Zaragozic acid

Zaragozic acid A
Names
	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
Identifiers
CAS Number	142561-96-4 ;
3D model (JSmol)	Interactive image;
ChEBI	CHEBI:75170 ;
ChEMBL	ChEMBL40991 ;
ChemSpider	4942838 ;
IUPHAR/BPS	3057;
PubChem CID	6438355;
UNII	1117HVX02L ;
	InChI InChI=1S/C35H46O14/c1-7-19(2)17-20(3)13-14-25(37)47-28-27(38)33(48-29(30(39)40)34(45,31(41)42)35(28,49-33)32(43)44)16-15-21(4)26(46-23(6)36)22(5)18-24-11-9-8-10-12-24/h8-14,19-20,22,26-29,38,45H,4,7,15-18H2,1-3,5-6H3,(H,39,40)(H,41,42)(H,43,44)/b14-13+/t19-,20+,22+,26+,27+,28+,29+,33-,34+,35-/m0/s1 Key: DFKDOZMCHOGOBR-NCSQYGPNSA-N ; InChI=1/C35H46O14/c1-7-19(2)17-20(3)13-14-25(37)47-28-27(38)33(48-29(30(39)40)34(45,31(41)42)35(28,49-33)32(43)44)16-15-21(4)26(46-23(6)36)22(5)18-24-11-9-8-10-12-24/h8-14,19-20,22,26-29,38,45H,4,7,15-18H2,1-3,5-6H3,(H,39,40)(H,41,42)(H,43,44)/b14-13+/t19-,20+,22+,26+,27+,28+,29+,33-,34+,35-/m0/s1 Key: DFKDOZMCHOGOBR-NCSQYGPNBY;
	SMILES CC[C@H](C)C[C@H](C)/C=C/C(=O)O[C@@H]1[C@H]([C@]2(O[C@@H]([C@]([C@@]1(O2)C(=O)O)(C(=O)O)O)C(=O)O)CCC(=C)[C@H]([C@H](C)CC3=CC=CC=C3)OC(=O)C)O;
Properties
Chemical formula	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). verify (what is ?) 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

Bergstrom JD, Kurtz MM, Rew DJ, Amend AM, Karkas JD, Bostedor RG, Bansal VS, Dufresne C, VanMiddlesworth FL, Hensens OD (January 1993). "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. doi:10.1073/pnas.90.1.80. PMC 45603. PMID 8419946.
Bergstrom JD, Dufresne C, Bills GF, Nallin-Omstead M, Byrne K (1995). "Discovery, biosynthesis, and mechanism of action of the zaragozic acids: potent inhibitors of squalene synthase". Annu. Rev. Microbiol. 49: 607–39. doi:10.1146/annurev.mi.49.100195.003135. PMID 8561474.
Do R, Kiss RS, Gaudet D, Engert JC (January 2009). "Squalene synthase: a critical enzyme in the cholesterol biosynthesis pathway". Clin. Genet. 75 (1): 19–29. doi:10.1111/j.1399-0004.2008.01099.x. PMID 19054015. S2CID 205406994.
Ness GC, Zhao Z, Keller RK (June 1994). "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. doi:10.1006/abbi.1994.1238. PMID 7911291.
Dufresne C, Wilson KE, Singh SB, Zink DL, Bergstrom JD, Rew D, Polishook JD, Meinz M, Huang L, Silverman KC (November 1993). "Zaragozic acids D and D2: potent inhibitors of squalene synthase and of Ras farnesyl-protein transferase". J. Nat. Prod. 56 (11): 1923–9. doi:10.1021/np50101a009. PMID 8289063.
Chen TS, Petuch B, MacConnell J, White R, Dezeny G, Arison B, Bergstrom JD, Colwell L, Huang L, Monaghan RL (November 1994). "The preparation of zaragozic acid A analogues by directed biosynthesis". J Antibiot (Tokyo). 47 (11): 1290–4. doi:10.7164/antibiotics.47.1290. PMID 8002393.

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[pmid8419946-1] Bergstrom JD, Kurtz MM, Rew DJ, Amend AM, Karkas JD, Bostedor RG, Bansal VS, Dufresne C, VanMiddlesworth FL, Hensens OD (January 1993). "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. doi:10.1073/pnas.90.1.80. PMC 45603. PMID 8419946.

[pmid8561474-2] Bergstrom JD, Dufresne C, Bills GF, Nallin-Omstead M, Byrne K (1995). "Discovery, biosynthesis, and mechanism of action of the zaragozic acids: potent inhibitors of squalene synthase". Annu. Rev. Microbiol. 49: 607–39. doi:10.1146/annurev.mi.49.100195.003135. PMID 8561474.

[pmid19054015-3] Do R, Kiss RS, Gaudet D, Engert JC (January 2009). "Squalene synthase: a critical enzyme in the cholesterol biosynthesis pathway". Clin. Genet. 75 (1): 19–29. doi:10.1111/j.1399-0004.2008.01099.x. PMID 19054015. S2CID 205406994.

[pmid7911291-4] Ness GC, Zhao Z, Keller RK (June 1994). "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. doi:10.1006/abbi.1994.1238. PMID 7911291.

[pmid8289063-5] Dufresne C, Wilson KE, Singh SB, Zink DL, Bergstrom JD, Rew D, Polishook JD, Meinz M, Huang L, Silverman KC (November 1993). "Zaragozic acids D and D2: potent inhibitors of squalene synthase and of Ras farnesyl-protein transferase". J. Nat. Prod. 56 (11): 1923–9. doi:10.1021/np50101a009. PMID 8289063.

[6] Chen TS, Petuch B, MacConnell J, White R, Dezeny G, Arison B, Bergstrom JD, Colwell L, Huang L, Monaghan RL (November 1994). "The preparation of zaragozic acid A analogues by directed biosynthesis". J Antibiot (Tokyo). 47 (11): 1290–4. doi:10.7164/antibiotics.47.1290. PMID 8002393.