{{chembox | Verifiedfields = changed | Watchedfields = changed | verifiedrevid = 457152393 | ImageFile=Aristolochene.png | ImageSize=200px | IUPACName=7α-Eremophila-9,11-diene | SystematicName=(4''S'',4a''R'',6''S'')-4,4a-Dimethyl-6-(prop-1-en-2-yl)-1,2,3,4,4a,5,6,7-octahydronaphthalene | OtherNames=(+)-Aristolochene |Section1={{Chembox Identifiers | CASNo_Ref = {{cascite|changed|??}} | CASNo=123408-96-8 | UNII_Ref = {{fdacite|correct|FDA}} | UNII = 459BG6ZY5H | ChEBI_Ref = {{ebicite|correct|EBI}} | ChEBI = 43445 | PubChem=656496 | SMILES=C[C@H]1CCCC2=CC[C@@H](C[C@]12C)C(=C)C | ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} | ChemSpiderID = 570881 | InChI = 1/C15H24/c1-11(2)13-8-9-14-7-5-6-12(3)15(14,4)10-13/h9,12-13H,1,5-8,10H2,2-4H3/t12-,13-,15+/m0/s1 | InChIKey = YONHOSLUBQJXPR-KCQAQPDRBL | StdInChI_Ref = {{stdinchicite|correct|chemspider}} | StdInChI = 1S/C15H24/c1-11(2)13-8-9-14-7-5-6-12(3)15(14,4)10-13/h9,12-13H,1,5-8,10H2,2-4H3/t12-,13-,15+/m0/s1 | StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} | StdInChIKey = YONHOSLUBQJXPR-KCQAQPDRSA-N }} |Section2={{Chembox Properties | C=15 | H=24 | Appearance= | Density=0.894 g/mL | MeltingPt= | BoilingPt= | Solubility= }} |Section3={{Chembox Hazards | MainHazards= | FlashPt= | AutoignitionPt = }} }}
'''Aristolochene''' is a bicyclic sesquiterpene produced by certain fungi, most notably the cheese mold ''Penicillium roqueforti''. It is biosynthesized from farnesyl pyrophosphate by the enzyme aristolochene synthase and serves as the parent hydrocarbon for a variety of fungal toxins.<ref>[http://www.pharmacy.arizona.edu/faculty/moorelab/classes/chem549/terpenes.pdf Terpene Biosynthesis] {{webarchive |url=https://web.archive.org/web/20070225231653/http://www.pharmacy.arizona.edu/faculty/moorelab/classes/chem549/terpenes.pdf |date=February 25, 2007 }}, Chem 549, College of Pharmacy, University of Arizona</ref>
== Discovery ==
Aristolochene was first isolated and structurally characterized in 1969 from the roots of ''Aristolochia indica'' by Govindachari, Mohamed, and Parthasarathy.<ref>Govindachari, T. R., P. A. Mohamed, and P. C. Parthasarathy. "Ishwarane and Aristolochene, Two New Sesquiterpene Hydrocarbons from Aristolochia indica." Tetrahedron, vol. 26, 1970, pp. 615–619. </ref> However, this discovery involved the (−)-enantiomeric form, not the bioactive (+)-enantiomer characteristic of fungal biosynthetic pathways. The (+)-enantiomer was later identified and experimentally confirmed in ''Penicillium roqueforti'' through studies centered around aristolochene synthase activity and the ''ari1'' locus which encodes the enzyme.<ref>Hohn, Thomas M., and Ronald D. Plattner. "Purification and Characterization of the Sesquiterpene Cyclase Aristolochene Synthase from Penicillium roqueforti." Archives of Biochemistry and Biophysics, vol. 272, no. 1, 1989, pp. 137–143.</ref><ref name="pmid8440737">{{cite journal|vauthors=Proctor RH, Hohn TM |title=Aristolochene synthase. Isolation, characterization, and bacterial expression of a sesquiterpenoid biosynthetic gene (Ari1) from ''Penicillium roqueforti'' |journal=J. Biol. Chem. |volume=268 |issue=6 |pages=4543–8 |date=February 1993 |doi=10.1016/S0021-9258(18)53644-9 |pmid=8440737 |doi-access=free }}</ref>
thumb|250px|Aristolochene enantiomers
== Applications ==
Aristolochene is primarily recognized as the precursor to PR toxin, a mycotoxin produced in large quantities by ''Penicillium roqueforti''. PR toxin has been implicated in incidents of mycotoxicoses resulting from consumption of contaminated grains;<ref name="pmid7080052">{{cite journal |vauthors=Chen FC, Chen CF, Wei RD |title=Acute toxicity of PR toxin, a mycotoxin from ''Penicillium roqueforti'' |journal=Toxicon |volume=20 |issue=2 |pages=433–41 |year=1982 |pmid=7080052 |doi= 10.1016/0041-0101(82)90006-X|bibcode=1982Txcn...20..433C }}</ref> moreover, strains of ''Penicillium roqueforti'' are frequently used in commercial blue cheese production. Common blue cheese products include, Roquefort, Danish Blue, Stilton cheese, and Gorgonzola.
In addition to PR toxin, aristolochene is a biosynthetic precursor to eremofortins (A-C), a group of metabolites that function as canonical upstream intermediates in the PR toxin biosynthetic pathway.<ref>{{cite journal |title= Eremofortin C, a new metabolite obtained from ''Penicillium roqueforti'' cultures and from biotransformation of PR toxin |first1= Serge |last1= Moreau |first2= Monique |last2= Cacan |first3= Alain |last3= Lablache-Combier |journal= J. Org. Chem. |year= 1997 |volume= 42 |issue= 15 |pages= 2632–2634 |doi= 10.1021/jo00435a023 |pmid= 874620 }}</ref><ref>{{cite journal |last1=Hidalgo |first1=Pedro I. |title=Molecular characterization of the PR-toxin gene cluster in Penicillium roqueforti and Penicillium chrysogenum: Cross talk of secondary metabolite pathways |journal=Fungal Genetics and Biology |volume=56 |year=2014 |pages=69–78 |doi=10.1016/j.fgb.2013.10.009 |pmid=24239699 }}</ref><ref>{{cite journal | last1 = Riclea | first1 = Ramona | last2 = Dickschat | first2 = Jeroen S. | title = Identification of Intermediates in the Biosynthesis of PR Toxin by ''Penicillium roqueforti'' | journal = Angewandte Chemie International Edition | date = 2015 | volume = 54 | issue = 41 | pages = 12167–12170 | doi = 10.1002/anie.201506128 | pmid = 26274339 | bibcode = 2015ACIE...5412167R }}</ref><ref>Dubey, Manish K., et al. "PR toxin–biosynthesis, genetic regulation, toxicological potential, prevention and control measures: overview and challenges." Frontiers in Pharmacology 9 (2018): 288. </ref> Variation in their expression can influence host-organism metabolism and modulate interactions with the surrounding environment.<ref>{{cite journal | last1 = Rojas-Aedo | first1 = Juan F. | last2 = Gil-Durán | first2 = Carlos | last3 = Goity | first3 = Alejandra | last4 = Vaca | first4 = Inmaculada | last5 = Levicán | first5 = Gloria | last6 = Larrondo | first6 = Luis F. | last7 = Chávez | first7 = Renato | title = The developmental regulator Pcz1 affects the production of secondary metabolites in the filamentous fungus Penicillium roqueforti | journal = Microbiological Research | date = 2018 | volume = 212-213 | pages = 67–74 | doi = 10.1016/j.micres.2018.05.005 | pmid = 29853169 | url = http://repositorio.uchile.cl/handle/2250/152897 }}</ref>
The influence of aristolochene on fungal metabolic regulation is an evolving area of research. Its role as an upstream precursor has relevance towards food safety, natural product chemistry, and pharmaceutical development.
== Biosynthesis and enzymatic mechanism ==
The natural biosynthetic pathway of aristolochene in ''Penicillium roqueforti'' begins with farnesyl pyrophosphate, a 15-C substrate. Aristolochene synthase catalyzes two sequential cyclization steps in this reaction and is considered the rate-limiting enzyme in both this pathway and the downstream production of PR toxin. The enzyme active site of aristolochene synthase features highly conserved aspartate residues which chelate three divalent Mg²⁺ metal ions per reaction. These metal ions serve two key functions: (1) they coordinate with the pyrophosphate moiety of farnesyl pyrophosphate via Lewis acid-base interactions (2) they establish and maintain the necessary electrostatic environment for carbocation formation within the active site.<ref>Chen, Mengbin, et al. "Probing the role of active site water in the sesquiterpene cyclization reaction catalyzed by aristolochene synthase." Biochemistry 55.20 (2016): 2864-2874. </ref><ref>{{cite journal | last1 = Felicetti | first1 = Brunella | last2 = Cane | first2 = David E. | title = Aristolochene Synthase: Mechanistic Analysis of Active Site Residues by Site-Directed Mutagenesis | journal = Journal of the American Chemical Society | date = 2004 | volume = 126 | issue = 23 | pages = 7212–7221 | doi = 10.1021/ja0499593 | pmid = 15186158 | bibcode = 2004JAChS.126.7212F }}</ref>
frameless|center|600px| Enzyme Catalyzed Cyclization of Farnesyl Pyrophosphate to Aristolochene
Upon ionization and loss of the pyrophosphate leaving group, a cationic polyene cyclization reaction is favored and proceeds with configurational inversion at C-15 followed by an intramolecular ring closure to form the 10-membered sesquiterpene hydrocarbon, germacrene A.<ref>{{cite journal | last1 = Rising | first1 = Kathleen A. | last2 = Starks | first2 = Courtney M. | last3 = Noel | first3 = Joseph P. | last4 = Chappell | first4 = Joseph | title = Demonstration of Germacrene a as an Intermediate in 5-Epi-aristolochene Synthase Catalysis | journal = Journal of the American Chemical Society | date = 2000 | volume = 122 | issue = 9 | pages = 1861–1866 | doi = 10.1021/JA993584H | bibcode = 2000JAChS.122.1861R }}</ref>
Subsequent protonation of germacrene A at C-1 of the double bond favors intramolecular electrophilic attack from C-5 of the double bond between C-4 and C-5 onto the C-10 tertiary carbocation to form a dual six-membered ring eudesmane cation. After this stereoselective cyclization, a series of hydride shifts along with a single 1,2-rearrangement forms the stable enantioselective (+)-aristolochene product. A proposed barbed-arrow mechanism for aristolochene synthase's mechanism is depicted above.<ref>Cane, D. E. (1985). Isoprenoid biosynthesis: Stereochemistry of the cyclization of allylic pyrophosphates. Accounts of Chemical Research, 18(7), 220–226. </ref><ref>{{cite journal | last1 = Cane | first1 = David E. | last2 = Prabhakaran | first2 = P. C. | last3 = Salaski | first3 = E. J. | last4 = Harrison | first4 = Paul H. M. | last5 = Noguchi | first5 = Hiroshi | last6 = Rawlings | first6 = Bernard J. | title = Aristolochene biosynthesis and enzymatic cyclization of farnesyl pyrophosphate | journal = Journal of the American Chemical Society | date = 1989 | volume = 111 | issue = 24 | pages = 8914–8916 | doi = 10.1021/ja00206a022 | bibcode = 1989JAChS.111.8914C }}</ref>
== Related compounds == * Roquefortine C * Aflatoxin * Patulin
==References== {{reflist}}
Category:Sesquiterpenes Category:Mycotoxins Category:Bicyclic compounds Category:Hydrocarbons Category:Isopropenyl compounds