Disease relevance of cerulenin

• Both systemic and intracerebroventricular treatment of mice with fatty acid synthase (FAS) inhibitors (cerulenin and a synthetic compound C75) led to inhibition of feeding and dramatic weight loss [1].
• Cerulenin, a drug which specifically blocks lipid synthesis, prevented both the trimerization of OmpF monomers and their assembly into the outer membrane of Escherichia coli B cells [2].
• The presence of cerulenin after virus entry prevents the synthesis of poliovirus proteins [3].
• The synthesis and processing of structural proteins of human immunodeficiency virus type 1 (HIV-1) were studied in infected cells treated with monensin and cerulenin [4].
• Here, we report that cerulenin treatment of human breast cancer cells inhibits fatty acid synthesis within 6 h after exposure, that loss of clonogenic capacity occurs within the same interval, and that DNA fragmentation and morphological changes characteristic of apoptosis ensue [5].

Psychiatry related information on cerulenin

• The present study was conducted to investigate the effects of several energy balance-related factors (leptin, cerulenin, food deprivation, genotype, and gender) on SCD gene expression in chickens [6].

High impact information on cerulenin

• Cerulenin, an inhibitor for fatty acid synthesis, produced the lsd phenotype in wild type [7].
• When Fas is inactivated by a specific inhibitor (cerulenin), NMT1 cells are not viable unless the media is supplemented with long chain fatty acids [8].
• Finally, the synthesis of phospholipids and the proliferation of membranes does not take place if cerulenin is added to the culture medium [3].
• Cerulenin, an inhibitor of lipid biosynthesis, effectively blocks the growth of poliovirus in HeLa cells [3].
• Pharmacological FAS inhibitors cerulenin and C75 were found to suppress p185(HER2) oncoprotein expression and tyrosine-kinase activity in breast and ovarian HER2 overexpressors [9].

Chemical compound and disease context of cerulenin

• We have found that cerulenin, an antibiotic that inhibits de novo fatty acid and cholesterol biosynthesis and fatty acylation of proteins, strongly inhibited the cytotoxicity of ricin, modeccin, Pseudomonas toxin, and diphtheria toxin in a brefeldin A (BFA)-resistant mutant of Vero cells (BER-40) [10].
• Many strains of Pseudomonas aeruginosa are resistant to the antibiotics cerulenin and thiolactomycin, potent inhibitors of bacterial fatty acid biosynthesis [11].
• Inhibition of Vibrio harveyi bioluminescence by cerulenin: in vivo evidence for covalent modification of the reductase enzyme involved in aldehyde synthesis [12].
• Export of extracellular levansucrase by Bacillus subtilis: inhibition by cerulenin and quinacrine [13].
• Cellular autolytic activity as well as lipid and lipoteichoic acid metabolism have been studied in cultures of Streptococcus faecalis receiving various combinations of the following treatments: chloramphenicol addition, starvation for an essential amino acid (valine), and cerulenin treatment [14].

Biological context of cerulenin

• The described complementation assay can be used to detect condensing enzymes with other substrate specificities by supplementing the cerulenin-treated extract with appropriate purified KAS enzymes [15].
• Key role of mitochondria in cerulenin-mediated apoptosis [16].
• Fatty acid synthetic metabolism is abnormally elevated in tumor cells, and pharmacological inhibitors of the anabolic enzyme fatty acid synthase (FAS), including the natural product cerulenin and the novel synthetic compound c75, are selective inhibitors of tumor cell growth [17].
• The mechanism of DNA synthesis inhibition by cerulenin is indirect, because expression of certain viral oncogenes rescues DNA synthesis/S phase progression in cerulenin-exposed cells [18].
• Cells grown in the presence of exogenous fatty acid partially downmodulate FAS expression and increase mean cell volume (phospholipid mass/cell) but retain their sensitivity to cerulenin, which is reversed by 3-fold excess oleate supplementation [19].

Anatomical context of cerulenin

• Cerulenin inhibited acylglycerol synthesis in tumor cells and fibroblast controls in a dose-dependent fashion and also caused a growth inhibition which generally paralleled the level of endogenous fatty acid synthesis [20].
• Recent studies have shown that the FAS inhibitor, cerulenin, is selectively cytotoxic to cell lines derived from human malignancies, suggesting that those carcinoma cells are dependent upon endogenous fatty acid synthesis for growth [19].
• Our data strongly indicate that mitochondria play a key role in the cerulenin-mediated pathway [16].
• Following exposure to 12-O-tetradecanoylphorbol-13-acetate, the FAS expression in HL60 cells is abolished, fatty acid synthesis diminishes, and the cells become insensitive to cerulenin while acquiring a differentiated, macrophage-like phenotype [19].
• Here we report that cerulenin is an effective inducer of apoptosis in different wild-type p53 and mutant p53 tumor cell lines, whereas normal human keratinocytes and fibroblasts are resistant to the apoptotic effect [16].

Associations of cerulenin with other chemical compounds

• Supraphysiologic levels of palmitate, 14 microM in dimethyl sulfoxide, significantly reversed the growth inhibition caused by cerulenin at concentrations of up to 5 micrograms/ml, indicating that cerulenin-mediated growth inhibition was due to fatty acid synthase inhibition [20].
• HL60 cells adapted to growth in serum- and fatty acid-free medium show a dose-dependent sensitivity to cerulenin, which is reversed by palmitate, the major product of FAS, indicating that cerulenin cytotoxicity is mediated through fatty acid starvation [19].
• The protein acylation inhibitor cerulenin inhibited both phases of glucose-stimulated insulin secretion [21].
• In addition, purified mtFabH was sensitive to thiolactomycin and resistant to cerulenin in an in vitro assay [22].
• Genetic complementation studies revealed that rat liver acyl-CoA synthetase (RLACS) rescues the viability of faa1 delta faa4 delta cells in media containing a fermentable carbon source, myristate or palmitate, plus cerulenin [23].

Gene context of cerulenin

• FAT1 deletion strains exhibited decreased growth on medium containing dextrose, oleic acid, and cerulenin, an inhibitor of fatty acid synthesis [24].
• Most importantly, experiments in vivo using the fatty acid synthesis inhibitor cerulenin demonstrated that deletion of TGL3 resulted in a decreased mobilization of TAG from lipid particles [25].
• YAP1 confers resistance to the fatty acid synthase inhibitor cerulenin through the transporter Flr1p in Saccharomyces cerevisiae [26].
• A non-toxic concentration of the isonitrile (41.5 microg/ml, 255 microM) inhibited Pdr5p-mediated efflux of cycloheximide or cerulenin in Pdr5p-overexpressing cells [27].
• Treatment with cerulenin or a novel small-molecule inhibitor of FAS C75 resulted in a dramatic accumulation of CDKi p27KIP1, which was accompanied by a noteworthy translocation of p27KIP1 from cytosol to cell nuclei [28].

Analytical, diagnostic and therapeutic context of cerulenin

• In situ hybridization study revealed that a single injection of cerulenin did not affect the expression of orexigenic neuropeptide mRNA [29].
• The inhibition of fatty acylation by cerulenin blocks further posttranslational maturation of the invariant chain as shown by two-dimensional gel electrophoresis of Ii immunoprecipitates [30].
• Cerulenin is a powerful inhibitor of viral RNA synthesis, as analyzed by [3H]uridine incorporation, incorporation of [32P]phosphate into viral replication complexes, or Northern blot analysis of viral RNAs hybridized with minus- or plus-stranded riboprobes [31].
• This analysis indicated that cerulenin interferes with cell division by inhibiting normal constriction of the division furrow and centripetal growth of the cross wall in envelope growth sites [32].
• Although cerulenin itself is cytotoxic and inappropriate for clinical use, it may provide leads for the rational design of inhibitors of the HIV proteinase which could have application in the chemotherapy of AIDS [33].

References