Chemistry:Zaragozic acid
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| Preferred IUPAC name
(1S,3S,4S,5R,6R,7R)-1-[(4S,5R)-4-(Acetyloxy)-5-methyl-3-methylidene-6-phenylhexyl]-6-{[(2E,4S,6S)-4,6-dimethyloct-2-enoyl]oxy}-4,7-dihydroxy-2,8-dioxabicyclo[3.2.1]octane-3,4,5-tricarboxylic acid | |
| Other names
Squalestatin 1
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| Identifiers | |
3D model (JSmol)
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PubChem CID
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| Properties | |
| C35H46O14 | |
| Molar mass | 690.73134 |
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa). | |
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| Infobox references | |
Zaragozic acids are a family of natural products produced by fungi. The first characterized zaragozic acids, A, B, and C were isolated from an unidentified sterile fungal culture, Sporormiella intermedia, and L. elatius, respectively.[1] just outside the European city Zaragoza, Spain on the Jalón river. This family of natural products possesses a unique 4,8-dioxabicyclo[3.2.1]octane core, and vary in their 1-alkyl and their 6-acyl side chains.[2]
Uses
Zaragozic acids are potent inhibitors of S. cervisiae, fungal and mammalian squalene synthase and therefore inhibitors of sterol synthesis.[2] Squalene synthase is the first committed enzyme in sterol synthesis, catalyzing the reductive condensation of farnesyl pyrophosphate to form squalene.[3] As a squalene synthase inhibitor, zaragozic acid produces lower plasma cholesterol levels in primates.[2] Treatment of rats with zaragozic acid A caused an increase in hepatic low density lipoprotein (LDL) receptor mRNA levels.[4]
Zaragozic acids also mildly inhibit Ras farnesyl-protein transferase.[5]
Zaragozic acid D and D2 have been isolated from the keratinophilic fungus Amauroascus niger.[5]
Biosynthesis
The core biosynthetic route is via a polyketide synthase pathway from 10 acetates, 4 methyls of methionines, 1 succinate, and 1 benzoic acid.[6]
References
- ↑ "Zaragozic acids: a family of fungal metabolites that are picomolar competitive inhibitors of squalene synthase". Proc. Natl. Acad. Sci. U.S.A. 90 (1): 80–4. January 1993. doi:10.1073/pnas.90.1.80. PMID 8419946.
- ↑ 2.0 2.1 2.2 "Discovery, biosynthesis, and mechanism of action of the zaragozic acids: potent inhibitors of squalene synthase". Annu. Rev. Microbiol. 49: 607–39. 1995. doi:10.1146/annurev.mi.49.100195.003135. PMID 8561474.
- ↑ "Squalene synthase: a critical enzyme in the cholesterol biosynthesis pathway". Clin. Genet. 75 (1): 19–29. January 2009. doi:10.1111/j.1399-0004.2008.01099.x. PMID 19054015.
- ↑ "Effect of squalene synthase inhibition on the expression of hepatic cholesterol biosynthetic enzymes, LDL receptor, and cholesterol 7 alpha hydroxylase". Arch. Biochem. Biophys. 311 (2): 277–85. June 1994. doi:10.1006/abbi.1994.1238. PMID 7911291.
- ↑ 5.0 5.1 "Zaragozic acids D and D2: potent inhibitors of squalene synthase and of Ras farnesyl-protein transferase". J. Nat. Prod. 56 (11): 1923–9. November 1993. doi:10.1021/np50101a009. PMID 8289063.
- ↑ "The preparation of zaragozic acid A analogues by directed biosynthesis". J Antibiot (Tokyo) 47 (11): 1290–4. November 1994. doi:10.7164/antibiotics.47.1290. PMID 8002393.
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