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Chemical Compound Review

Squalestatin     (1R,2S,3S,5S,6R,7R)-5- [(4S,5R)-4-acetyloxy...

Synonyms: squalestatin 1, zaragozic acid, CHEMBL280978, SureCN408941, CHEBI:75170, ...
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Disease relevance of Squalestatin

  • RESULTS: Continuous squalestatin infusion (15 micrograms/h) decreased C7 alpha H specific activities to 4% and 12% of paired biliary fistula controls at 24 and 48 hours, respectively (P < 0.05) without any changes in S27H specific activities (82% and 95% of controls) [1].
  • They inhibited cholesterol synthesis in Hep G2 cells, and zaragozic acid A was an inhibitor of acute hepatic cholesterol synthesis in the mouse (50% inhibitory dose of 200 micrograms/kg of body weight) [2].
  • To verify whether cholesterol synthesis was required for the induction of hsp70 by OxLDL, squalestatin I (25 nM to 100 nM), an inhibitor of squalene synthase, another key enzyme of the cholesterol pathway, was used: OxLDL toxicity and hsp70 expression were not affected by this compound [3].

High impact information on Squalestatin


Biological context of Squalestatin


Anatomical context of Squalestatin


Associations of Squalestatin with other chemical compounds


Gene context of Squalestatin


Analytical, diagnostic and therapeutic context of Squalestatin

  • METHODS: Expression and activity of LDLR were assessed by RT-PCR and LDL entry, in the absence or presence of squalestatin or 25-hydroxycholesterol that up- or down-regulates LDLR expression, respectively [16].
  • PCR primers designed to selectively amplify the unique C-methyltransferase domain of fungal polyketide synthases were used to selectively clone a polyketide synthase gene involved in the biosynthesis of the squalene synthase inhibitor squalestatin S1 , heterologous expression of which led to the biosynthesis of the squalestatin side-chain [18].
  • Quantitative analysis of these FPP-derived dicarboxylic acids by gas-liquid chromatography revealed that approximately 11 mg of total dicarboxylic acids is excreted per day into the urine of a mouse after 3 days of treatment with zaragozic acid A [17].
  • Immunoblots were used to determine the effects of simvastatin or squalestatin on the distribution of the PAF receptor and an enzyme linked immunoassay was used to quantify the amounts of PAF receptor [19].


  1. Quantitative estimations of the contribution of different bile acid pathways to total bile acid synthesis in the rat. Vlahcevic, Z.R., Stravitz, R.T., Heuman, D.M., Hylemon, P.B., Pandak, W.M. Gastroenterology (1997) [Pubmed]
  2. Zaragozic acids: a family of fungal metabolites that are picomolar competitive inhibitors of squalene synthase. Bergstrom, J.D., Kurtz, M.M., Rew, D.J., Amend, A.M., Karkas, J.D., Bostedor, R.G., Bansal, V.S., Dufresne, C., VanMiddlesworth, F.L., Hensens, O.D. Proc. Natl. Acad. Sci. U.S.A. (1993) [Pubmed]
  3. Simvastatin modulates the heat shock response and cytotoxicity mediated by oxidized LDL in cultured human endothelial smooth muscle cells. Pirillo, A., Jacoviello, C., Longoni, C., Radaelli, A., Catapano, A.L. Biochem. Biophys. Res. Commun. (1997) [Pubmed]
  4. Manipulation of isoprenoid biosynthesis as a possible therapeutic option in mevalonate kinase deficiency. Schneiders, M.S., Houten, S.M., Turkenburg, M., Wanders, R.J., Waterham, H.R. Arthritis Rheum. (2006) [Pubmed]
  5. Squalestatin cures prion-infected neurons and protects against prion neurotoxicity. Bate, C., Salmona, M., Diomede, L., Williams, A. J. Biol. Chem. (2004) [Pubmed]
  6. Inhibition of mammalian squalene synthetase activity by zaragozic acid A is a result of competitive inhibition followed by mechanism-based irreversible inactivation. Lindsey, S., Harwood, H.J. J. Biol. Chem. (1995) [Pubmed]
  7. Squalestatin 1-inducible expression of rat CYP2B: evidence that an endogenous isoprenoid is an activator of the constitutive androstane receptor. Kocarek, T.A., Mercer-Haines, N.A. Mol. Pharmacol. (2002) [Pubmed]
  8. Inhibition of cholesterol production but not of nonsterol isoprenoid products induces neuronal cell death. Michikawa, M., Yanagisawa, K. J. Neurochem. (1999) [Pubmed]
  9. Compensatory responses to inhibition of hepatic squalene synthase. Lopez, D., Chambers, C.M., Keller, R.K., Ness, G.C. Arch. Biochem. Biophys. (1998) [Pubmed]
  10. Peroxisome proliferators and fatty acids negatively regulate liver X receptor-mediated activity and sterol biosynthesis. Johnson, T.E., Ledwith, B.J. J. Steroid Biochem. Mol. Biol. (2001) [Pubmed]
  11. Effect of squalene synthase inhibition on the expression of hepatic cholesterol biosynthetic enzymes, LDL receptor, and cholesterol 7 alpha hydroxylase. Ness, G.C., Zhao, Z., Keller, R.K. Arch. Biochem. Biophys. (1994) [Pubmed]
  12. Squalestatin 1, a potent inhibitor of squalene synthase, which lowers serum cholesterol in vivo. Baxter, A., Fitzgerald, B.J., Hutson, J.L., McCarthy, A.D., Motteram, J.M., Ross, B.C., Sapra, M., Snowden, M.A., Watson, N.S., Williams, R.J. J. Biol. Chem. (1992) [Pubmed]
  13. Regulation of rat hepatic cytochrome P450 expression by sterol biosynthesis inhibition: inhibitors of squalene synthase are potent inducers of CYP2B expression in primary cultured rat hepatocytes and rat liver. Kocarek, T.A., Kraniak, J.M., Reddy, A.B. Mol. Pharmacol. (1998) [Pubmed]
  14. J-104,871, a novel farnesyltransferase inhibitor, blocks Ras farnesylation in vivo in a farnesyl pyrophosphate-competitive manner. Yonemoto, M., Satoh, T., Arakawa, H., Suzuki-Takahashi, I., Monden, Y., Kodera, T., Tanaka, K., Aoyama, T., Iwasawa, Y., Kamei, T., Nishimura, S., Tomimoto, K. Mol. Pharmacol. (1998) [Pubmed]
  15. Regulation of cholesterol 7 alpha-hydroxylase expression by sterols in primary rat hepatocyte cultures. Doerner, K.C., Gurley, E.C., Vlahcevic, Z.R., Hylemon, P.B. J. Lipid Res. (1995) [Pubmed]
  16. The low-density lipoprotein receptor plays a role in the infection of primary human hepatocytes by hepatitis C virus. Molina, S., Castet, V., Fournier-Wirth, C., Pichard-Garcia, L., Avner, R., Harats, D., Roitelman, J., Barbaras, R., Graber, P., Ghersa, P., Smolarsky, M., Funaro, A., Malavasi, F., Larrey, D., Coste, J., Fabre, J.M., Sa-Cunha, A., Maurel, P. J. Hepatol. (2007) [Pubmed]
  17. Massive production of farnesol-derived dicarboxylic acids in mice treated with the squalene synthase inhibitor zaragozic acid A. Vaidya, S., Bostedor, R., Kurtz, M.M., Bergstrom, J.D., Bansal, V.S. Arch. Biochem. Biophys. (1998) [Pubmed]
  18. Rapid cloning and expression of a fungal polyketide synthase gene involved in squalestatin biosynthesis. Cox, R.J., Glod, F., Hurley, D., Lazarus, C.M., Nicholson, T.P., Rudd, B.A., Simpson, T.J., Wilkinson, B., Zhang, Y. Chem. Commun. (Camb.) (2004) [Pubmed]
  19. Cholesterol synthesis inhibitors protect against platelet-activating factor-induced neuronal damage. Bate, C., Rumbold, L., Williams, A. Journal of neuroinflammation (2007) [Pubmed]
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