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Results for “Fatty Acid Synthesis Inhibitors”

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At least 19 recordsLinked to original sources
PubMed2004

Determination of selectivity and efficacy of fatty acid synthesis inhibitors.

Type II fatty acid synthesis (FASII) is essential to bacterial cell viability and is a promising target for the development of novel antibiotics. In the past decade, a few inhibitors have been identified for this pathway, but none of them lend themselves to drug development. To find better inhibitors that are potential drug candidates, we developed a high throughput assay that identifies inhibitors simultaneously against multiple targets within the FASII pathway of most bacterial pathogens. We demonstrated that the inverse t(1/2) value of the FASII enzyme-catalyzed reaction gives a measure of FASII activity. The Km values of octanoyl-CoA and lauroyl-CoA were determined to be 1.1 +/- 0.3 and 10 +/- 2.7 microM in Staphylococcus aureus and Bacillus subtilis, respectively. The effects of free metals and reducing agents on enzyme activity showed an inhibition hierarchy of Zn2+ > Ca2+ > Mn2+ > Mg2+; no inhibition was found with beta-mercaptoethanol or dithiothreitol. We used this assay to screen the natural product libraries and isolated an inhibitor, bischloroanthrabenzoxocinone (BABX) with a new structure. BABX showed IC50 values of 11.4 and 35.3 microg/ml in the S. aureus and Escherichia coli FASII assays, respectively, and good antibacterial activities against S. aureus and permeable E. coli strains with minimum inhibitory concentrations ranging from 0.2 to 0.4 microg/ml. Furthermore, the effectiveness, selectivity, and the in vitro and in vivo correlations of BABX as well as other fatty acid inhibitors were elucidated, which will aid in future drug discovery.

Anti-Bacterial Agents↗
PubMed1992

Inhibition of polyketide synthesis in Alternaria alternata by the fatty acid synthesis inhibitor cerulenin.

The fatty acid synthase inhibitor cerulenin (50 to 100 micrograms/ml) inhibited production of the polyketide mycotoxins alternariol (AOH) and alternariol monomethyl ether (AME) by the mold Alternaria alternata. The results suggested that AOH synthesis was inhibited by a direct mechanism by cerulenin, whereas production of AME was probably limited by a shortage of the precursor AOH.

Alternaria↗
PubMed1986

Effect of cerulenin, an inhibitor of fatty acid synthesis, on the immune cytolysis of tumor cells.

Effect of cerulenin, an inhibitor of biosynthesis of fatty acids and sterols on the immune cytolysis of tumor cells was investigated. In cytotoxicity experiment, MH134 cells pretreated with cerulenin in a range of concentrations causing minor cellular injuries were lysed by xenogeneic antiserum and complement in a significantly higher degree than non-treated MH134 cells. C3H/He mice inoculated ip with 1 X 10(5) syngeneic MH134 cells, received cerulenin on days 3 and 6, and then the antiserum against MH134 cells on days 4 and 7. Such mice survived markedly longer than 3 control groups of mice carrying MH134 tumor cells; one without treatments, one treated only with cerulenin and the other only with the antiserum. Inhibition of biosynthesis of cell membrane fatty acid and sterols, that was indicated by inhibition of 14C-acetate incorporation, is thought to enhance the susceptibility of the tumor cells to killing by antibodies and complement. Such an inhibitor of fatty acids and sterols might be a beneficial adjuvant to the adoptive cancer immunotherapy.

Acetates↗
PubMed1990

Effects of cerulenin, an inhibitor of fatty acid synthesis on reconstitution of the dental basement membrane.

When trypsin-dissociated enamel organs and dental papillae were recombined in the presence of cerulenin--an antibiotic which is a potent inhibitor of fatty acid synthesis--the newly synthesized basement membrane seemed defective in a dose-dependent manner. The three-dimensional relationship between the basement membrane components and the plasma membrane appears to be regulated in part by lipids.

Animals↗
PubMedDate not supplied

The role of fatty acids and eicosanoid synthesis inhibitors in breast carcinoma.

We have reviewed the literature concerning the role of fatty acids and eicosanoid synthesis inhibitors in breast carcinoma. The omega-6 polyunsaturated fatty acids (PUFAs), primarily linoleic acid, promote breast cancer tumorigenesis and tumor cell proliferation directly and indirectly via increased synthesis of cyclooxygenase- and lipoxygenase-catalyzed products. The omega-3 PUFAs, primarily docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), suppress breast carcinoma tumorigenesis and tumor cell proliferation, although the effect of DHA may be partly ascribed to increased amounts of EPA derived from DHA. Both cyclooxygenase and lipoxygenase inhibitors suppress tumorigenesis and/or tumor proliferation, with the latter being more active. Thus, arachidonic acid-derived eicosanoids play an important role in breast cancer, and the balance of the various eicosanoids may be a critical determinant of cell proliferation. However, the exact mechanism by which fatty acids and eicosanoid synthesis inhibitors exert stimulatory and inhibitory effects on breast carcinoma is still not well understood.

Animals↗
PubMed1975

Effect of renal microsomes and renal lysosomes on in vitro hepatic fatty acid synthesis.

An inhibitor and stimulator of in vitro hepatic fatty acid synthesis are present in renal microsomes. In addition, a stimulator of fatty acid synthesis is present in renal lysosomes. Renal microsomal inhibition of hepatic fatty acid synthesis is not due to the depletion of cofactors in the system. This inhibitor appears to be located exclusively in the kidney medullary microsomes. It is destroyed by Pronase and heat treatment suggesting it may be a protein. Its effects on fatty acid synthesis may be attributed in part to ATPase activity as well as a direct effect on the hepatic fatty acid synthesizing system. A stimulator of hepatic fatty acid synthesis is present in the buffer insoluble fraction of an acetone powder preparation of renal microsomes. This stimulator is relatively heat labile and does not appear to be a phospholipid. The lysosomal stimulator of hepatic fatty acid synthesis is associated with the contents of renal lysosomes and not with the lysosomal membranes. It acts at the acetyl-CoA carboxylase step and its activity is not affected by fasting or aminonucleoside induced nephrosis.

Adenosine Triphosphate↗
PubMed2002

Use of a YAP1 overexpression cassette conferring specific resistance to cerulenin and cycloheximide as an efficient selectable marker in the yeast Saccharomyces cerevisiae.

Drug-resistance markers for yeast transformation are useful because they can be applied to strains without auxotrophic mutations. However, they are susceptible to technical difficulties, namely lower transformation efficiency and the appearance of drug-resistant mutants without the marker. To avoid these problems, we have constructed a phosphoglycerate kinase (PGK) promoter-driven YAP1 expression cassette, called PGKp-YAP1. Yeast cells containing PGKp-YAP1 were resistant to cycloheximide, a protein synthesis inhibitor, and also to cerulenin, a fatty acid synthesis inhibitor, but not to other drugs tested. The transformation efficiency of PGKp-YAP1 using cerulenin selection was comparable to that using a URA3 auxotrophic marker when low concentrations of cerulenin were used. Non-transformed drug-resistant colonies did appear on the low-concentration cerulenin plates. However, these non-transformed colonies could easily be identified, based on their cycloheximide sensitivity and/or their resistance to aureobasidin A to which the transformants were sensitive. Therefore, the dual drug resistance of PGKp-YAP1 could be used as an effective selection for PGKp-YAP1 recipient cells. The PGKp-YAP1 marker was used to disrupt the LYS2 gene and to transform an industrial yeast strain, indicating that this marker can be used for efficient and reliable gene manipulations in any Saccharomyces cerevisiae strain.

Antifungal Agents↗
PubMed2000

Biosynthesis of fatty acids in the docosahexaenoic acid-producing bacterium Moritella marina strain MP-1.

We have isolated the fatty acid biosynthetic (fab) gene cluster taking part in the synthesis of middle-chain fatty acids and a genomic segment which was homologous with the eicosapentaenoic acid-biosynthetic gene cluster from the docosahexaenoic acid (DHA)-producing bacterium Moritella marina strain MP-1. This segment was presumed to include the DHA-biosynthetic gene cluster of M. marina strain MP-1. When M. marina strain MP-1 was cultured in medium containing cerulenin, a fatty acid synthesis inhibitor, decreases in levels of middle-chain fatty acids and remarkable increases in levels of DHA were observed. These results suggest that the synthesis of middle-chain fatty acids works independently of the synthesis of DHA.

Bacillus subtilis↗
PubMed2002

Inhibitors of fatty acid synthesis as antimicrobial chemotherapeutics.

Fatty acid biosynthesis is an emerging target for the development of novel antibacterial chemotherapeutics. The dissociated bacterial system is substantially different from the large, multifunctional protein of mammals, and many possibilities exist for type-selective drugs. Several compounds, both synthetic and natural, target bacterial fatty acid synthesis. Three compounds target the FabI enoyl-ACP reductase step; isoniazid, a clinically used antituberculosis drug, triclosan, a widely used consumer antimicrobial, and diazaborines. In addition, cerulenin and thiolactomycin, two fungal products, inhibit the FabH, FabB and FabF condensation enzymes. Finally, the synthetic reaction intermediates BP1 and decynoyl- N-acetyl cysteamine inhibit the acetyl-CoA carboxylase and dehydratase isomerase steps, respectively. The mechanisms of action of these compounds, as well as the potential development of new drugs targeted against this pathway, are discussed.

Anti-Infective Agents↗
PubMed2004

Cyclohexylcarbamic acid 3'- or 4'-substituted biphenyl-3-yl esters as fatty acid amide hydrolase inhibitors: synthesis, quantitative structure-activity relationships, and molecular modeling studies.

Fatty acid amide hydrolase (FAAH) is a promising target for modulating endocannabinoid and fatty acid ethanolamide signaling, which may have important therapeutic potential. We recently described a new class of O-arylcarbamate inhibitors of FAAH, including the cyclohexylcarbamic acid biphenyl-3-yl ester URB524 (half-maximal inhibitory concentration, IC(50) = 63 nM), which have significant anxiolytic-like properties in rats. In the present study, by introducing a selected group of substituents at the meta and para positions of the distal phenyl ring of URB524, we have characterized structure-activity profiles for this series of compounds and shown that introduction of small polar groups in the meta position greatly improves inhibitory potency. Most potent in the series was the m-carbamoyl derivative URB597 (4i, IC(50) = 4.6 nM). Furthermore, quantitative structure-activity relationship (QSAR) analysis of an extended set of meta-substituted derivatives revealed a negative correlation between potency and lipophilicity and suggested that small-sized substituents may undertake polar interactions with the binding pocket of the enzyme. Docking studies and molecular dynamics simulations, using the crystal structure of FAAH, indicated that the O-biphenyl scaffold of the carbamate inhibitors can be accommodated within a lipophilic region of the substrate-binding site, where their folded shape mimics the initial 10-12 carbon atoms of the arachidonyl moiety of anandamide (a natural FAAH substrate) and methyl arachidonyl fluorophosphonate (a nonselective FAAH inhibitor). Moreover, substituents at the meta position of the distal phenyl ring can form hydrogen bonds with atoms located on the polar section of a narrow channel pointing toward the membrane-associated side of the enzyme. The structure-activity characterization reported here should help optimize the pharmacodynamic and pharmacokinetic properties of this class of compounds.

Amidohydrolases↗
PubMed2004

Evaluation of epigallocatechin gallate and related plant polyphenols as inhibitors of the FabG and FabI reductases of bacterial type II fatty-acid synthase.

Epigallocatechin gallate (EGCG) is the major component of green tea extracts and possesses antibacterial, antiviral, and antitumor activity. Our study focused on validating the inhibition of the bacterial type II fatty acid synthesis system as a mechanism for the antibacterial effects of EGCG and related plant polyphenols. EGCG and the related tea catechins potently inhibited both the FabG and FabI reductase steps in the fatty acid elongation cycle with IC(50) values between 5 and 15 microm. The presence of the galloyl moiety was essential for activity, and EGCG was a competitive inhibitor of FabI and a mixed type inhibitor of FabG demonstrating that EGCG interfered with cofactor binding in both enzymes. EGCG inhibited acetate incorporation into fatty acids in vivo, although it was much less potent than thiolactomycin, a validated fatty acid synthesis inhibitor, and overexpression of FabG, FabI, or both did not confer resistance. A panel of other plant polyphenols was screened for FabG/FabI inhibition and antibacterial activity. Most of these inhibited both reductase steps, possessed antibacterial activity, and inhibited cellular fatty acid synthesis. The ability of the plant secondary metabolites to interfere with the activity of multiple NAD(P)-dependent cellular processes must be taken into account when assessing the specificity of their effects.

Acetyltransferases↗
PubMed1982

Lactate metabolism and cytosolic NADH reducing equivalents in ovine adipocytes.

1. Isolated ovine adipocytes, unlike rat adipose tissue, could utilize lactate at a high rate. 2. When the rate of fatty acid synthesis was attenuated with 5-(tetradecyloxy)-2-furoic acid, a fatty acid synthesis inhibitor, there was a good positive correlation between the rates of lactate oxidation to CO2 and lactate incorporation into fatty acids. 3. Addition of 2,4-dinitrophenol enhanced lactate oxidation to CO2 independent of fatty acid synthesis. Under this condition, estimated cytosolic NADH formation from lactate dehydrogenation exceeded the need of NADH for cytosolic oxaloacetate reduction and for glyceride glycerol formation. 4. Mitochondria isolated from ovine adipocytes oxidized added NADH rapidly in a reconstituted alpha-glycerophosphate shuttle system. 5. It is possible that the ability of ovine adipocytes to utilize lactate may be related to the active alpha-glycerophosphate shuttle for cytosolic NADH reoxidation.

2,4-Dinitrophenol↗
PubMed1991

Effects of fatty acids and eicosanoid synthesis inhibitors on the growth of two human prostate cancer cell lines.

Dietary fatty acids (FAs) may be involved in the carcinogenic process within the prostate gland and progression to clinically manifest disease. We have shown that growth of the androgen-unresponsive PC-3 human prostate cancer cell line is stimulated in vitro by the presence of linoleic acid (LA), an omega-6 polyunsaturated FA. The response was positively related to the FA concentration over the entire range examined (5-750 ng/ml). Conversely, docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), two omega-3 FAs present in fish oils, inhibited PC-3 cell growth in a dose-dependent manner; both were equally effective, with an approximately 65% reduction in growth occurring at a concentration of 2.0 micrograms/ml (P less than 0.001). The DU 145 human prostate cancer cell line, which is also androgen-unresponsive, showed no growth response to LA and was less susceptible to growth inhibition when cultured in the presence of omega-3 FAs. Growth experiments with indomethacin, esculetin, and piroxicam, pharmacological inhibitors of eicosanoid biosynthesis with differing sites of action, indicated that human prostate cancer cell growth requires intact metabolic pathways for both leukotriene and prostaglandin production.

Cell Division↗
PubMed1981

Effects of metabolic inhibitors on extracellular fructosyltransferase production in Actinomyces viscosus.

Extracellular fructosyltransferase (levansucrase; EC 2.4.1.10) production in Actinomyces viscosus T14AV was demonstrated to occur concomitantly with cellular growth. The inhibition of both cellular ribonucleic acid and protein synthesis resulted in no further accumulation of enzyme activity. The antibiotic sodium clofibrate differentially inhibited the production of fructosyltransferase by strain T14AV. Furthermore, the antibiotic preferentially inhibited [14C]acetate incorporation into cellular lipid, but did not affect protein synthesis. In addition, no inhibition of fructosyltransferase production was observed upon the addition of the fatty acid acid synthesis inhibitor cerulenin. On the other hand, extracellular fructosyltransferase production was apparently stimulated in the presence of the cell wall synthesis inhibitors penicillin, amphomycin, and tunicamycin. These results are discussed in terms of the mechanism of extracellular protein production in A. viscosus.

Actinomyces↗