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Issue 13, 2008

Stereochemistry of eudesmane cation formation during catalysis by aristolochene synthase from Penicillium roqueforti

Author affiliations

Abstract

The aristolochene synthase catalysed cyclisation of farnesyl diphosphate (1) has been postulated to proceed through (S)-germacrene A (3). However, the active site acid that reprotonates this neutral intermediate has so far proved difficult to identify and, based on high level ab initio molecular orbital and density functional theory calculations, a proton transfer mechanism has recently been proposed, in which proton transfer from C12 of germacryl cation to the C6,C7-double bond of germacryl cation (2) proceeds either directly or via a tightly bound water molecule. In this work, the stereochemistry of the elimination and protonation reactions was investigated by the analysis of the reaction products from incubation of 1 and of [12,12,12,13,13,13-2H6]-farnesyl diphosphate (15) with aristolochene synthase from Penicillium roqueforti (PR-AS) in H2O and D2O. The results reveal proton loss from C12 during the reaction and incorporation of another proton from the solvent. Incubation of 1 with PR-AS in D2O led to the production of (6R)-[6-2H] aristolochene, indicating that protonation occurs from the face of the 10-membered germacrene ring opposite the isopropylidene group. Hence these results firmly exclude proton transfer from C12 to C6 of germacryl cation. We propose here Lys 206 as the general acid/base during PR-AS catalysis. This residue is part of a conserved network of hydrogen bonds, along which protons could be delivered from the solvent to the active site.

Graphical abstract: Stereochemistry of eudesmane cation formation during catalysis by aristolochene synthase from Penicillium roqueforti

Supplementary files

Article information


Submitted
11 Mar 2008
Accepted
28 Mar 2008
First published
28 Apr 2008

Org. Biomol. Chem., 2008,6, 2346-2354
Article type
Paper

Stereochemistry of eudesmane cation formation during catalysis by aristolochene synthase from Penicillium roqueforti

D. J. Miller, J. Gao, D. G. Truhlar, N. J. Young, V. Gonzalez and R. K. Allemann, Org. Biomol. Chem., 2008, 6, 2346 DOI: 10.1039/B804198A

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