First Principles Model Calculations of the Biosynthetic Pathway in Selinadiene Synthase

Susanta Das susanta.das@biu.ac.il Mudit Dixit Dan Thomas Major
Department of Chemistry, Bar-Ilan University, Ramat-Gan

Terpenes represent the largest class of natural products currently known. These natural compounds are derived from a few linear precursors, such as geranyl diphosphate (GPP), farnesyl diphosphate (FPP) and geranylgeranyl diphosphate (GGPP). Terpenes have diverse biological functions that are widespread across all three domains of life. Terpene synthases (TPSs) naturally catalyze the synthesis of terpenes via cationic mechanisms, which include numerous highly reactive intermediates. A common feature in all TPSs is highly evolved active sites that can seclude and protect highly reactive carbocation intermediates.1 In this study, we present a detailed mechanistic investigation of the biosynthesis of Selinadien.2-4 We employ density functional theory (DFT) to understand the exact pathways of the reaction in the gas-phase. Our investigation revealed that during the formation of the product, Selina-4 (15), 7 (11) -diene, FPP folds into a conformation conducive to several sequential cyclizations. We suggest that a required proton transfer cannot occur intramolecularly in the gas phase due to a high free energy barrier, and that enzyme assistance is essential for this step. Hybrid quantum mechanics-molecular mechanics (QM/MM) docking studies suggest that enzyme intervention could be realized through electrostatic guidance.5 Initial free energy QM/MM simulations are also presented.

Graphical Abstract

References:

[1] Roland D. Kersten, Jolene K. Diedrich, John R. Yates, Joseph P. Noel ACS Chem. Biol., 2015, 10, 2501-2511.

[2] Philipp Baer, Patrick Rabe, Katrin Fischer, Christian A. Citron, Tim A. Klapschinski, Michael Groll, Jeroen S. Dickschat Angew. Chem. Int. Ed. 2014, 53, 7652-7656.

[3] Philipp Baer, Patrick Rabe, Christian A. Citron, Carina C. de Oliveira Mann, Norman Kaufmann, Michael Groll, Jeroen S. Dickschat Chem. Bio. Chem, 2014, 15, 213-216.

[4] Susanta Das, Mudit Dixit, Dan T. Major. Bioorg. & Med. Chem. 2016, 24, 4867–4870

[5] Dan T. Major, Y. Freud, M. Weitman. Curr. Opin. Chem. Biol. 2014, 21, 25-33.

Susanta Das
Dr. Susanta Das
Post Doctorate
Bar-Ilan University








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