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Substrate Pre‐Folding and Water Molecule Organization Matters for Terpene Cyclase Catalyzed Conversion of Unnatural Substrates
Author(s) -
Hammer Stephan C.,
Syrén PerOlof,
Hauer Bernhard
Publication year - 2016
Publication title -
chemistryselect
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.437
H-Index - 34
ISSN - 2365-6549
DOI - 10.1002/slct.201600572
Subject(s) - terpene , chemistry , substrate (aquarium) , catalysis , biocatalysis , selectivity , cyclase , directed evolution , combinatorial chemistry , triterpene , stereochemistry , enzyme , organic chemistry , biochemistry , biology , reaction mechanism , ecology , medicine , alternative medicine , pathology , gene , mutant
Terpene cyclase enzymes have recently been challenged with terpene substrate derivatives to generate additional chemical complexity beyond to what is currently found in nature. Herein, molecular dynamics and biocatalysis are used to shed light on the flexibility and inherent limitation of a triterpene cyclase in converting unnatural substrates. Our studies suggest that populating binding modes which allows for concerted reaction pathways is a key element towards an expanded substrate scope and new chemistries displayed by terpene cyclases. Additionally, we show that the spatial organization of water, which is influenced by both the substrate architecture as well as the active site geometry, controls the product selectivity. This highlights that activity and selectivity displayed by terpene cyclases acting on unnatural substrates is particularly difficult to predict, since they depend on various parameters.

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