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Enzymatic synthesis of natural (+)-aristolochene from a non-natural substrate

Author:
Faraldos, Juan A., Grundy, Daniel J., Cascon, Oscar, Leoni, Stefano, van der Kamp, Marc W., Allemann, Rudolf K.
Source:
Chemical communications 2016 v.52 no.97 pp. 14027-14030
ISSN:
1364-548X
Subject:
Penicillium roquefortii, active sites, cations, chemical reactions, germacrene, isomers, mycotoxins, trichodiene synthase
Abstract:
The sesquiterpene cyclase aristolochene synthase from Penicillium roquefortii (PR-AS) has evolved to catalyse with high specificity (92%) the conversion of farnesyl diphosphate (FDP) to the bicyclic hydrocarbon (+)-aristolochene, the natural precursor of several fungal toxins. Here we report that PR-AS converts the unnatural FDP isomer 7-methylene farnesyl diphosphate to (+)-aristolochene via the intermediate 7-methylene germacrene A. Within the confined space of the enzyme's active site, PR-AS stabilises the reactive conformers of germacrene A and 7-methylene germacrene A, respectively, which are protonated by the same active site acid (most likely HOPPᵢ) to yield the shared natural bicyclic intermediate eudesmane cation, from which (+)-aristolochene is then generated.
Agid:
6390193