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Synthesis of β-Branched Tryptophan Analogues Using an Engineered Subunit of Tryptophan Synthase

Herger, Michael and van Roye, Paul and Romney, David K. and Brinkmann-Chen, Sabine and Buller, Andrew R. and Arnold, Frances H. (2016) Synthesis of β-Branched Tryptophan Analogues Using an Engineered Subunit of Tryptophan Synthase. Journal of the American Chemical Society, 138 (27). pp. 8388-8391. ISSN 0002-7863. PMCID PMC4948191. https://resolver.caltech.edu/CaltechAUTHORS:20160706-081124141

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Abstract

We report that l-threonine may substitute for l-serine in the β-substitution reaction of an engineered subunit of tryptophan synthase from Pyrococcus furiosus, yielding (2S,3S)-β-methyltryptophan (β-MeTrp) in a single step. The trace activity of the wild-type β-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 β-MeTrp in nature and offers a simple and expandable route to preparing derivatives of this valuable building block.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1021/jacs.6b04836DOIArticle
http://pubs.acs.org/doi/abs/10.1021/jacs.6b04836PublisherArticle
http://pubs.acs.org/doi/suppl/10.1021/jacs.6b04836PublisherSupporting Information
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4948191PubMed CentralArticle
ORCID:
AuthorORCID
Romney, David K.0000-0003-0498-7597
Brinkmann-Chen, Sabine0000-0002-5419-4192
Buller, Andrew R.0000-0002-9635-4844
Arnold, Frances H.0000-0002-4027-364X
Additional Information:© 2016 American Chemical Society. Received: May 10, 2016; Publication Date (Web): June 29, 2016. The authors thank Hans Renata, Javier Murciano-Calles, and Chris Prier for helpful discussion and comments on the manuscript. We thank Dr. Jens Kaiser of the Caltech Molecular Observatory, which is supported by the Gordon and Betty Moore Foundation, the Beckman Institute, and the Sanofi-Aventis Bioengineering Research Program at Caltech. We thank Dr. Scott Virgil and the Center for Catalysis and Chemical Synthesis, and Dr. Mona Shahgholi and Naseem Torian from the Caltech Mass Spectrometry Laboratory. This work was funded through the Jacobs Institute for Molecular Engineering for Medicine and Ruth Kirschstein NIH Postdoctoral Fellowships F32G110851 (to A.R.B.) and F32GM117635 (to D.K.R.). M.H. and P.vR. contributed equally. The authors declare no competing financial interest.
Group:Jacobs Institute for Molecular Engineering for Medicine
Funders:
Funding AgencyGrant Number
Jacobs Institute for Molecular Engineering for MedicineUNSPECIFIED
NIH Postdoctoral FellowshipF32G110851
NIH Postdoctoral FellowshipF32GM117635
Gordon and Betty Moore FoundationUNSPECIFIED
Caltech Beckman InstituteUNSPECIFIED
Sanofi-Aventis Bioengineering Research ProgramUNSPECIFIED
Issue or Number:27
PubMed Central ID:PMC4948191
Record Number:CaltechAUTHORS:20160706-081124141
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20160706-081124141
Official Citation:Synthesis of β-Branched Tryptophan Analogues Using an Engineered Subunit of Tryptophan Synthase Michael Herger, Paul van Roye, David K. Romney, Sabine Brinkmann-Chen, Andrew R. Buller, and Frances H. Arnold Journal of the American Chemical Society 2016 138 (27), 8388-8391 DOI: 10.1021/jacs.6b04836
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:68843
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:06 Jul 2016 21:17
Last Modified:14 Oct 2019 18:05

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