1di1

Structural highlights

Function

PRX2_PENRO Aristolochene synthase; part of the gene cluster that mediates the biosynthesis of PR-toxin, a bicyclic sesquiterpene belonging to the eremophilane class and acting as a mycotoxin (PubMed:24239699, PubMed:27921136). The first step of the pathway is catalyzed by the aristolochene synthase which performs the cyclization of trans,trans-farnesyl diphosphate (FPP) to the bicyclic sesquiterpene aristolochene (PubMed:8440737, PubMed:15186158, PubMed:24239699). Following the formation of aristolochene, the non-oxygenated aristolochene is converted to the trioxygenated intermediate eremofortin B, via 7-epi-neopetasone (PubMed:24239699, PubMed:26274339). This conversion appears to involve three enzymes, a hydroxysterol oxidase-like enzyme, the quinone-oxidase prx3 that forms the quinone-type-structure in the bicyclic nucleus of aristolochene with the C8-oxo group and the C-3 hydroxyl group, and the P450 monooxygenase ORF6 that introduces the epoxide at the double bond between carbons 1 and 2 (PubMed:24239699, PubMed:27921136). No monoxy or dioxy-intermediates have been reported to be released to the broth, so these three early oxidative reactions may be coupled together (PubMed:24239699). Eremofortin B is further oxidized by another P450 monooxygenase, that introduces a second epoxide between carbons 7 and 11 prior to acetylation to eremofortin A by the acetyltransferase ORF8 (PubMed:16345540, PubMed:24239699, PubMed:27921136). The second epoxidation may be performed by a second P450 monooxygenase (PubMed:24239699). After the acetylation step, the conversion of eremofortin A to eremofortin C and then to PR-toxin requires only two enzymes (PubMed:24239699). First the conversion of eremofortin A to eremofortin C proceeds by oxidation of the side chain of the molecule at C-12 and is catalyzed by the short-chain oxidoreductase prx1 (PubMed:16345540, PubMed:24239699). The cytochrome P450 monooxygenase ORF5 also plays a role in this step (PubMed:27921136). The primary alcohol formed at C-12 is finally oxidized by the short-chain alcohol dehydrogenase prx4 that forms PR-toxin (PubMed:16345540, PubMed:24239699).^{[1] [2] [3] [4] [5] [6]}

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

References

1. ↑ Felicetti B, Cane DE. Aristolochene synthase: mechanistic analysis of active site residues by site-directed mutagenesis. J Am Chem Soc. 2004 Jun 16;126(23):7212-21. PMID:15186158 doi:10.1021/ja0499593
2. ↑ Moreau S, Lablache-Combier A, Biguet J. Production of Eremofortins A, B, and C Relative to Formation of PR Toxin by Penicillium roqueforti. Appl Environ Microbiol. 1980 Apr;39(4):770-6. PMID:16345540 doi:10.1128/aem.39.4.770-776.1980
3. ↑ Hidalgo PI, Ullán RV, Albillos SM, Montero O, Fernández-Bodega MÁ, García-Estrada C, Fernández-Aguado M, Martín JF. Molecular characterization of the PR-toxin gene cluster in Penicillium roqueforti and Penicillium chrysogenum: cross talk of secondary metabolite pathways. Fungal Genet Biol. 2014 Jan;62:11-24. PMID:24239699 doi:10.1016/j.fgb.2013.10.009
4. ↑ Riclea R, Dickschat JS. Identification of intermediates in the biosynthesis of PR toxin by Penicillium roqueforti. Angew Chem Int Ed Engl. 2015 Oct 5;54(41):12167-70. PMID:26274339 doi:10.1002/anie.201506128
5. ↑ Hidalgo PI, Poirier E, Ullán RV, Piqueras J, Meslet-Cladière L, Coton E, Coton M. Penicillium roqueforti PR toxin gene cluster characterization. Appl Microbiol Biotechnol. 2017 Mar;101(5):2043-2056. PMID:27921136 doi:10.1007/s00253-016-7995-5
6. ↑ Proctor RH, Hohn TM. Aristolochene synthase. Isolation, characterization, and bacterial expression of a sesquiterpenoid biosynthetic gene (Ari1) from Penicillium roqueforti. J Biol Chem. 1993 Feb 25;268(6):4543-8. PMID:8440737