Terpene synthases - mechanistic investigations and applications in the synthesis of non-natural compounds

Introduction

Terpene synthases catalyse the conversion of acyclic and achiral oligoprenyl diphosphate precursors into usually (poly)cyclic, chiral and enantiomerically enriched terpene hydrocarbons or alcohols. These reactions proceed with multiple carbon-carbon bond formations and changes of the hybridisation of often more than half of the precursor carbons in just one enzymatic step. The mechanisms of terpene synthases can be investigated through isotopic labelling experiments,^[1,2] structure based^[3] site-directed mutagenesis,^[4,5] computational chemistry,^[6] and, ideally, combinations thereof.^[7] Enzyme variants obtained through site-directed mutagenesis often show the formation of new products, making this approach interesting to expand the reachable chemical space. Further possibilities include the usage of terpene synthases for the conversion of non-natural substrate analogs.^[8] This approach demonstrates a remarkable tolerance of terpene synthases towards substrate modifications and allows for the efficient enzymatic synthesis of highly complex non-natural terpene analogs.

 

 

References

[1]    P. Rabe, J. Rinkel, E. Dolja, T. Schmitz, B. Nubbemeyer, T. H. Luu, J. S. Dickschat, Angew. Chem. Int. Ed. 2017, 56, 2776.

[2]    A. Hou, J. S. Dickschat, Angew. Chem. Int. Ed. 2020, 59, 19961.

[3]    P. Baer, P. Rabe, K. Fischer, C. A. Citron, T. A. Klapschinski, M. Groll, J. S. Dickschat, Angew. Chem. Int. Ed. 2014, 53, 7652.

[4]    A. Hou, B. Goldfuss, J. S. Dickschat, Angew. Chem. Int. Ed. 2021, 60, 20781.

[5]    A. Hou, J. S. Dickschat, Beilstein J. Org. Chem. 2021, 17, 2441-2449.

[6]    H. Xu, B. Goldfuss, J. S. Dickschat, Chem. Eur. J. 2021, 27, 9758.

[7]    Y.-H. Wang, H. Xu, J. Zou, X.-B. Chen, Y.-Q. Zhuang, W.-L. Liu, E. Celik, G.-D. Chen, D. Hu, H. Gao, R. Wu, P.-H. Sun, J. S. Dickschat, Nat. Catal. 2022, 5, 128.

[8]    H. Li, J. S. Dickschat, Angew. Chem. Int. Ed. 2022, 61, e202211054.

 

Jeroen S. Dickschat

Jeroen S. Dickschat studied chemistry at TU Braunschweig. He then worked with Prof. Stefan Schulz on the synthesis and biosynthesis of microbial volatiles and obtained his Ph.D. in 2004. He continued his research with postdoctoral stays at Saarland University with Prof. Rolf Müller and at the University of Cambridge with Prof. Peter Leadlay. In 2008 he started his independent research group at TU Braunschweig, culminating in his habilitation in 2013. In 2014 he was appointed Professor of Organic Chemistry and Biochemistry at the Kekulé-Institute at the University of Bonn. Since 2016 he is an Honorary Fellow of the Netherlands Institute of Chemical Ecology in Wageningen, was entitled Honorary Professor of Zhejiang University of Technology in 2019, and serves as an editor for the Beilstein Journal of Organic Chemistry since 2014. His research interests include the discovery, synthesis and biosynthesis of natural products with a special focus on the mechanistic characterisation of terpene synthases and other enzymes involved in natural product biosynthesis.