fatty acid elongations were inhibited by fibrates at concentrations well within the physiological range (IC50 values for GFB were between 0.1 and 0.3 mM). The potency order was GFB > BFB > CFB. Inhibition was not due to an impairment of the activation step from free fatty acids to acyl-CoAs, as palmitoyl-CoA synthetase was only slightly inhibited (IC50 value for GFB = 2.8 mM). Fibrates (GFB) appeared to behave as mixed non-competitive inhibitors with respect to malonyl-CoA when the rate limiting step of elongation, the condensing enzyme, is assayed. Further, delta 6 and delta 5 desaturates were inhibited by the three drugs (GFB > BFB > CFB), although not to the same extent as the elongation system. In contrast, delta 9 desaturase activity was not affected by fibrates.
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PMID:Fibrates modify rat hepatic fatty acid chain elongation and desaturation in vitro. 825 Sep 65

The whiE gene cluster of Streptomyces coelicolor, which is related to gene sets encoding the biosynthesis of polycyclic aromatic polyketide antibiotics, determines a spore pigment. Southern blotting using probes from three different parts of the whiE cluster revealed related gene sets in about half of a collection of diverse Streptomyces strains. A 5.2-kb segment of one such cluster, sch, previously shown to determine spore pigmentation in Streptomyces halstedii, was sequenced. Seven open reading frames (ORFs), two of them incomplete, were found. Six of the ORFs resemble the known part of the whiE cluster closely. The derived gene products include a ketosynthase (= condensing enzyme) pair, acyl carrier protein and cyclase, as well as two of unidentified function. The seventh ORF diverges from the main cluster and encodes a protein that resembles a dichlorophenol hydroxylase. Comparison with sequences of related gene sets for the biosynthesis of antibiotics suggests that gene clusters destined to specify pigment production diverged from those destined to specify antibiotics early in the evolution of the Streptomyces genus.
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PMID:Hybridization and DNA sequence analyses suggest an early evolutionary divergence of related biosynthetic gene sets encoding polyketide antibiotics and spore pigments in Streptomyces spp. 834 17

Yeast fatty-acid synthase (FAS) inhibition by cerulenin analogs with varying side-chain lengths was compared with that of cerulenin, tetrahydrocerulenin and iodoacetamide. Although inhibition by cerulenin was the highest, the analogs having (E,E)-delta 7,10 double bonds showed high inhibition. This strongly suggests that the (E,E)-delta 7,10 double bonds play an important role in the interaction of the inhibitors with the enzyme. It was suggested that the size of the hydrophobic cavity in the condensing enzyme terminates fatty-acid chain elongation by decreasing inhibition by the C18 analog. Like cerulenin itself, the shortest analog (C6) did not induce malonyl-CoA decarboxylase activity.
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PMID:Effect of side-chain structure on inhibition of yeast fatty-acid synthase by cerulenin analogues. 842 21

There are two genes, fabA and fabZ, encoding beta-hydroxyacyl-acyl carrier protein (ACP) dehydratases that function in the dissociated, type II fatty acid synthase system of Escherichia coli. We have investigated their roles in fatty acid synthesis by purifying the two proteins and reconstituting cycles of fatty acid synthesis in vitro using five other purified proteins. FabA and FabZ exhibited broad, overlapping chain length specificities. The FabZ dehydratase efficiently catalyzed the dehydration of short chain beta-hydroxyacyl-ACPs and long chain saturated and unsaturated beta-hydroxyacyl-ACPs. FabA was most active on intermediate chain length beta-hydroxyacyl-ACPs and also possessed significant activity toward both short and long chain saturated beta-hydroxyacyl-ACPs. Significantly, FabA was virtually inactive in the dehydration of long chain unsaturated beta-hydroxyacyl-ACP. The introduction of the double bond at the 10-carbon stage of fatty acid synthesis by FabA was only detected in the presence of beta-ketoacyl-ACP synthase I (FabB). A yeast two-hybrid analysis failed to detect an interaction between FabA and FabB, therefore the channeling of intermediates toward unsaturated fatty acid synthesis by FabB was attributed to the affinity of the condensing enzyme for cis-decenoyl-ACP. The broad substrate specificity of FabZ coupled with the inactivity of FabA toward a long chain unsaturated beta-hydroxyacyl-ACP provides a biochemical explanation for the phenotypes of cells with genetically altered levels of the two dehydratases.
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PMID:Roles of the FabA and FabZ beta-hydroxyacyl-acyl carrier protein dehydratases in Escherichia coli fatty acid biosynthesis. 891 Mar 76

A 30-kD coenzyme A (CoA)-binding protein was isolated from spinach (Spinacea oleracea) chloroplast soluble extracts using affinity chromatography under conditions in which 95% of the total protein was excluded. The 30-kD protein contains an eight-amino-acid sequence, DVRLYYGA, that is identical to a region in a 36-kD protein of unknown function that is encoded by a kiwifruit (Actinidia deliciosa) cDNA. Southern blotting also detected a spinach gene that is related to the kiwifruit cDNA. The kiwifruit 36-kD protein that was synthesized in Escherichia coli was imported into chloroplasts and cleaved to a 30-kD form; it was processed to the same size in an organelle-free assay. Furthermore, the kiwifruit protein specifically bound to CoA. The kiwifruit protein contains a single cysteine within a domain that is related to the peroxisomal beta-ketoacyl-CoA thiolases, which catalyze the CoA-dependent degradative step of fatty acid beta-oxidation. Within 50 amino acids surrounding the cysteine, considered to be part of the thiolase active site, the kiwifruit protein shows approximately 26% sequence identity with the mango, cucumber, and rat peroxisomal thiolases. N-terminal alignment with these enzymes, relative to the cysteine, indicates that the 36-kD protein is cleaved after serine-58 during import, agreeing with the estimated size (approximately 6 kD) of a transit peptide. The 30-kD protein is also related to the E. coli and mitochondrial thiolases, as well as to the acetoacetyl-CoA thiolases of prokaryotes. Features distinguish it from members of the thiolase family, suggesting that it carries out a related but novel function. The protein is more distantly related to chloroplast beta-ketoacyl-acyl carrier protein synthase III, the initial condensing enzyme of fatty acid synthetase that utilizes acetyl-CoA.
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PMID:Identification of a chloroplast coenzyme A-binding protein related to the peroxisomal thiolases. 897 3

The Arabidopsis FATTY ACID ELONGATION1 (FAE1) gene encodes a putative seed-specific condensing enzyme. It is the first of four enzyme activities that comprise the microsomal fatty acid elongase (FAE) involved in the biosynthesis of very-long-chain fatty acids (VLCFAs). FAE1 has been expressed in yeast and in tissues of Arabidopsis and tobacco, where significant quantities of VLCFAs are not found. The introduction of FAE1 alone in these systems is sufficient for the production of VLCFAs, for wherever FAE1 was expressed, VLCFAs accumulated. These results indicate that FAE1 is the rate-limiting enzyme for VLCFA biosynthesis in Arabidopsis seed, because introduction of extra copies of FAE1 resulted in higher levels of the VLCFAs. Furthermore, the condensing enzyme is the activity of the elongase that determines the acyl chain length of the VLCFAs produced. In contrast, it appears that the other three enzyme activities of the elongase are found ubiquitously throughout the plant, are not rate-limiting and play no role in the control of VLCFA synthesis. The ability of yeast containing FAE1 to synthesize VLCFAs suggests that the expression and the acyl chain length specificity of the condensing enzyme, along with the apparent broad specificities of the other three FAE activities, may be a universal eukaryotic mechanism for regulating the amounts and acyl chain length of VLCFAs synthesized.
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PMID:Very-long-chain fatty acid biosynthesis is controlled through the expression and specificity of the condensing enzyme. 926 55

Microspore-derived embryos of Brassica napus cv Reston were used to examine the effects of exogenous (+)-abscisic acid (ABA) and related compounds on the accumulation of very-long-chain monounsaturated fatty acids (VLCMFAs), VLCMFA elongase complex activity, and induction of the 3-ketoacyl-coenzyme A synthase (KCS) gene encoding the condensing enzyme of the VLCMFA elongation system. Of the concentrations tested, (+)-ABA at 10 &mgr;M showed the strongest effect. Maximum activity of the elongase complex, observed 6 h after 10 &mgr;M (+)-ABA treatment, was 60% higher than that of the untreated embryos at 24 h. The transcript of the KCS gene was induced by 10 &mgr;M (+)-ABA within 1 h and further increased up to 6 h. The VLCMFAs eicosenoic acid (20:1) and erucoic acid (22:1) increased by 1.5- to 2-fold in embryos treated with (+)-ABA for 72 h. Also, (+)-8'-methylene ABA, which is metabolized more slowly than ABA, had a stronger ABA-like effect on the KCS gene transcription, elongase complex activity (28% higher), and level of VLCMFAs (25-30% higher) than ABA. After 24 h approximately 60% of the added (+)-[3H]ABA (10 &mgr;M) was metabolized, yielding labeled phaseic and dihydrophaseic acid. This study demonstrates that (+)-ABA promotes VLCMFA biosynthesis via increased expression of the KCS gene and that reducing ABA catabolism would increase VLCMFAs in microspore-derived embryos.
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PMID:(+)-Abscisic acid metabolism, 3-ketoacyl-coenzyme A synthase gene expression, and very-long-chain monounsaturated fatty acid biosynthesis in brassica napus embryos 966 40

Some plant oils contain non-methylene-interrupted polyunsaturated fatty acids (NMIFAs). Pinolenic acid (all cis delta-5,9,12/18:3) and columbinic acid (trans,cis,cis delta-5,9,12/18:3) are NMIFAs that exist in pine seed oil and columbine seed oil, respectively. We investigated the double bond position of fatty acid recognized by the fatty acid chain elongation system (FACES) of rat liver using NMIFAs as experimental tools. In the total elongation assay, amounts of C2 unit chain-elongated metabolites of pinolenic acid and columbinic acid were 32% and 11%, respectively, compared to that of gamma-linolenic (all cis delta-6,9,12/18:3) as the substrate. In the condensation reaction assay, the rate limiting step of FACES, the conversion rates of pinolenic acid and columbinic acid to the corresponding C20 beta-keto fatty acids were 19% and 9% of that of gamma-linolenic acid, respectively. The formation of elongated metabolite of podocarpic acid (all cis delta-5,11,14/20:3) was only 7% of that of arachidonic acid (all cis delta-5,8,11,14/20:4). From these results it was concluded that the condensing enzyme of FACES could recognize the methylene-interrupted cis double bond structure vicinal to the carboxyl group in the fatty acid molecule.
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PMID:Methylene-interrupted double bond in polyunsaturated fatty acid is an essential structure for metabolism by the fatty acid chain elongation system of rat liver. 974 38

cDNA clones encoding a novel 3-ketoacyl-ACP synthase (KAS) have been isolated from Cuphea. The amino acid sequence of this enzyme is different from the previously characterized classes of KASs, designated KAS I and III, and similar to those designated as KAS II. To define the acyl chain specificity of this enzyme, we generated transgenic Brassica plants over-expressing the cDNA encoded protein in a seed specific manner. Expression of this enzyme in transgenic Brassica seeds which normally do not produce medium chain fatty acids does not result in any detectable modification of the fatty acid profile. However, co-expression of the Cuphea KAS with medium chain specific thioesterases, capable of production of either 12:0 or 8:0/10:0 fatty acids in seed oil, strongly enhances the levels of these medium chain fatty acids as compared with seed oil of plants expressing the thioesterases alone. By contrast, co-expression of the Cuphea KAS along with an 18:0/18.1-ACP thioesterase does not result in any detectable modification of the fatty acids. These data indicate that the Cuphea KAS reported here has a different acyl-chain specificity to the previously characterized KAS I, II and III. Therefore, we designate this enzyme KAS IV, a medium chain specific condensing enzyme.
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PMID:KAS IV: a 3-ketoacyl-ACP synthase from Cuphea sp. is a medium chain specific condensing enzyme. 975 Mar 49

Land plants secrete a layer of wax onto their aerial surfaces that is essential for survival in a terrestrial environment. This wax is composed of long-chain, aliphatic hydrocarbons derived from very-long-chain fatty acids (VLCFAs). Using the Arabidopsis expressed sequence tag database, we have identified a gene, designated CUT1, that encodes a VLCFA condensing enzyme required for cuticular wax production. Sense suppression of CUT1 in transgenic Arabidopsis plants results in waxless (eceriferum) stems and siliques as well as conditional male sterility. Scanning electron microscopy revealed that this was a severe waxless phenotype, because stems of CUT1-suppressed plants were completely devoid of wax crystals. Furthermore, chemical analyses of waxless plants demonstrated that the stem wax load was reduced to 6 to 7% of wild-type levels. This value is lower than that reported for any of the known eceriferum mutants. The severe waxless phenotype resulted from the downregulation of both the decarbonylation and acyl reduction wax biosynthetic pathways. This result indicates that CUT1 is involved in the production of VLCFA precursors used for the synthesis of all stem wax components in Arabidopsis. In CUT1-suppressed plants, the C24 chain-length wax components predominate, suggesting that CUT1 is required for elongation of C24 VLCFAs. The unique wax composition of CUT1-suppressed plants together with the fact that the location of CUT1 on the genetic map did not coincide with any of the known ECERIFERUM loci suggest that we have identified a novel gene involved in wax biosynthesis. CUT1 is currently the only known gene with a clearly established function in wax production.
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PMID:CUT1, an Arabidopsis gene required for cuticular wax biosynthesis and pollen fertility, encodes a very-long-chain fatty acid condensing enzyme. 1033 Apr 68


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