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Protein engineering of esterases: climbing the protein fitness landscape

18 November 2011

PhD ceremony: Mr. L.F. da Silva Godinho, 12.45 uur, Aula Academiegebouw, Broerstraat 5, Groningen

Dissertation: Protein engineering of esterases: climbing the protein fitness landscape

Promotor(s): prof. W.J. Quax

Faculty: Mathematics and Natural Sciences

The thesis of Luis da Silva Godinho describes the application of esterases originated from B. subtilis and E. coli species for the enantiopure production of a chiral synthon of great interest for the pharmaceutical industry. The goal was to develop a biocatalytic process for the kinetic resolution of racemic 1,2-O-isopropylideneglycerol (IPG) esters. In the ideal case, a biocatalyst converts only the R-enantiomer of the substrate, yielding the optically pure product (S)-IPG, which is an important chiral synthon in the synthesis of many biologically active compounds, such as phospholipids and β-adrenoceptor antagonists. Esterases are of great interest due to their favorable properties in terms of broad substrate acceptance, high stability, enantioselectivity, and the fact that they do not require cofactors for activity, that make them attractive biocatalysts for use in organic synthesis. During his project, it was discovered by Da Silva Godinho that an enzyme from E.coli, YbfF, exhibits hydrolytic activity towards IPG esters with significant enantiopreference towards the substrate of interest.

Protein engineering techniques, such as rational design and directed evolution, allowed in the past years the creation of new enzymes with important practical applications. To enhance the enantioselectivity of wild type enzymes in the resolution of IPG esters, two strategies were applied: structure comparison with a homologous esterase and structure-substrate interaction analysis. The identification and characterization of novel esterase variants with enhanced enantioselectivity in the resolution of IPG esters were reported. Kinetic studies and molecular docking experiments were performed in order to increase our understanding of structure-function relationship for altering esterase enantioselectivity.

Last modified:13 March 2020 01.09 a.m.
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