"Engineering the substrate scope of the Fe(II) dependent halogenase Wel" by Sabrina Hoebenreich, Sabine Düwel et al.
 

Title

Engineering the substrate scope of the Fe(II) dependent halogenase WelO15

Conference Dates

September 24-28, 2017

Abstract

Selective halogenation is an important reaction for late-stage functionalisation of drug-like molecules. Performing halogenations under mild conditions using sodium chloride as the chlorine source has great potential for sustainable catalysis. The discovery of non-heme iron (NHI) and 2-oxoglutarate dependent halogenases, acting directly on a small organic molecule and not on acyl-carrier bound substrates,[1,2] has eliminated a major drawback of know NHI-halogenases. Hence, these enzymes represent attractive starting points for developing biocatalytic routs for selective, aliphatic chlorination, a paramount challenge in organic synthesis. The wild-types have a narrow natural substrate-scope and are unexplored for biocatalytic applications.[3] After solving the crystal structure of WelO15 from Westiella intricata, we used directed evolution to redesign the active site using a small-but-smart amino acid alphabet, thereby limiting the screening effort to a HPLC compatible throughput. New variants were found, able to chlorinate novel synthesized non-natural substrates. This study represents a first step towards milder, selective chlorination using biocatalysis.

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