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Query: UNIPROT:P06889 (Mol)
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The present review focuses on microbial type I fatty acid synthases (FASs), demonstrating their structural and functional diversity. Depending on their origin and biochemical function, multifunctional type I FAS proteins form dimers or hexamers with characteristic organization of their catalytic domains. A single polypeptide may contain one or more sets of the eight FAS component functions. Alternatively, these functions may split up into two different and mutually complementing subunits. Targeted inactivation of the individual yeast FAS acylation sites allowed us to define their roles during the overall catalytic process. In particular, their pronounced negative cooperativity is presumed to coordinate the FAS initiation and chain elongation reactions. Expression of the unlinked genes, FAS1 and FAS2, is in part constitutive and in part subject to repression by the phospholipid precursors inositol and choline. The interplay of the involved regulatory proteins, Rap1, Reb1, Abf1, Ino2/Ino4, Opi1, Sin3 and TFIIB, has been elucidated in considerable detail. Balanced levels of subunits alpha and beta are ensured by an autoregulatory effect of FAS1 on FAS2 expression and by posttranslational degradation of excess FAS subunits. The functional specificity of type I FAS multienzymes usually requires the presence of multiple FAS systems within the same cell. De novo synthesis of long-chain fatty acids, mitochondrial fatty acid synthesis, acylation of certain secondary metabolites and coenzymes, fatty acid elongation, and the vast diversity of mycobacterial lipids each result from specific FAS activities. The microcompartmentalization of FAS activities in type I multienzymes may thus allow for both the controlled and concerted action of multiple FAS systems within the same cell.
Microbiol Mol Biol Rev 2004 Sep
PMID:Microbial type I fatty acid synthases (FAS): major players in a network of cellular FAS systems. 1535 67

We designed our experiments to evaluate whether fatty acid synthase (FAS), a lipogenic enzyme linked to tumor virulence in population studies of human cancer, is necessary for the malignant transformation induced by Her-2/neu (erbB-2) oncogene, which is overexpressed not only in invasive breast cancer but also in premalignant atypical duct proliferations and in ductal carcinoma in situ of the breast. To avoid the genetic complexities associated with established breast cancer cell lines, we employed NIH-3T3 mouse fibroblasts engineered to overexpress human Her-2/neu coding sequence. NIH-3T3/Her-2 cells demonstrated a significant upregulation of FAS protein expression, which was dependent on the upstream activation of mitogen-activated protein kinase and phosphatidylinositol 3'-kinase/AKT pathways. Remarkably, pharmacological FAS blockade using the mycotoxin cerulenin or the novel small compound C75 completely suppressed the state of Her-2/neu-induced malignant transformation by inhibiting the ability of NIH-3T3/Her-2 cells to grow under either anchorage-independent (i.e., to form colonies in soft agar) or low-serum monolayer conditions. Moreover, NIH-3T3/Her-2 fibroblasts were up to three times more sensitive to chemical FAS inhibitors relative to untransformed controls as determined by MTT-based cell viability assays. In addition, pharmacological FAS blockade preferentially induced apoptotic cell death of NIH-3T3/Her-2 fibroblasts, as determined by an ELISA for histone-associated DNA fragments and by the terminal deoxynucleotidyltransferase (TdT)-mediated nick end labeling assay (TUNEL). Interestingly, the degree of Her-2/neu oncogene expression in a panel of breast cancer cell lines was predictive of sensitivity to chemical FAS inhibitors-induced cytotoxicity, while low-FAS expressing and chemical FAS inhibitors-resistant MDA-MB-231 breast cancer cells became hypersensitive to FAS blockade when they were engineered to overexpress Her-2/neu. Our observations strongly suggest that inhibition of FAS activity may provide a new molecular avenue for chemotherapeutic prevention and/or treatment of Her-2/neu-related breast carcinomas.
Mol Carcinog 2004 Nov
PMID:Pharmacological inhibition of fatty acid synthase (FAS): a novel therapeutic approach for breast cancer chemoprevention through its ability to suppress Her-2/neu (erbB-2) oncogene-induced malignant transformation. 1539 78

Intra-abdominal fat accumulation is related to several diseases, especially diabetes and heart disease. Molecular mechanisms associated with this independent risk factor are not well established. Through the serial analysis of gene expression (SAGE) strategy, we have studied the transcriptomic effects of castration and dihydrotestosterone (DHT) in retroperitoneal adipose tissue of C57BL6 male mice. Approximately 50,000 SAGE tags were isolated in intact and gonadectomized mice, as well as 3 and 24 h after DHT administration. Transcripts involved in energy metabolism, such as glyceraldehyde-3-phosphate dehydrogenase, malic enzyme supernatant, fatty acid synthase, lipoprotein lipase, hormone-sensitive lipase and monoglyceride lipase, were upregulated by DHT. Transcripts involved in adipogenesis, and cell cycle and cell shape organization, such as DDX5, C/EBPalpha, cyclin I, procollagen types I, III, IV, V and VI, SPARC and matrix metalloproteinase 2, were upregulated by DHT. Cell defense, division and signaling, protein expression and many novel transcripts were regulated by castration and DHT. The present results provide global genomic evidence for a stimulation of glycolysis, fatty acids and triacylglycerol production, lipolysis and cell shape reorganization, as well as cell proliferation and differentiation, by DHT. The novel transcripts regulated by DHT may contribute to identify new mechanisms involved in the action of sex hormones and their potential role in obesity.
J Mol Endocrinol 2004 Oct
PMID:Effects of dihydrotestosterone on adipose tissue measured by serial analysis of gene expression. 1552 99

De novo synthesis of fatty acids in the cytosol of animal cells is carried out by the multifunctional, homodimeric fatty acid synthase (FAS). Cryo-EM analysis of single FAS particles imaged under conditions that limit conformational variability, combined with gold labeling of the N termini and structural analysis of the FAS monomers, reveals two coiled monomers in an overlapping arrangement. Comparison of dimeric FAS structures related to different steps in the fatty acid synthesis process indicates that only limited local rearrangements are required for catalytic interaction among different functional domains. Monomer coiling probably contributes to FAS efficiency and provides a structural explanation for the reported activity of a FAS monomer dimerized to a catalytically inactive partner. The new FAS structure provides a new paradigm for understanding the architecture of FAS and the related modular polyketide synthases.
Nat Struct Mol Biol 2005 Mar
PMID:Structure and molecular organization of mammalian fatty acid synthase. 1571 65

The present investigation aimed at evaluating the role of fatty acid synthesis inhibition in enhancing transcutaneous delivery of levodopa (LD). Rat epidermis was treated with ethanol and various doses of cerulenin (an inhibitor of fatty acid synthase enzyme system) for reducing the normal level of fatty acids. Calcium chloride (0.1 mM) and/or verapamil (1 microM) were coapplied to cerulenin treated skin in order to modulate duration of epidermal perturbation. These treated skin portions were used for estimation of altered triglyceride content (an indicator of fatty acid synthesis), differential scanning calorimetry (DSC) analysis, and in vitro permeation of LD. Plasma concentration of LD was monitored in rats following topical application of various transdermal formulations. Application of cerulenin (0.1 or 0.15 mM/7 cm(2)) to viable rat skin inhibited approximately 60% triglyceride synthesis with respect to control at 2 h. Coapplication of calcium chloride (0.1 mM) significantly increased this inhibition, whereas verapamil application reduced this effect. The decrease in triglyceride content reduced the enthalpy of the lipid endothermic transition. The in vitro permeation of LD was enhanced 3-fold across skin excised after treatment with cerulenin. LD did not permeate across normal skin. The effective plasma concentration (C(eff)) of LD was achieved within 3 h and maintained till 10 h by a single topical application of a carbidopa-levodopa combination (1:4) to ethanol-perturbed cerulenin-treated skin. Coapplication of calcium chloride reduced the time lag to achieve C(eff) to 2 h and maintained it till 24 h. A single transdermal LD (64 mg) patch formulated with calcium chloride (0.1 mM) and cerulenin (0.1 mM) dissolved in a propylene glycol:ethanol (7:3) mixture seems to offer a noninvasive approach for transcutaneous delivery of levodopa.
Mol Pharm
PMID:Transcutaneous delivery of levodopa: enhancement by fatty acid synthesis inhibition. 1580 78

The adipocyte differentiation process involves a cascade of transcriptional events that culminates in the expression of peroxisome proliferator-activated receptor-gamma (PPARgamma) and CCAAT/enhancer binding protein-alpha (C/EBPalpha). These adipogenic transcription factors regulate the expression of genes necessary for the development of mature adipocytes in mammals. The current study was undertaken to identify regulatory factors that affect adipogenesis and to analyze species-specific mRNA expression of factors involved in chicken adipocyte differentiation. We developed a system for differentiation of chicken (Gallus gallus) adipocytes in culture using medium containing 500 nM dexamethasone, 0.5 mM 3-isobutyl-1-methylxanthine, 20 microg/mL bovine insulin, 300 microM oleate, and 10% fetal bovine serum. The rapid differentiation of cells to mature adipocytes in this culture system was verified by observed increases in adipocyte fatty acid-binding protein (aP2) expression, glycerol-3-phosphate dehydrogenase (GPDH) activity and intracellular triglyceride accumulation. In contrast, cells cultured in a differentiation medium without fatty acids did not differentiate into mature adipocytes. The expression profiles of genes involved in the regulation of adipocyte differentiation, such as PPARgamma, C/EBPalpha, beta, delta, sterol regulatory element binding protein-1 (SREBP-1), fatty acid synthase (FAS), lipoprotein lipase (LPL), and glucose transporters 1 and 8 (GLUT1 and GLUT8) were studied. Rapid increases in PPARgamma and aP2 expression were observed after 9 and 12 h of culture in differentiation medium, respectively. In contrast, the expression patterns of the other adipogenic genes only differed slightly from those previously determined for mammalian adipocytes. These results suggest that exogenous fatty acid is essential for adipocyte differentiation in chickens, and that PPARgamma is possibly a key regulator in the early stages of chicken preadipocyte differentiation.
Comp Biochem Physiol A Mol Integr Physiol 2005 May
PMID:Changes in mRNA expression of regulatory factors involved in adipocyte differentiation during fatty acid induced adipogenesis in chicken. 1592 39

The receptor tyrosine kinase ErbB2 (HER-2/neu) is overexpressed in up to 30% of breast cancers and is associated with poor prognosis and an increased likelihood of metastasis especially in node-positive tumors. In this proteomic study, to identify the proteins that are associated with the aggressive phenotype of HER-2/neu-positive breast cancer, tumor cells from both HER-2/neu-positive and -negative tumors were procured by laser capture microdissection. Differentially expressed proteins in the two subsets of tumors were identified by two-dimensional electrophoresis and MALDI-TOF/TOF MS/MS. We found differential expression of several key cell cycle modulators, which were linked with increased proliferation of the HER-2/neu-overexpressing cells. Nine proteins involved in glycolysis (triose-phosphate isomerase (TPI), phosphoglycerate kinase 1 (PGK1), and enolase 1 (ENO1)), lipid synthesis (fatty acid synthase (FASN)), stress-mediated chaperonage (heat shock protein 27 (Hsp27)), and antioxidant and detoxification pathways (haptoglobin, aldo-keto reductase (AKR), glyoxalase I (GLO), and prolyl-4-hydrolase beta-isoform (P4HB)) were found to be up-regulated in HER-2/neu-positive breast tumors. HER-2/neu-dependent differential expression of PGK1, FASN, Hsp27, and GLO was further validated in four breast cancer cell lines and 12 breast tumors by immunoblotting and confirmed by partially switching off the HER-2/neu signaling in the high HER-2/neu-expressing SKBr3 cell line with Herceptin treatment. Statistical correlations of these protein expressions with HER-2/neu status were further verified by immunohistochemistry on a tissue microarray comprising 97 breast tumors. Our findings suggest that HER-2/neu signaling may result, directly or indirectly, in enhanced activation of various metabolic, stress-responsive, antioxidative, and detoxification processes within the breast tumor microenvironment. We hypothesize that these identified changes in the cellular proteome are likely to drive cell proliferation and tissue invasion and that the key cell cycle modulators involved, when uncovered by future research, would serve as naturally useful targets for the development of therapeutic strategies to negate the metastatic potential of HER-2/neu-positive breast tumors.
Mol Cell Proteomics 2005 Nov
PMID:Proteomic study reveals that proteins involved in metabolic and detoxification pathways are highly expressed in HER-2/neu-positive breast cancer. 1604 8

Systematic thin layer chromatographic (TLC) analysis of apolar lipids in Mycobacterium kansasii revealed the presence of a previously uncharacterized novel component. The product was ubiquitously found in a panel of M. kansasii clinical isolates, as well as other pathogenic and non-pathogenic mycobacterial species. TLC analysis of [(14)C]-acetate- or [(14)C]-glycerol-labelled M. kansasii cultures tentatively assigned the novel product as an unusual triacylglycerol-related lipid. Subsequent purification, followed by structural determination using (1)H-nuclear magnetic resonance (NMR) and electrospray mass spectrometry (ES/MS), led to the identification of this product as a monomeromycolyl-diacylglycerol (MMDAG). Treatment of M. kansasii with either isoniazid (INH), a well-known type II fatty acid synthase (FAS-II) and mycolic acid biosynthesis inhibitor, or tetrahydrolipstatin (THL), a drug approved for treating obesity, correlated with a reduced incorporation of [(14)C]-acetate into both mycolic acids and MMDAG. Addition of INH or THL to the cultures induced major morphological changes and, surprisingly, resulted in an increased number of lipid storage bodies, as determined by electron microscopy. The potent antimycobacterial activity of THL was confirmed against a variety of mycobacterial species, including INH-susceptible and -resistant Mycobacterium tuberculosis strains. Therefore, THL and other beta-lactones may be promising drugs for the development of new antitubercular therapy.
Mol Microbiol 2005 Aug
PMID:Identification and structural characterization of an unusual mycobacterial monomeromycolyl-diacylglycerol. 1609 Oct 48

Nonalcoholic fatty liver disease (NAFLD) is one of the most frequent causes of abnormal liver dysfunction, and its prevalence has markedly increased; however, the mechanisms involved in the pathogenesis of NAFLD have not been thoroughly investigated in humans. In this study, we evaluated the expression of fatty acid metabolism-related genes in NAFLD. Real-time RT-PCR was performed using liver biopsy samples from 12 NAFLD patients. The target genes studied were: acetyl-CoA carboxylase (ACC) 1, ACC2, and fatty acid synthase (FAS) for the evaluation of de novo fatty acid synthesis; carnitine palmitoyltransferase 1a (CPT1a), long-chain acyl-CoA dehydrogenase (LCAD), and long-chain L-3-hydroxyacyl-coenzyme A dehydrogenase alpha (HADHalpha) for beta-oxidation in the mitochondria; peroxisome proliferator-activated receptor- (PPAR-) alpha and cytochrome P450 2E1 (CYP2E1) for oxidation in peroxisomes and microsomes (endoplasmic reticulum) respectively; and diacylglycerol O-acyltransferase 1 (DGAT1), PPAR-gamma, and hormone sensitive lipase (HSL) for triglyceride synthesis and catalysis. In NAFLD, expression of ACC1 and ACC2, but not FAS was increased, indicating that de novo fatty acid synthesis is enhanced in NAFLD. In contrast, expression of CTP1a, a rate-limiting enzyme, was remarkably decreased, indicating that beta-oxidation in the mitochondria was decreased, although the expression of LCAD and HADHalpha was increased. Expression of PPAR-alpha was increased, whereas that of CYP2E1 was reduced. The expression of DGAT1, PPAR-gamma, and HSL was enhanced. These data suggest that in NAFLD, increased de novo synthesis and decreased beta-oxidation in the mitochondria lead to accumulation of fatty acids in hepatocytes, although the extent of oxidation in peroxisomes and microsomes remains unclear.
Int J Mol Med 2005 Oct
PMID:Evaluation of fatty acid metabolism-related gene expression in nonalcoholic fatty liver disease. 1614 97

Tuberculosis kills about two million people every year and remains one of the leading causes of mortality worldwide. As a result of the increasing antibiotic resistance of Mycobacterium tuberculosis (Mtb) strains, there is an urgent need for new antitubercular drugs. Several efficient antibiotics, including isoniazid, specifically target the fatty acid synthase-II (FAS-II) complex of mycolic acid biosynthesis. We have previously shown that there are protein-protein interactions between the components of FAS-II that are essential for mycobacterial survival. We have now looked at the potential partners of FAS-II, mtFabD, the methyltransferases MmaAs, and Pks13. A combination of yeast two-hybrid and co-immunoprecipitation experiments showed that mtFabD interacts with each beta-ketoacyl-synthase (KasA, KasB and mtFabH) and with the core of FAS-II (InhA and MabA). The methyltransferases have a greater affinity for KasA and KasB than for mtFabH, suggesting that modifications on the meromycolic chains may occur during their elongation. Finally, Pks13, which catalyzes the final Claisen condensation of mycolic acids, interacts specifically with KasB. These data allowed us to determine the architecture of the multiple specialized FAS-II complexes, giving us insights into the organization of the complete mycolic acids biosynthesis. Our studies suggest a new and crucial interaction (KasB-Pks13) as a putative target for peptidomimetic antibiotics.
J Mol Biol 2005 Nov 04
PMID:The biosynthesis of mycolic acids in Mycobacterium tuberculosis relies on multiple specialized elongation complexes interconnected by specific protein-protein interactions. 1621 23


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