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Intermediacy of Eudesmane Cation during Catalysis by Aristolochene Synthase

Faraldos, Juan A., Kariuki, Benson and Allemann, Rudolf Konrad 2010. Intermediacy of Eudesmane Cation during Catalysis by Aristolochene Synthase. Journal of Organic Chemistry 75 (4) , pp. 1119-1125. 10.1021/jo902397v

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Aristolochene synthase from Penicillium roqueforti (PR-AS) catalyzes the formation of the bicyclic sesquiterpene (+)-aristolochene (5) from farnesyl diphosphate (1, FDP) in two mechanistically distinct cyclization reactions. The first reaction transforms farnesyl diphosphate to the uncharged intermediate (S)-(−)-germacrene A (3) through a macrocyclization process that links C1 and C10 upon magnesium ion-assisted diphosphate ester activation. In the second reaction mediated by PR-AS, a protonation induced cyclization has been suggested to generate the highly reactive trans-fused eudesmane cation 4 as a consequence of the precise folding of the enzyme-bound germacrene A intermediate. This contribution describes the use of the transition state analogue inhibitor 4-aza-eudesm-11-ene to explore the intermediacy of cation 4 as an on-path intermediate in the biosynthesis of aristolochene. 4-Aza-eudesm-11-ene as the hydrochloride salt 6 was stereospecifically synthesized in seven steps and 37% overall yield starting from chiral enamine 9. The synthetic sequence featured a highly regio- and stereoselective deracemization reaction of 9 that gave rise to the corresponding Michael adduct in >95% diastereomeric excess as evidenced by optical rotation and NMR measurements. 6 acts as a potent competitive inhibitor of PR-AS (Ki = 0.35 ± 0.12 μM) independent of the presence of diphosphate (Ki = 0.24 ± 0.09 μM). The failure of exogenous PPi to enhance the binding affinity of 6 for PR-AS could be interpreted against an eudesmyl cation/diphosphate anion pair mechanism as the enzymatic strategy to stabilize the highly reactive eudesmane cation 4. In addition, these observations seem to rule out simple favorable electrostatic and/or hydrogen bonding interactions between the active site anchored diphosphate ion and the ammonium ion 6 as the binding mode. Ammonium ion 6 seems to act as a genuine mimic of eudesmane cation (4) that most likely binds the active site of PR-AS in a productive conformation resembling that adapted by 4 during the PR-AS-catalyzed synthesis of 5.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Chemistry
Cardiff Catalysis Institute (CCI)
Subjects: Q Science > QD Chemistry
Publisher: ACS
ISSN: 0022-3263
Funders: BBSRC
Last Modified: 04 Jun 2017 03:09

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