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Unexpected Enzymatic Activity

Overall structure and point cloud of search template (left) compared to newly identified enzyme (right).

Back in 2014, we developed a structural bioinformatics method for predicting catalytic activities of enzymes based on three-dimensional constellations of functional groups in active sites (‘catalophores’). As a proof-of-concept, we identified two
enzymes with predicted promiscuous ene-reductase activity (reduction of activated C=C double bonds) and compared them with known ene reductases. Despite completely different amino acid sequences (sequence identity of 9%), overall structures and protein folds, high-resolution crystal structures revealed equivalent binding modes of typical Old Yellow Enzyme substrates and ligands and comparable catalytic activities. It was also possible to identify enzymes with switched enantioselectivity.

Selected substrates used to verify the ene reductase activity of the newly found enzymes (PhENR = ene reductase from Pyrococcus horikoshii, TtENR = ene reductase from Thermus thermophilus).