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Entropy is Key to the Formation of Pentacyclic Terpenoids by Enzyme-Catalyzed Polycyclization

Authors

  • Dr. Per-Olof Syrén,

    Corresponding author
    1. Institute of Technical Biochemistry, University of Stuttgart, Allmandring 31, 70569 Stuttgart (Germany)
    2. Present address: Division of Proteomics, KTH Royal Institute of Technology, AlbaNova University Center, Roslagstullsbacken 21, 10691 Stockholm (Sweden)
    • Institute of Technical Biochemistry, University of Stuttgart, Allmandring 31, 70569 Stuttgart (Germany)===

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  • Stephan C. Hammer,

    1. Institute of Technical Biochemistry, University of Stuttgart, Allmandring 31, 70569 Stuttgart (Germany)
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  • Dr. Birgit Claasen,

    1. Institute for Organic Chemistry, Pfaffenwaldring 55, 70569 Stuttgart (Germany)
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  • Prof. Dr. Bernhard Hauer

    1. Institute of Technical Biochemistry, University of Stuttgart, Allmandring 31, 70569 Stuttgart (Germany)
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  • The Alexander von Humboldt foundation, the Royal Swedish Academy of Sciences, Fonds der Chemischen Industrie, and the European Union’s Seventh Framework Programme FP7/2007-2013 under grant agreement no 289646 are gratefully acknowledged for financial support.

Abstract

Polycyclizations constitute a cornerstone of chemistry and biology. Multicyclic scaffolds are generated by terpene cyclase enzymes in nature through a carbocationic polycyclization cascade of a prefolded polyisoprene backbone, for which electrostatic stabilization of transient carbocationic species is believed to drive catalysis. Computational studies and site-directed mutagenesis were used to assess the contribution of entropy to the polycyclization cascade catalyzed by the triterpene cyclase from A. acidocaldarius. Our results show that entropy contributes significantly to the rate enhancement through the release of water molecules through specific channels. A single rational point mutation that results in the disruption of one of these water channels decreased the entropic contribution to catalysis by 60 kcal mol−1. This work demonstrates that entropy is the key to enzyme-catalyzed polycyclizations, which are highly relevant in biology since 90 % of all natural products contain a cyclic subunit.

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