NDLI: Directed evolution of RebH for catalyst-controlled halogenation of indole C

Content Provider	Royal Society of Chemistry (RSC)
Author	Vergara-Coll, Jaylie Lewis, Jared C. Park, Hyun June Andorfer, Mary C.
Copyright Year	2016
Abstract	RebH variants capable of chlorinating substituted indoles ortho-, meta-, and para- to the indole nitrogen were evolved by directly screening for altered selectivity on deuterium-substituted probe substrates using mass spectrometry. This systematic approach allowed for rapid accumulation of beneficial mutations using simple adaptive walks and should prove generally useful for altering and optimizing the selectivity of C–H functionalization catalysts. Analysis of the beneficial mutations showed that structure-guided selection of active site residues for targeted mutagenesis can be complicated either by activity/selectivity tradeoffs that reduce the possibility of detecting such mutations or by epistatic effects that actually eliminate the benefits of a mutation in certain contexts. As a corollary to this finding, the precise manner in which the beneficial mutations identified led to the observed changes in RebH selectivity is not clear. Docking simulations suggest that tryptamine binds to these variants as tryptophan does to native halogenases, but structural studies will be required to confirm these models and shed light on how particular mutations impact tryptamine binding. Similar directed evolution efforts on other enzymes or artificial metalloenzymes could enable a wide range of C–H functionalization reactions.
Starting Page	3720
Ending Page	3729
Page Count	10
File Format	HTM / HTML PDF
ISSN	20416520
Volume Number	7
Issue Number	6
Journal	Chemical Science
DOI	10.1039/c5sc04680g
Language	English
Publisher	Royal Society of Chemistry
Access Restriction	Subscribed
Subject Keyword	Tryptamine Directed evolution Water chlorination Indole Active site Tryptophan Mutation Nitrogen Mass spectrometry
Content Type	Text
Resource Type	Article
Subject	Chemistry

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Directed Evolution of RebH for Catalyst-Controlled Halogenation of Indole C–H Bonds

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