Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:Q8NEX9 (reductase)
 26,410 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Polypeptides of the animal fatty acid synthase (FAS) consist of three amino-terminal catalytic domains, beta-ketoacyl synthase, malonyl/acetyltransacylase, and dehydrase, separated by a 600-residue structural core from four carboxyl-terminal catalytic domains, enoyl reductase, beta-ketoacyl reductase, acyl carrier protein, and thioesterase. In the active dimeric form of the protein the two identical multifunctional polypeptides are oriented head-to-tail such that two sites for palmitate synthesis are formed at the subunit interface. In order to map the functional interactions between domains of the two subunits that contribute to the two sites of synthesis, we have utilized a strategy based on complementation analysis in vitro of modified FASs carrying mutations in specific catalytic domains. Homodimeric mutant FASs lacking functional beta-ketoacyl synthase (KS-), dehydrase (DH-), acyl carrier protein (ACP-), or thioesterase (TE-) domains, as well as heterodimers formed between ACP- and TE- subunits, between ACP- and DH- subunits, and between DH- and TE- subunits, were unable to synthesize fatty acids. However, heterodimers formed between KS- and either DH-, ACP-, or TE- subunits regained partial FAS activity. These data indicate that the dehydrase domain, although located in the amino-terminal half of the polypeptide, should be assigned to the complementation group located in the carboxy-terminal half that includes the acyl carrier protein and thioesterase domains. Thus, the current model for the animal FAS must be revised to reflect the finding that the two constituent polypeptides are not simply positioned side-by-side in a fully extended conformation but are coiled in a manner that allows the dehydrase domain to access the beta-hydroxyacyl-ACP located more than 1100 residues distant on the same subunit.
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PMID:Mapping of functional interactions between domains of the animal fatty acid synthase by mutant complementation in vitro. 904 34

The fungal maize pathogen Cochliobolus carbonum produces a phytotoxic and cytostatic cyclic peptide, HC-toxin, of structure cyclo(D-prolyl-L-alanyl-D-alanyl-L-Aeo), in which Aeo stands for 2-amino-9,10-epoxi-8-oxodecanoic acid. Here we report the isolation of a gene, TOXC, that is present only in HC-toxin-producing (Tox2+) fungal strains. TOXC is present in most Tox2+ strains in three functional copies, all of which are on the same chromosome as the gene encoding HC-toxin synthetase. When all copies of TOXC are mutated by targeted gene disruption, the fungus grows and sporulates normally in vitro but no longer makes HC-toxin and is not pathogenic, indicating that TOXC has a specific role in HC-toxin production and hence virulence. The TOXC mRNA is 6.5 kb and the predicted product has 2,080 amino acids and a molecular weight of 233,000. The primary amino acid sequence is highly similar (45 to 47% identity) to the beta subunit of fatty acid synthase from several lower eukaryotes, and contains, in the same order as in other beta subunits, domains predicted to encode acetyl transferase, enoyl reductase, dehydratase, and malonyl-palmityl transferase. The most plausible function of TOXC is to contribute to the synthesis of the decanoic acid backbone of Aeo.
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PMID:A fatty acid synthase gene in Cochliobolus carbonum required for production of HC-toxin, cyclo(D-prolyl-L-alanyl-D-alanyl-L-2-amino-9, 10-epoxi-8-oxodecanoyl). 905 26

Animal fatty acid synthase (FAS; EC 2.3.1.85) is a homodimer of a multifunctional subunit protein and catalyzes the synthesis of palmitate from acetyl-CoA, malonyl-CoA, and NADPH. The subunit (Mr approximately 270,000) carries seven distinct component activities and a site for the prosthetic group 4'-phosphopantetheine (acyl carrier protein). Based on proteolytic mapping, the organization of the activity domains along the subunit polypeptide from the N terminus is as follows: beta-ketoacyl synthase, acetyl and malonyl transacylases, beta-hydroxyacyl dehydratase, enoyl reductase, beta-ketoacyl reductase, acyl carrier protein, and thioesterase. By comparing the amino acid sequences of the chicken, rat, and human synthases, we found that kallikrein cleavage sites occur in the least conserved regions of the FAS polypeptide subunit. Determining the amino acid sequences of the N-terminal end of the major kallikrein cleavage peptides helped delineate the most likely boundaries of the component activities in the cDNA-derived amino acid sequence. To confirm this organization, we cloned the chicken FAS cDNA coding for domain I and expressed it in Escherichia coli as a maltose-binding fusion protein. The isolated recombinant protein contained the activities of the acetyl and malonyl transacylases and the beta-hydroxyacyl dehydratase. Based on the boundaries of the acetyl and malonyl transacylases and the beta-hydroxyacyl dehydratase, we also cloned the appropriate cDNA fragments encoding the domains that contain the transacylases and the dehydratase in pET vectors and expressed them in E. coli as thioredoxin-6xHis fusion proteins. The purified recombinant proteins contained, respectively, the activities of the acetyl and malonyl transacylases and the dehydratase. These results not only confirmed the order of the component activities in domain I, but also paved the way for successful expression and characterization of the remaining activities.
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PMID:Animal fatty acid synthase: functional mapping and cloning and expression of the domain I constituent activities. 915 16

We examined the effect of pravastatin sodium (pravastatin), a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, on fatty acid synthesis in rat liver. The repeated administration of pravastatin to rats at 250 mg/kg for 7 days led to a 2.8-fold increase in fatty acid synthesis in the liver. The diurnal change of fatty acid synthesis was not affected by the treatment. Hepatic fatty acid synthase activity was increased 3.2-fold, while acetyl-CoA carboxylase activity was not changed by the repeated administration of pravastatin. In rat hepatocytes, the incubation with 2 microg/ml pravastatin for 24 h increased fatty acid synthase activity 1.5-fold, as well as HMG-CoA reductase activity 2.8-fold. These results suggest that HMG-CoA reductase inhibitors might increase fatty acid synthesis in vivo through the induction of hepatic fatty acid synthase.
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PMID:Induction of fatty acid synthesis by pravastatin sodium in rat liver and primary hepatocytes. 921 6

In order to find further genes of the mitochondrial fatty acid synthase, we searched the genome of Saccharomyces cerevisiae for sequences that are homologous to conserved regions of bacterial fatty acid synthase genes. We found the gene products of ORF YKL055c (EMBL Accession No. X75781) and of YOR221C (EMBL Accession No. X92441) to be homologous to bacterial 3-oxoacyl-(acyl carrier protein) reductases and to malonyl-CoA:ACP-transferases, respectively. We disrupted these two genes which in both cases led to a respiratory deficient phenotype, as is the case for the genes encoding a mitochondrial acyl carrier protein and a beta-ketoacyl-ACP synthase. We propose to call the above mentioned genes OAR1 [3-oxo-acyl-(acyl carrier protein) reductase] and MCT1 (malonyl-CoA:ACP transferase). They are presumed to be part of a type-II mitochondrial fatty acid synthase, a relic of the endosymbiontic origin of mitochondria, delivering substrates for phospholipid re-modelling and/or repair.
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PMID:Two genes of the putative mitochondrial fatty acid synthase in the genome of Saccharomyces cerevisiae. 938 93

In a previous report we demonstrated that androgens markedly stimulate accumulation of lipid droplets in LNCaP cells. The effects were already evident at low concentrations of androgens optimal for proliferation but became much more pronounced at high concentrations optimal for differentiation. In the present report we explored whether other agonists acting by nuclear receptors and modulating LNCaP growth and differentiation also affect lipid accumulation. The agonists investigated were 1alpha,25-dihydroxycholecalciferol (VD3), all-trans-retinoic acid (atRA), and triiodothyronine (T3). Lipid accumulation was evaluated by Oil Red O staining followed by image analysis of Oil Red O-stained cells or by extraction and measurement of absorbency. Only marginal effects were noted for VD3 and T3. The atRA, on the contrary, increased lipid staining 5-12-fold. This effect required high concentrations of retinoids (10[-6] M) and was accompanied by growth stimulation. Lipid accumulation was less pronounced than that observed with maximally effective concentrations of androgens (10[-3] M R1881). Thin layer chromatography (TLC) and enzymatic determination of the various lipid fractions demonstrated that retinoids increase triacylglycerides and an unidentified lipid fraction with a slightly higher mobility. In contrast with androgens, however, they did not stimulate the accumulation of cholesterol esters. Incorporation studies with [2-14C]acetate revealed that the increased accumulation of the mentioned lipids is related both to increased synthesis and to decreased secretion. Retinoid-induced lipid accumulation is accompanied by increased steady-state levels of the mRNA encoding fatty acid synthase (FAS), a key enzyme involved in lipid synthesis, while the expression of HMG-CoA-reductase, an enzyme controlling cholesterol synthesis is only marginally affected. It is concluded that retinoids share the ability of androgens to increase lipid accumulation in LNCaP cells. The nature of the lipids affected by both agonists, however, differs at least in part suggesting that the underlying mechanisms may also be different. For the studied compounds (androgens, VD3, atRA, and T3) no simple and consistent relationship could be observed between their ability to decrease proliferation and increase differentiation on the one hand and their ability to promote lipid accumulation on the other hand.
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PMID:Retinoids stimulate lipid synthesis and accumulation in LNCaP prostatic adenocarcinoma cells. 951 66

The diazaborine family of compounds have antibacterial properties against a range of gram-negative bacteria. Initially, this was thought to be due to the prevention of lipopolysaccharide synthesis. More recently, the molecular target of diazaborines has been identified as the NAD(P)H-dependent enoyl acyl carrier protein reductase (ENR), which catalyses the last reductive step of fatty acid synthase. ENR from Mycobacterium tuberculosis is the target for the front-line antituberculosis drug isoniazid. The emergence of isoniazid resistance strains of M. tuberculosis, a chronic infectious disease that already kills more people than any other infection, is currently causing great concern over the prospects for its future treatment, and it has reawakened interest in the mechanism of diazaborine action. Diazaborines only inhibit ENR in the presence of the nucleotide cofactor, and this has been explained through the analysis of the x-ray crystallographic structures of a number of Escherichia coli ENR-NAD+-diazaborine complexes that showed the formation of a covalent bond between the boron atom in the diazaborines and the 2'-hydroxyl of the nicotinamide ribose moiety that generates a noncovalently bound bisubstrate analogue. The similarities in catalytic chemistry and in the conformation of the nucleotide cofactor across the wider family of NAD(P)-dependent oxidoreductases suggest that there are generic opportunities to mimic the interactions seen here in the rational design of bisubstrate analogue inhibitors for other NAD(P)H-dependent oxidoreductases.
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PMID:Mechanism of action of diazaborines. 963 89

The broad spectrum antibacterial properties of 2-hydroxydiphenyl ethers have been appreciated for decades, and their use in consumer products is rapidly increasing. We identify the enoyl-acyl carrier protein reductase (fabI) component of the type II fatty acid synthase system as the specific cellular target for these antibacterials. Biologically active 2-hydroxydiphenyl ethers effectively inhibit fatty acid synthesis in vivo and FabI activity in vitro. Resistant mechanisms include up-regulation of fabI expression and spontaneously arising missense mutations in the fabI gene. These results contradict the view that these compounds directly disrupt membranes and suggest that their widespread use will select for resistant bacterial populations.
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PMID:Broad spectrum antimicrobial biocides target the FabI component of fatty acid synthesis. 980 93

These studies were designed to test the hypolipidemic activity of green tea epicatechins (GTE) isolated from jasmine green tea. In Experiment 1, three groups of hamsters were given a semisynthetic diet containing 200 g lard/kg and 1 g cholesterol/kg for 4 wk. The control group received distilled water, and the other two groups received either 15 g/L green tea water extract (GTWE) or 5.0 g/L GTE solution. Both the GTWE and GTE groups had lower concentrations of serum total cholesterol (TC) and triacylglycerols (TG) than the controls (P < 0.05). In Experiment 2, four groups of hamsters received tap water as the drinking fluid, but they were given the same high fat and cholesterol diet supplemented with 0 (control), 1.1, 3.4 or 5.7 g GTE/kg diet. The hypolipidemic effect of jasmine GTE was dose dependent. In Experiment 3, the time-course of changes in serum TC and TG was monitored in hamsters given the high fat diet supplemented with 5.7 g GTE/kg in comparison with that of controls. The hypolipidemic effects of dietary GTE were evident after feeding for 2 wk. Dietary supplementation of GTE did not affect liver fatty acid synthase. However, GTE-supplemented hamsters had higher fecal excretions of total fatty acids, neutral sterols and acidic sterols compared with the control group. In Experiment 4, hamsters were fed nonpurified diet; the control group drank distilled water, and the GTE group drank distilled water containing 5.0 g GTE/L. No differences in activities of 3-hydroxy-3-methyl glutaryl coenzyme A reductase and intestinal acyl CoA:cholesterol acyltransferase were observed. This study suggests that the hypolipidemic activity of GTE is not due to inhibition of synthesis of cholesterol or fatty acid but is most likely mediated by its influence on absorption of dietary fat and cholesterol.
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PMID:Jasmine green tea epicatechins are hypolipidemic in hamsters (Mesocricetus auratus) fed a high fat diet. 1035 71

Lung Chen Tea, a Chinese green tea, has been found to lower serum and liver cholesterol. In this study, its dose response and mechanisms of action on cholesterol lowering in diet-induced hypercholesterolemic Sprague-Dawley rats were investigated. The activities of three major lipid metabolizing enzymes, 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-Co A) reductase, cholesterol 7alpha-hydroxylase and fatty acid synthase (FAS), as well as fecal excretion of bile acids and cholesterol were examined. Lung Chen Tea administration for eight weeks significantly lowered the serum cholesterol in the 2% and 4% groups. The activities of the three enzymes were not affected by Lung Chen Tea, but the fecal bile acids and cholesterol excretions were significantly increased. These results demonstrated that Lung Chen Tea lowered plasma cholesterol by increasing fecal bile acids and cholesterol excretion. Further investigation is required to evaluate the exact mechanisms of action of Lung Chen Tea.
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PMID:Chinese green tea lowers cholesterol level through an increase in fecal lipid excretion. 1067 Aug 29


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