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The enzymatic tools that catalyze a stepwise demethylation process on terpene scaffold

A research team led by Dr. Hsiao-Ching Lin, an assistant research fellow at the Institute of Biological Chemistry, has elucidated and characterized the biosynthetic pathway of the aculenes, a unique class of fungal norsequiterpenes. This work reveals new enzymatic tools to expand chemical diversity and was recently published in Angewandte Chemie International Edition.

In nature, demethylation processes have been observed in some terpenoid families, such as steroids and norterpenes, generating new terpene skeletons and, in turn, producing molecules with a variety of biological activities. However, only a limited number of examples of biosynthetic machineries that catalyze demethylation have been reported. Therefore, understanding the function and catalytic mechanism of enzymes promoting demethylation in terpenoid biosynthetic pathways, and exploring new catalysts involved in C–C bond cleavage, is of both great fundamental and practical importance.

The daucane sesquiterpenes are widely found in plants and fungi and exhibit a variety of biological activities. As such, a number of total syntheses of daucane sesquiterpenes have been reported. Aculenes, produced by fungi, are a unique class of norsequiterpenes (C14) derived from demethylation of a daucane sesquiterpene (C15) precursor. Biosynthetically, the genetic and biochemical basis of aculene biosynthesis have remained unexplored. The Lin’s group report the identification and characterization of the aculenes (ane) biosynthetic gene cluster from Aspergillus aculeatus and also the sequence of biosynthetic steps. They discovered a terpene cyclase (AneC) that form a new C15 sesquiterpene that serves as the precursor skeleton of the aculenes. Most importantly, they characterzied three novel cytochrome P450 monoxygenases that are required to catalyze the stepwise demethylation process. These results not only provide critical new insights into the biosynthesis of fungal norsesquiterpenes, but also open up opportunities for terpene skeleton derivatization using enzymatic approaches.

Article title: “The Biosynthesis of Norsesquiterpene Aculenes Requires Three Cytochrome P450 Enzymes to Catalyze a Stepwise Demethylation Process”

Article link: https://onlinelibrary.wiley.com/doi/full/10.1002/ange.201910200

Authors: Chi-Fang Lee, Li-Xun Chen, Chen-Yu Chiang, Chen-Yu Lai, Hsiao-Ching Lin*

Updated: 2019.11.22

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