Understanding the competing pathways leading to hydropyrene and isoelisabethatriene

Shani Zev; Marion Ringel; Ronja Driller; Bernhard Loll; Thomas Brück; Dan T Major

doi:10.3762/bjoc.18.97

Understanding the competing pathways leading to hydropyrene and isoelisabethatriene

Beilstein J Org Chem. 2022 Aug 4:18:972-978. doi: 10.3762/bjoc.18.97. eCollection 2022.

Authors

Shani Zev¹, Marion Ringel², Ronja Driller^{3

4}, Bernhard Loll³, Thomas Brück², Dan T Major¹

Affiliations

¹ Department of Chemistry and Institute for Nanotechnology & Advanced Materials, Bar-Ilan University, Ramat-Gan 52900, Israel.
² Werner Siemens Chair of Synthetic Biotechnology, Department of Chemistry, Technical University of Munich, Lichtenbergstraße 4, 85748 Garching, Germany.
³ Institute for Chemistry and Biochemistry, Structural Biochemistry Laboratory, Freie Universität Berlin, Takustr. 6, 14195 Berlin, Germany.
⁴ Department of Molecular Biology and Genetics, Aarhus University, Danish Research Institute of Translational Neuroscience - DANDRITE, Universitetsbyen 81, 8000 Aarhus C, Denmark.

Abstract

Terpene synthases are responsible for the biosynthesis of terpenes, the largest family of natural products. Hydropyrene synthase generates hydropyrene and hydropyrenol as its main products along with two byproducts, isoelisabethatrienes A and B. Fascinatingly, a single active site mutation (M75L) diverts the product distribution towards isoelisabethatrienes A and B. In the current work, we study the competing pathways leading to these products using quantum chemical calculations in the gas phase. We show that there is a great thermodynamic preference for hydropyrene and hydropyrenol formation, and hence most likely in the synthesis of the isoelisabethatriene products kinetic control is at play.

Keywords: diterpenes; enzyme mechanism; quantum mechanics; terpene synthases; thermodynamic and kinetic control.

Grants and funding

MR and TB gratefully acknowledge funding by the Werner Siemens foundation for establishing the field of Synthetic Biotechnology at TUM. This work was supported by a grant from the Israel Science Foundation (Grant 1683/18) (DTM) and by a grant from the German-Israeli Foundation for Scientific Research and Development (Grant I-85-302.14-2018) (DTM, TB, BL).