Cofactor-Independent Pinacolase Directs Non-Diels-Alderase Biogenesis of the Brevianamides
1970
Fungal bicyclo[2.2.2]diazaoctane indole
alkaloids demonstrate intriguing structures
and a wide spectrum of biological activities. Although biomimetic total syntheses
have been completed for representative compounds of this structural family, the
details of their biogenesis have remained largely uncharacterized. Among them, Brevianamide A represents the most
basic form within this class bearing a dioxopiperazine core structure and a rare
3-spiro-psi-indoxyl skeleton. Here, we identified
the Brevianamide A biosynthetic gene cluster from Penicillium brevicompacticum
NRRL 864 and fully elucidated the metabolic pathway by targeted gene disruption, heterologous expression,
precursor incorporation studies, and in
vitro biochemical analysis. In particular, we determined that BvnE is a cofactor-independent
isomerase that is essential for selective production
of Brevianamide A. Based on a high resolution crystal structure of BvnE,
molecular modeling, mutational analysis, and computational studies provided new
mechanistic insights into the
diastereoselective formation of the 3-spiro-psi-indoxyl moiety in Brevianamide A.
This occurs through a biocatalyst controlled semi-Pinacol rearrangement and a
subsequent
spontaneous intramolecular [4+2] hetero-Diels-Alder
cycloaddition.
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