Halogenation is an important chemical modification with a potential to provide additional biological activity and bioavailability to molecules. Moreover, halogenation in synthetic chemistry offers a useful chemical handle for selective post-modification and elaboration of natural and non-natural products. Halogenase enzymes are attractive for development as enzymatic tools because of, unlike synthetic halogenation, the innate ability of the enzyme for regiospecificity and green chemistry. Herein, we biochemically and structurally characterized a unique flavin-dependent halogenase. This halogenase is capable of utilizing a wide range of halides (Cl, Br, and I), which had never been described before, for installation in a diverse array of phenolic and anilic compounds, including FAD-approved drugs and natural products, such as fenoterol, terbutaline, catechin, and resveratrol. Quantitative analysis showed kinetic properties of this enzyme and substrate preference for those compounds that contain electron donating groups. Crystal structures of this halogenase in complex with FAD in the holo state and an intermediate of apo to holo state yielded insight into an unusual FAD recycling mechanism. The unique C-terminus region of this enzyme forms a relatively large substrate binding site that is close to the enzyme surface. This feature could explain its ability to adopt a variety of substrates. Finally, the large scale enzymatic reactions allowed us to determine the specific halogenation sites by this enzyme and also showed a promising capability of using this enzyme as an enzymatic tool for the synthetic purpose.

Characterization and development of a halogenase enzyme as a tool for synthesis

2019 Spring National Meeting

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