zaragozic acid
{{cs1 config|name-list-style=vanc}}
{{chembox
| Verifiedfields = changed
| Watchedfields = changed
| verifiedrevid = 398570534
| Name = Zaragozic acid A
| ImageFile = Zaragozic acid A.svg
| ImageSize = 300
| PIN = (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
| OtherNames = Squalestatin 1
| Section1 = {{Chembox Identifiers
| IUPHAR_ligand = 3057
| CASNo_Ref = {{cascite|correct|??}}
| CASNo=142561-96-4
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = 1117HVX02L
| ChEBI_Ref = {{ebicite|changed|EBI}}
| ChEBI = 75170
| ChEMBL_Ref = {{ebicite|changed|EBI}}
| ChEMBL = 40991
| PubChem = 6438355
| ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}}
| ChemSpiderID = 4942838
| 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
| 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
| InChIKey = DFKDOZMCHOGOBR-NCSQYGPNBY
| StdInChI_Ref = {{stdinchicite|changed|chemspider}}
| StdInChI = 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
| StdInChIKey_Ref = {{stdinchicite|changed|chemspider}}
| StdInChIKey = DFKDOZMCHOGOBR-NCSQYGPNSA-N
}}
| Section2 = {{Chembox Properties
| Formula = C35H46O14
| MolarMass = 690.73134
| Appearance =
| Density =
| MeltingPt =
| BoilingPt =
| Solubility =
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| Section3 = {{Chembox Hazards
| MainHazards =
| FlashPt =
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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.{{cite journal |vauthors=Bergstrom JD, Kurtz MM, Rew DJ, Amend AM, Karkas JD, Bostedor RG, Bansal VS, Dufresne C, VanMiddlesworth FL, Hensens OD | title = Zaragozic acids: a family of fungal metabolites that are picomolar competitive inhibitors of squalene synthase | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 90 | issue = 1 | pages = 80–4 |date=January 1993 | pmid = 8419946 | pmc = 45603 | doi = 10.1073/pnas.90.1.80| doi-access = free | bibcode = 1993PNAS...90...80B }} 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.{{cite journal |vauthors=Bergstrom JD, Dufresne C, Bills GF, Nallin-Omstead M, Byrne K | title = Discovery, biosynthesis, and mechanism of action of the zaragozic acids: potent inhibitors of squalene synthase | journal = Annu. Rev. Microbiol. | volume = 49 | pages = 607–39 | year = 1995 | pmid = 8561474 | doi = 10.1146/annurev.mi.49.100195.003135 }}
Uses
Zaragozic acids are potent inhibitors of S. cerevisiae, fungal and mammalian squalene synthase and therefore inhibitors of sterol synthesis. Squalene synthase is the first committed enzyme in sterol synthesis, catalyzing the reductive condensation of farnesyl pyrophosphate to form squalene.{{cite journal |vauthors=Do R, Kiss RS, Gaudet D, Engert JC | title = Squalene synthase: a critical enzyme in the cholesterol biosynthesis pathway | journal = Clin. Genet. | volume = 75 | issue = 1 | pages = 19–29 |date=January 2009 | pmid = 19054015 | doi = 10.1111/j.1399-0004.2008.01099.x | s2cid = 205406994 }} As a squalene synthase inhibitor, zaragozic acid produces lower plasma cholesterol levels in primates. Treatment of rats with zaragozic acid A caused an increase in hepatic low density lipoprotein (LDL) receptor mRNA levels.{{cite journal |vauthors=Ness GC, Zhao Z, Keller RK | title = Effect of squalene synthase inhibition on the expression of hepatic cholesterol biosynthetic enzymes, LDL receptor, and cholesterol 7 alpha hydroxylase | journal = Arch. Biochem. Biophys. | volume = 311 | issue = 2 | pages = 277–85 |date=June 1994 | pmid = 7911291 | doi = 10.1006/abbi.1994.1238}}
Zaragozic acids also mildly inhibit Ras farnesyl-protein transferase.{{cite journal |vauthors=Dufresne C, Wilson KE, Singh SB, Zink DL, Bergstrom JD, Rew D, Polishook JD, Meinz M, Huang L, Silverman KC | title = Zaragozic acids D and D2: potent inhibitors of squalene synthase and of Ras farnesyl-protein transferase | journal = J. Nat. Prod. | volume = 56 | issue = 11 | pages = 1923–9 |date=November 1993 | pmid = 8289063 | doi = 10.1021/np50101a009}}
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.{{cite journal | journal=J Antibiot (Tokyo) |date=November 1994| volume=47 | issue=11 |pages=1290–4 |title= The preparation of zaragozic acid A analogues by directed biosynthesis |vauthors=Chen TS, Petuch B, MacConnell J, White R, Dezeny G, Arison B, Bergstrom JD, Colwell L, Huang L, Monaghan RL | pmid= 8002393 | doi=10.7164/antibiotics.47.1290| doi-access=free }}