Zaragozic acid explained

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.

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]

Notes and References

1. Bergstrom JD, Kurtz MM, Rew DJ, Amend AM, Karkas JD, Bostedor RG, Bansal VS, Dufresne C, VanMiddlesworth FL, Hensens OD . 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 . 8419946 . 45603 . 10.1073/pnas.90.1.80. free . 1993PNAS...90...80B .
2. Bergstrom JD, Dufresne C, Bills GF, Nallin-Omstead M, Byrne K . Discovery, biosynthesis, and mechanism of action of the zaragozic acids: potent inhibitors of squalene synthase . Annu. Rev. Microbiol. . 49 . 607–39 . 1995 . 8561474 . 10.1146/annurev.mi.49.100195.003135 .
3. Do R, Kiss RS, Gaudet D, Engert JC . Squalene synthase: a critical enzyme in the cholesterol biosynthesis pathway . Clin. Genet. . 75 . 1 . 19–29 . January 2009 . 19054015 . 10.1111/j.1399-0004.2008.01099.x . 205406994 .
4. Ness GC, Zhao Z, Keller RK . 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 . 7911291 . 10.1006/abbi.1994.1238.
5. Dufresne C, Wilson KE, Singh SB, Zink DL, Bergstrom JD, Rew D, Polishook JD, Meinz M, Huang L, Silverman KC . 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 . 8289063 . 10.1021/np50101a009.
6. J Antibiot (Tokyo) . November 1994. 47 . 11 . 1290–4 . The preparation of zaragozic acid A analogues by directed biosynthesis . Chen TS, Petuch B, MacConnell J, White R, Dezeny G, Arison B, Bergstrom JD, Colwell L, Huang L, Monaghan RL . 8002393 . 10.7164/antibiotics.47.1290. free .