ECHO grant for Prof.dr. G.J. Poelarends

Prof. dr. Gerrit J. Poelarends (Pharmaceutical Biology) recently received an ECHO award from NWO for his proposal entitled

"Exploiting enzyme promiscuity for biocatalysis: Engineering novel ‘Michaelases’ for carbon-carbon bond formation"

A powerful theme that has recently emerged and that is highly relevant to both natural and laboratory evolution of new enzymes is that of catalytic promiscuity, where an enzyme catalyzes an alternative reaction (or reactions) in addition to its biologically relevant one. Recent studies from our laboratory on the enzyme 4-oxalocrotonate tautomerase (4-OT), which in nature catalyzes an enol-keto tautomerization step as part of a catabolic pathway for aromatic compounds, uncovered extreme catalytic promiscuity for this enzyme. 4-OT, which carries a unique catalytic amino-terminal proline (Pro-1), has been found to promiscuously catalyze a wide variety of Michael-type addition reactions. This proposal aims to exploit the promiscuous ‘Michaelase’ activity of 4-OT as a starting point to develop novel synthetically useful C-C bond-forming enzymes, as well as to provide insight into the manner in which a promiscuous protein might evolve to acquire more active and specific enzyme functions. The proposed work is at the interface of fundamental and applied molecular evolution, will yield detailed insight into structure-function relationships of a promiscuous protein, and has the exciting potential to yield efficient and enantioselective ‘Michaelases’ for pharmaceutical synthesis.

For more information see NWO .