Non-Canonical C₁₆ Homoterpene Biosynthesis Widespread in Actinobacteria

Area of Science:

• Natural Product Biosynthesis
• Enzymology
• Synthetic Biology

Background:

• Homoterpenes are a rare, underexplored class of non-canonical terpenoids.
• Understanding their biosynthesis is crucial for discovering novel natural products.

Purpose of the Study:

• To elucidate a novel biosynthetic pathway for homoterpenes in actinobacteria.
• To characterize the enzymes involved and discover new homoterpene natural products.

Main Methods:

• Targeted genome mining in actinobacteria.
• In vitro enzymatic reconstitution and functional characterization of enzymes.
• Discovery and structural elucidation of new homoterpenes.

Main Results:

• Identified a novel pathway involving methylation-induced isomerization of farnesyl diphosphate (FPP).
• Discovered a new family of methyltransferases with dual function.
• Characterized a distinct family of type I terpene cyclases acting on a C16 FPP isomer.
• Discovered five unprecedented homoterpene natural products.

Conclusions:

• The novel pathway provides a foundation for understanding homoterpene biosynthesis.
• Enzymatic novelty enables biocatalytic and synthetic strategies for methylated terpenoids.
• Potential for the "magic methyl effect" in developing compounds with unique properties.