Disease relevance of FASN

• The complete amino acid sequence of thioesterase domain of chicken liver fatty acid synthase has been determined by sequencing peptides produced by trypsin, Staphylococcus aureus V8 protease, and cyanogen bromide cleavage [1].
• 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 [2].
• The presence of a novel type of surface polysaccharide in Rhizobium meliloti requires a new fatty acid synthase-like gene cluster involved in symbiotic nodule development [3].
• Here we investigated whether EGCG inhibits FAS activity in cultured prostate cancer cells and how this inhibition affects endogenous lipid synthesis, cell proliferation and cell viability [4].
• A petroleum ether-soluble fraction of HPBF produced 3 effects: an increase in body weight (18%), a strong suppression of HMG-CoA reductase (-36%) and FAS (-40%) accompanied by decreases in serum triglyceride (-9%) and cholesterol levels (-23%) [5].

High impact information on FASN

• The complete amino acid sequence of chicken liver fatty acid synthase [acyl-CoA:malonyl-CoA C-acyltransferase (decarboxylating, oxoacyl- and enoyl-reducing, and thioester-hydrolyzing), EC 2.3.1.85] has been determined from the corresponding cDNA sequence [6].
• This study suggests that the genes for the functional domains of fatty acid synthase were originally separated, and these genes were connected to each other by using different connecting nucleotide sequences in different species [7].
• The partial amino acid sequence of the chicken liver fatty acid synthase shows greater than 70% similarity with the rat mammary gland enzyme [8].
• A second NF-Y binding site is located in the FAS promoter at the more usual position of -103 to -87, and it too has a neighboring Sp1 site [9].
• In vitro DNase I footprint analysis of the rat fatty acid synthase (FAS) promoter from -568 to -468 revealed four protein binding sites: A, B, and C boxes and the FAS insulin-responsive element 1 (FIRE1) [9].

Chemical compound and disease context of FASN

• Epigallocatechin-3-gallate is a potent natural inhibitor of fatty acid synthase in intact cells and selectively induces apoptosis in prostate cancer cells [4].
• Here we report on the insulin-responsiveness in the rat hepatoma cell line H4IIE of four cis-elements in the FAS promoter: the FAS insulin-responsive elements, FIRE2 and FIRE3; the inverted CCAAT element, ICE; and the insulin/glucose-binding element, designated hepatic FIRE element, hFIRE, originally identified in rat hepatocytes [10].
• Cerulenin, a natural fatty acid synthase (FAS) inhibitor, and its synthetic analog C75 are hypothesized to alter the metabolism of neurons in the hypothalamus that regulate ingestive behavior to cause a profound decrease of food intake and an increase in metabolic rate, leading to body weight loss [11].
• In each experiment, body weight, feed consumption, liver weight, liver fat, body fat, in vivo lipogenesis, and the hepatic activities of the lipogenic enzymes, acetyl-Coenzyme A carboxylase (ACC) and fatty acid synthetase (FAS), were measured [12].

Biological context of FASN

• Measurements taken included in vitro lipogenesis (IVL), malic enzyme (ME), isocitrate dehydrogenase (ICD) and aspartate aminotransferase (AAT) activities and the expression of the genes for ME, fatty acid synthase (FAS) and acetyl coenzyme carboxylase (ACC) [13].
• Sequencing, Polymerase Chain Reaction (PCR) and Restriction Fragment Length Polymorphism (RFLP) were carried out to detect polymorphism in the last intron of the FASN gene of the Campero broiler line [14].
• The sequence has an open reading frame coding for 945 amino acids of the fatty acid synthase [15].
• The amino acid sequences associated with pyridoxal 5'-phosphate binding sites in chicken liver fatty acid synthase have been determined: a site whose modification causes selective inhibition of the enoyl reductase activity and a site (site I) that is not associated with enzymatic activity [16].
• We have isolated a positive clone, lambda CFAS, containing FAS gene sequences by screening a chicken genomic library with a segment of a 3' untranslated region of goose fatty acid synthase cDNA clone, pGFAS3, as a hybridization probe [17].

Anatomical context of FASN

• Hormonal regulation of lipogenic enzymes in chick embryo hepatocytes in culture. Expression of the fatty acid synthase gene is regulated at both translational and pretranslational steps [18].
• Chemical inhibitors of fatty acid synthase (FAS) inhibit growth and induce apoptosis in several cancer cell lines in vitro and in tumor xenografts in vivo [4].
• Treatment of nonmalignant cells with low levels of FAS activity (fibroblasts) with EGCG led to a decrease in growth rate but not to induction of apoptosis [4].
• First, we demonstrate that FAS messenger and protein are expressed in the hypothalamus of chickens [11].
• For instance, thyroid hormones stimulate the transcription of the fatty acid synthase and malic enzyme genes in chick embryonic hepatocytes, while insulin amplifies these effects [19].

Associations of FASN with chemical compounds

• The active site of the thioesterase domain of chicken fatty acid synthase was suggested to be the serine on position 101 according to its homology with other serine-type esterases and proteases which have a common structure of -Gly-X-Ser-Y-Gly- with the variable amino acids X and Y disrupting the homology [1].
• Thus, triiodothyronine regulates fatty acid synthase primarily by controlling the amount of its mRNA [18].
• The 4'-phosphopantetheine of chicken liver fatty acid synthase was specifically labeled with the fluorescent substrate analog coenzyme A 6-[7-nitrobenz-2-oxa-1,3-diazol-4-yl]aminohexanoate at low salt concentrations [20].
• Hexanoate and octanoate inhibit transcription of the malic enzyme and fatty acid synthase genes in chick embryo hepatocytes in culture [21].
• Elementary steps in the reaction mechanism of chicken liver fatty acid synthase. pH dependence of NADPH binding and isotope rate effect for beta-ketoacyl reductase [22].

Regulatory relationships of FASN

• Thus, glucagon regulates fatty acid synthase by controlling the concentration of its mRNA [18].
• IGF-1 regulates transcription of the fatty acid synthase gene [23].

Other interactions of FASN

• Complete sequence analyses of this segment including S1 nuclease mapping, showed that the lambda CFAS clone contains the entire 3' untranslated region of the chicken FAS gene and three exons that code for 162 amino acids of the thioesterase domain from the COOH-terminal end of the fatty acid synthase [17].
• In chick embryo hepatocytes in culture, the stimulatory effect of feeding on fatty acid synthase activity is mimicked by adding triiodothyronine and insulin; the inhibitory effect of starvation is mimicked by adding glucagon or cyclic AMP [23].
• Triiodothyronine stimulates transcription of the fatty acid synthase gene in chick embryo hepatocytes in culture. Insulin and insulin-like growth factor amplify that effect [23].
• Relative amounts of mRNAs coding for lipogenic enzymes (acetyl-CoA carboxylase, fatty acid synthase, delta 9 desaturase, malic enzyme) and apoproteins (apoprotein A1 and apoprotein B) were determined until the 12th day. beta-actin and albumin mRNA, as well as albumin secretion, were also assessed [24].
• Low dietary protein decreased activities of hepatic isocitrate dehydrogenase (EC 1.1.1.42), fructose-1,6-bisphosphatase (EC 3.1.3.11) and glucose-6-phosphatase (EC 3.1.3.9; GP) and increased activities of fatty acid synthase (FAS), citrate cleavage enzyme (EC 4.1.3.8; CCE) and malate dehydrogenase (decarboxylating) (EC 1.1.1.39) [25].

Analytical, diagnostic and therapeutic context of FASN

• Molecular cloning and sequencing of chicken liver fatty acid synthase cDNA [6].
• Site-directed mutagenesis studies on the recombinant thioesterase domain of chicken fatty acid synthase expressed in Escherichia coli [26].
• The binding of reduced nicotinamide adenine dinucleotide phosphate (NADPH) to chicken liver fatty acid synthase has been studied by using both fluorescence titrations and the direct binding method of forced dialysis [27].
• In the presence of malonyl-CoA, the activity loss of FAS decreased sharply and almost no cross-link was observed in SDS-PAGE [28].
• Transcription of fatty acid synthase (FAS) and malic enzyme (ME) in avian liver is low during starvation or feeding a low-carbohydrate, high-fat diet and high during feeding a high-carbohydrate, low-fat diet [29].

References