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Chemical Compound Review

cerulenin     3-[(4E,7E)-nona-4,7- dienoyl]oxirane-2...

Synonyms: CPD-6901, C2389_SIGMA, NSC-116069, NSC116069, LMFA08010013, ...
 
 
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Disease relevance of cerulenin

 

Psychiatry related information on cerulenin

 

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

 

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

 

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

  1. Reduced food intake and body weight in mice treated with fatty acid synthase inhibitors. Loftus, T.M., Jaworsky, D.E., Frehywot, G.L., Townsend, C.A., Ronnett, G.V., Lane, M.D., Kuhajda, F.P. Science (2000) [Pubmed]
  2. The assembly of the major outer membrane protein OmpF of Escherichia coli depends on lipid synthesis. Bolla, J.M., Lazdunski, C., Pagès, J.M. EMBO J. (1988) [Pubmed]
  3. Phospholipid biosynthesis and poliovirus genome replication, two coupled phenomena. Guinea, R., Carrasco, L. EMBO J. (1990) [Pubmed]
  4. Processing of the structural proteins of human immunodeficiency virus type 1 in the presence of monensin and cerulenin. Pal, R., Gallo, R.C., Sarngadharan, M.G. Proc. Natl. Acad. Sci. U.S.A. (1988) [Pubmed]
  5. Inhibition of fatty acid synthesis induces programmed cell death in human breast cancer cells. Pizer, E.S., Jackisch, C., Wood, F.D., Pasternack, G.R., Davidson, N.E., Kuhajda, F.P. Cancer Res. (1996) [Pubmed]
  6. The regulation of stearoyl-CoA desaturase gene expression is tissue specific in chickens. Dridi, S., Taouis, M., Gertler, A., Decuypere, E., Buyse, J. J. Endocrinol. (2007) [Pubmed]
  7. Aberrant mitosis in fission yeast mutants defective in fatty acid synthetase and acetyl CoA carboxylase. Saitoh, S., Takahashi, K., Nabeshima, K., Yamashita, Y., Nakaseko, Y., Hirata, A., Yanagida, M. J. Cell Biol. (1996) [Pubmed]
  8. Saccharomyces cerevisiae contains four fatty acid activation (FAA) genes: an assessment of their role in regulating protein N-myristoylation and cellular lipid metabolism. Johnson, D.R., Knoll, L.J., Levin, D.E., Gordon, J.I. J. Cell Biol. (1994) [Pubmed]
  9. Inhibition of fatty acid synthase (FAS) suppresses HER2/neu (erbB-2) oncogene overexpression in cancer cells. Menendez, J.A., Vellon, L., Mehmi, I., Oza, B.P., Ropero, S., Colomer, R., Lupu, R. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  10. Cerulenin inhibits the cytotoxicity of ricin, modeccin, Pseudomonas toxin, and diphtheria toxin in brefeldin A-resistant cell lines. Oda, T., Wu, H.C. J. Biol. Chem. (1993) [Pubmed]
  11. Intrinsic resistance to inhibitors of fatty acid biosynthesis in Pseudomonas aeruginosa is due to efflux: application of a novel technique for generation of unmarked chromosomal mutations for the study of efflux systems. Schweizer, H.P. Antimicrob. Agents Chemother. (1998) [Pubmed]
  12. Inhibition of Vibrio harveyi bioluminescence by cerulenin: in vivo evidence for covalent modification of the reductase enzyme involved in aldehyde synthesis. Byers, D.M., Meighen, E.A. J. Bacteriol. (1989) [Pubmed]
  13. Export of extracellular levansucrase by Bacillus subtilis: inhibition by cerulenin and quinacrine. Caulfield, M.P., Berkeley, R.C., Pepper, E.A., Melling, J. J. Bacteriol. (1979) [Pubmed]
  14. Effect of cerulenin on cellular autolytic activity and lipid metabolism during inhibition of protein synthesis in Streptococcus faecalis. Carson, D.D., Pieringer, R.A., Daneo-Moore, L. J. Bacteriol. (1981) [Pubmed]
  15. The fabJ-encoded beta-ketoacyl-[acyl carrier protein] synthase IV from Escherichia coli is sensitive to cerulenin and specific for short-chain substrates. Siggaard-Andersen, M., Wissenbach, M., Chuck, J.A., Svendsen, I., Olsen, J.G., von Wettstein-Knowles, P. Proc. Natl. Acad. Sci. U.S.A. (1994) [Pubmed]
  16. Key role of mitochondria in cerulenin-mediated apoptosis. Heiligtag, S.J., Bredehorst, R., David, K.A. Cell Death Differ. (2002) [Pubmed]
  17. Pharmacological inhibition of fatty acid synthase activity produces both cytostatic and cytotoxic effects modulated by p53. Li, J.N., Gorospe, M., Chrest, F.J., Kumaravel, T.S., Evans, M.K., Han, W.F., Pizer, E.S. Cancer Res. (2001) [Pubmed]
  18. Pharmacological inhibitors of mammalian fatty acid synthase suppress DNA replication and induce apoptosis in tumor cell lines. Pizer, E.S., Chrest, F.J., DiGiuseppe, J.A., Han, W.F. Cancer Res. (1998) [Pubmed]
  19. Fatty acid synthase (FAS): a target for cytotoxic antimetabolites in HL60 promyelocytic leukemia cells. Pizer, E.S., Wood, F.D., Pasternack, G.R., Kuhajda, F.P. Cancer Res. (1996) [Pubmed]
  20. Fatty acid synthesis: a potential selective target for antineoplastic therapy. Kuhajda, F.P., Jenner, K., Wood, F.D., Hennigar, R.A., Jacobs, L.B., Dick, J.D., Pasternack, G.R. Proc. Natl. Acad. Sci. U.S.A. (1994) [Pubmed]
  21. The effects of cerulenin, an inhibitor of protein acylation, on the two phases of glucose-stimulated insulin secretion. Straub, S.G., Yajima, H., Komatsu, M., Aizawa, T., Sharp, G.W. Diabetes (2002) [Pubmed]
  22. Identification and substrate specificity of beta -ketoacyl (acyl carrier protein) synthase III (mtFabH) from Mycobacterium tuberculosis. Choi, K.H., Kremer, L., Besra, G.S., Rock, C.O. J. Biol. Chem. (2000) [Pubmed]
  23. Complementation of Saccharomyces cerevisiae strains containing fatty acid activation gene (FAA) deletions with a mammalian acyl-CoA synthetase. Knoll, L.J., Johnson, D.R., Gordon, J.I. J. Biol. Chem. (1995) [Pubmed]
  24. Disruption of the Saccharomyces cerevisiae FAT1 gene decreases very long-chain fatty acyl-CoA synthetase activity and elevates intracellular very long-chain fatty acid concentrations. Watkins, P.A., Lu, J.F., Steinberg, S.J., Gould, S.J., Smith, K.D., Braiterman, L.T. J. Biol. Chem. (1998) [Pubmed]
  25. YMR313c/TGL3 encodes a novel triacylglycerol lipase located in lipid particles of Saccharomyces cerevisiae. Athenstaedt, K., Daum, G. J. Biol. Chem. (2003) [Pubmed]
  26. YAP1 confers resistance to the fatty acid synthase inhibitor cerulenin through the transporter Flr1p in Saccharomyces cerevisiae. Oskouian, B., Saba, J.D. Mol. Gen. Genet. (1999) [Pubmed]
  27. A new function of isonitrile as an inhibitor of the Pdr5p multidrug ABC transporter in Saccharomyces cerevisiae. Yamamoto, S., Hiraga, K., Abiko, A., Hamanaka, N., Oda, K. Biochem. Biophys. Res. Commun. (2005) [Pubmed]
  28. Novel signaling molecules implicated in tumor-associated fatty acid synthase-dependent breast cancer cell proliferation and survival: Role of exogenous dietary fatty acids, p53-p21WAF1/CIP1, ERK1/2 MAPK, p27KIP1, BRCA1, and NF-kappaB. Menendez, J.A., Mehmi, I., Atlas, E., Colomer, R., Lupu, R. Int. J. Oncol. (2004) [Pubmed]
  29. Carnitine palmitoyltransferase-1 (CPT-1) activity stimulation by cerulenin via sympathetic nervous system activation overrides cerulenin's peripheral effect. Jin, Y.J., Li, S.Z., Zhao, Z.S., An, J.J., Kim, R.Y., Kim, Y.M., Baik, J.H., Lim, S.K. Endocrinology (2004) [Pubmed]
  30. Ia-associated invariant chain is fatty acylated before addition of sialic acid. Koch, N., Hämmerling, G.J. Biochemistry (1985) [Pubmed]
  31. Synthesis of Semliki Forest virus RNA requires continuous lipid synthesis. Perez, L., Guinea, R., Carrasco, L. Virology (1991) [Pubmed]
  32. Morphological effect of cerulenin treatment on Streptococcus faecalis as studied by ultrastructure reconstruction. Higgins, M.L., Carson, D.D., Daneo-Moore, L. J. Bacteriol. (1980) [Pubmed]
  33. In vitro inhibition of HIV-1 proteinase by cerulenin. Moelling, K., Schulze, T., Knoop, M.T., Kay, J., Jupp, R., Nicolaou, G., Pearl, L.H. FEBS Lett. (1990) [Pubmed]
 
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