Biosynthesis of Norsesquiterpene Aculenes Requires Three Cytochrome P450s to Catalyze a Stepwise Demethylation Process.

Biosynthesis of Norsesquiterpene Aculenes Requires Three Cytochrome P450s to Catalyze a Stepwise Demethylation Process.

Angew Chem Int Ed Engl. 2019 Oct 16;:

Authors: Lee CF, Chen LX, Chiang CY, Lai CY, Lin HC

Abstract
Aculenes are a unique class of norsequiterpenes (C 14 ) produced from Aspergillus aculeatus. The nordaucane skeleton in aculenes A-D may be derived from an ent-daucane precursor through a demethylation process. Despite their unprecedented structures, the genetic basis and enzymatic mechanisms involved in the biosynthesis of aculenes remained unexplored. Here, we identified the biosynthetic gene cluster of aculenes and characterized the biosynthetic pathway based on gene inactivation, feeding experiments and heterologous reconstitution in both Saccharomyces cerevisiae and Aspergillus oryzae. Notably, we discovered three cytochrome P450 monoxygenases that are required to catalyze the stepwise demethylation process. AneF converts the 12-methyl group to a carboxylic acid and AneD installs the 10-hydroxyl group for later tautomerization and stabilization. Finally, AneG installs a necessary electron withdrawing carbonyl group at the C-2 position, which subsequently triggers C-12 decarboxylation to yield the nordaucane skeleton. A terpene cyclase (AneC) is also characterized to form a new product named dauca-4,7-diene.

PMID: 31618514 [PubMed – as supplied by publisher]

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