Journal
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
Volume 138, Issue 27, Pages 8388-8391Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jacs.6b04836
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Funding
- Gordon and Betty Moore Foundation
- Beckman Institute
- Sanofi-Aventis Bioengineering Research Program at Caltech
- Jacobs Institute for Molecular Engineering for Medicine and Ruth Kirschstein NIH Postdoctoral Fellowships [F32G110851, F32GM117635]
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We report that L-threonine may substitute for L-serine in the beta-substitution reaction of an engineered subunit of tryptophan synthase from Pyrococcus furiosus, yielding (2S,3S)-beta-methyltryptophan (beta-MeTrp) in a single step. The trace activity of the wild-type beta-subunit on this substrate was enhanced more than 1000-fold by directed evolution. Structural and spectroscopic data indicate that this increase is correlated with stabilization of the electrophilic aminoacrylate intermediate. The engineered biocatalyst also reacts with a variety of indole analogues and thiophenol for diastereoselective C-C, C-N, and C-S bond-forming reactions. This new activity circumvents the 3-enzyme pathway that produces beta-MeTrp in nature and offers a simple and expandable route to preparing derivatives of this valuable building block.
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