title: Squalene-hopene cyclases-evolution, dynamics and catalytic scope.
abstract: Herein we highlight recent mechanistic findings on the impact of solvent dynamics on catalysis displayed by squalene-hopene cyclases (SHCs). These fascinating biocatalysts that appeared early during the evolution of terpene biosynthetic machineries exploit a catalytic aspartic acid donating the anti-oriented proton to the terminal CC double bond of pre-folded isoprenoid substrates. We review how the unusual strength of this Brønsted acid can be used to harness a plethora of non-natural protonation-driven reactions in a plastic enzyme fold. Moreover, recent results underline how the reaction termination by deprotonation or water addition is governed by the spatial location of water in the active site. Site-directed mutagenesis of amino acids located in the hydrophobic binding pocket allows for the generation of novel catalytic function by active site reshaping with relatively small enzyme libraries. A deepened understanding of triterpene cyclase dynamics in concert with chemical expertise thus have a great potential to allow for the biocatalytic manufacturing of tailored building bricks that would expand the chemical repertoire currently found in nature.
authors.affiliation: School of Chemical Science and Engineering, Division of Applied Physical Chemistry, KTH Royal Institute of Technology, 100 44 Stockholm, Sweden; Science for Life Laboratory, KTH Royal Institute of Technology, School of Biotechnology, Division of Proteomics and Nanobiotechnology, 171 21 Stockholm, Sweden.
authors.forename: Per-Olof
authors.initials: PO
authors.lastname: Syrén
authors.affiliation: Institute of Technical Biochemistry, Universitaet Stuttgart, Allmandring 31, 70569 Stuttgart, Germany.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Henche
authors.affiliation: Institute of Technical Biochemistry, Universitaet Stuttgart, Allmandring 31, 70569 Stuttgart, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Eichler
authors.affiliation: Institute of Technical Biochemistry, Universitaet Stuttgart, Allmandring 31, 70569 Stuttgart, Germany.
authors.forename: Bettina M
authors.initials: BM
authors.lastname: Nestl
authors.affiliation: Institute of Technical Biochemistry, Universitaet Stuttgart, Allmandring 31, 70569 Stuttgart, Germany. Electronic address: bernhard.hauer@itb.uni-stuttgart.de.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Hauer
mesh_terms: D055162:Biocatalysis; D019143:Evolution, Molecular; D019751:Intramolecular Transferases / Q000378:metabolism*; D013379:Substrate Specificity
chemical_list: D019751:Intramolecular Transferases; C066630:squalene-hopene cyclase