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بیست و نهمین کنفرانس شیمی آلی ایران
Investigating Promiscuous Activity in Recombinant NADH-dependent Flavin Reductase
نویسندگان :
Hamid Reza Kalhor ( دانشگاه صنعتی شریف ) , Amene Navaser ( دانشگاه صنعتی شریف )
کلید واژه ها :
biocatalyst،enzyme promiscuity،tetraketone
چکیده مقاله :
Enzymes which are well known for their high regio, chemo, and stereo-selectivity, have been increasingly used as biocatalysts in synthesizing various organic compounds. Many enzymes have shown promiscuous activity by serving a non-native substrate or demonstrating non-native catalytic activity1. Recently, enzyme promiscuity; has earned much attention in organic synthesis. Introducing novel approaches to evolve a promiscuous activity in enzymes would improve the traditional organic synthesis routes. In the present study, promiscuous activities were developed in the E.coli NADH-dependent flavin reductase by removing the enzyme’s cofactor. However, in the absence of the cofactor; the flavin reductase was able to catalyze the Knoevenagel condensation and Michael addition reactions. Additionally, the enzyme's promiscuous performance was enhanced by optimizing the reaction condition including various solvents and temperature for the Knoevenagel-Michael addition cascade to produce tetraketones (Scheme 1). The scope of reaction indicated that a wide range of compounds including aliphatic, aromatic, and heterocyclic aldehydes can be used by the enzyme to generate the desired products. In the presence of the NADH, both Knoevenagel condensation and Michael addition reactions were blocked and no desired product was achieved. Molecular docking and molecular dynamics were exploited to identify key residues that play roles in the tetraketone synthesis. Removing the cofactor can stand as a novel method to induce promiscuity in enzymes. Furthermore, the NADH and its regenerating system are considered expensive, therefore, deletion of the cofactor could be a cost-effective approach for organic synthesis.
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