Zaragozic Acid A (CAS 142561-96-4)

Zaragozic Acid A is a squalene synthetase inhibitor and fungal metabolite containing a novel 4,6,7-trihydroxy-2,8-dioxobicyclo[3.2.1]octane-3,4,5-tricarboxylic acid core. Squalene synthase catalyzes the first committed step in cholesterol synthesis, mediating the reductive dimerization of farnesyl pyrophosphate to produce squalene. Zaragozic Acid A is a fungal metabolite that acts as a reversible competitive inhibitor of squalene synthase (Ki = 78 pM in vitro). Zaragozic Acid A dose-dependently reduces cholesterol synthesis in HepG2 cells (IC50 = 6 µM) and inhibits hepatic cholesterol synthesis in mice (ED50 = 0.2 mg/kg). Zaragozic Acid A also inhibits farnesy transferase (FTase) and geranylgeranyl transferase type I (GGTase I) (IC50s = 216 and 50 nM, respectively). Zaragozic Acid A is also known as (1R,2S,3S,5S,6R,7R)-5-[(4S,5R)-4-acetoxy-5-methyl-3-methylene-6-phenylhexyl]-7-[(E,4S,6S)-4,6-dimethyl-1-oxooct-2-enoxy]-2,6-dihydroxy-4,8-dioxabicyclo[3.2.1]octane-1,2,3-tricarboxylic acid, Squalestatin 1, Squalestatin S1, and (7S)-11-acetate 5-[(2E,4S,6S)-4,6-dimethyl-2-octenoate]-2,7-anhydro-3,4-di-C-carboxy-8,9,10,12,13-pentadeoxy-10-methylene-12-(phenylmethyl)-L-erythro-L-glycero-D-altro-7-trideculo-7,4-furanosonic acid.

References:

1. Nitrogen-bisphosphonates block retinoblastoma phosphorylation and cell growth by inhibiting the cholesterol biosynthetic pathway in a keratinocyte model for esophageal irritation.  |  Reszka, AA., et al. 2001. Mol Pharmacol. 59: 193-202. PMID: 11160853
2. The ergosterol biosynthesis inhibitor zaragozic acid promotes vacuolar degradation of the tryptophan permease Tat2p in yeast.  |  Daicho, K., et al. 2007. Biochim Biophys Acta. 1768: 1681-90. PMID: 17531951
3. Inhibition of squalene synthase upregulates PCSK9 expression in rat liver.  |  Bedi, M., et al. 2008. Arch Biochem Biophys. 470: 116-9. PMID: 18054775
4. Statins and the squalene synthase inhibitor zaragozic acid stimulate the non-amyloidogenic pathway of amyloid-beta protein precursor processing by suppression of cholesterol synthesis.  |  Kojro, E., et al. 2010. J Alzheimers Dis. 20: 1215-31. PMID: 20413873
5. Improvement of dolichol-linked oligosaccharide biosynthesis by the squalene synthase inhibitor zaragozic acid.  |  Haeuptle, MA., et al. 2011. J Biol Chem. 286: 6085-91. PMID: 21183681
6. Lovastatin-induced decrease of intracellular cholesterol level attenuates fibroblast-to-myofibroblast transition in bronchial fibroblasts derived from asthmatic patients.  |  Michalik, M., et al. 2013. Eur J Pharmacol. 704: 23-32. PMID: 23485731
7. Identification and Heterologous Production of a Benzoyl-Primed Tricarboxylic Acid Polyketide Intermediate from the Zaragozic Acid A Biosynthetic Pathway.  |  Liu, N., et al. 2017. Org Lett. 19: 3560-3563. PMID: 28605916
8. Metabolic Induction of Trained Immunity through the Mevalonate Pathway.  |  Bekkering, S., et al. 2018. Cell. 172: 135-146.e9. PMID: 29328908
9. Zaragozic acids: a family of fungal metabolites that are picomolar competitive inhibitors of squalene synthase.  |  Bergstrom, JD., et al. 1993. Proc Natl Acad Sci U S A. 90: 80-4. PMID: 8419946
10. Inhibitors of cholesterol biosynthesis increase hepatic low-density lipoprotein receptor protein degradation.  |  Ness, GC., et al. 1996. Arch Biochem Biophys. 325: 242-8. PMID: 8561503
11. Inhibition of squalene synthase but not squalene cyclase prevents mevalonate-mediated suppression of 3-hydroxy-3-methylglutaryl coenzyme A reductase synthesis at a posttranscriptional level.  |  Peffley, DM. and Gayen, AK. 1997. Arch Biochem Biophys. 337: 251-60. PMID: 9016820
12. Distribution Of Zaragozic Acids (Squalestatins) Among Filamentous Ascomycetes  |  Gerald F. Bills, et al. 1994. Mycological Research. 98: 733-739.