Enzymatic synthesis of new terpenes from terpene synthase substrate analogs

• Applicant: Professor Dr. Jeroen Dickschat
• Subject Area: Organic Molecular Chemistry - Synthesis and Characterisation
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 513548540

This project aims at the synthesis of substrate analogs of terpene synthases and their enzymatic conversions. The planned structural modifications include substrate analogs with shifted double bonds for an expected change of reactivity, with hydrogenated double bonds (blocked reactivity, expectedly leading to derailment products), and removed methyl groups (buffered reactivity). Furthermore, a series of substrate analogs with skeletal extensions by one to four carbons will be synthesised that allow to study functional switches between diterpene and sesterterpene, or between sesterterpene and triterpene synthases. All compounds obtained in this project will be isolated and their structures will be elucidated by spectroscopic methods. Absolute configurations will be determined through a stereoselective deuteration strategy previously established in our laboratory. If for steric reasons certain enzyme-substrate combinations fail to work, enzyme variants with enlarged active site cavities will be obtained by site-directed mutagenesis. DFT calculations in collaboration with Prof. Dr. Bernd Goldfuss (University of Cologne) will add to a deeper understanding of interesting cyclisation mechanisms. Overall, the aim of this project is to broadly show the applicability of terpene synthases in the conversion of substrate analogs to make new terpenes accessible that cannot be obtained from the natural substrates.

• DFG Programme: Research Grants