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Engineered biosynthesis of β‐alkyl tryptophan analogs

Boville, Christina E. and Scheele, Remkes A. and Koch, Philipp and Brinkmann-Chen, Sabine and Buller, Andrew R. and Arnold, Frances H. (2018) Engineered biosynthesis of β‐alkyl tryptophan analogs. Angewandte Chemie International Edition, 57 (45). pp. 14764-14768. ISSN 1433-7851. https://resolver.caltech.edu/CaltechAUTHORS:20180723-111237018

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Abstract

Noncanonical amino acids (ncAAs) with dual stereocenters at the α and β positions are valuable precursors to natural products and therapeutics. Despite the potential applications of such bioactive β‐branched ncAAs, their availability is limited due to the inefficiency of the multistep methods used to prepare them. Herein we report a stereoselective biocatalytic synthesis of β‐branched tryptophan analogues using an engineered variant of Pyrococcus furiosus tryptophan synthase (PfTrpB), PfTrpB^(7E6). PfTrpB^(7E6) is the first biocatalyst to synthesize bulky β‐branched tryptophan analogues in a single step, with demonstrated access to 27 ncAAs. The molecular basis for the efficient catalysis and broad substrate tolerance of PfTrpB^(7E6) was explored through X‐ray crystallography and UV/Vis spectroscopy, which revealed that a combination of active‐site and remote mutations increase the abundance and persistence of a key reactive intermediate. PfTrpB^(7E6) provides an operationally simple and environmentally benign platform for the preparation of β‐branched tryptophan building blocks.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1002/anie.201807998DOIArticle
https://chemrxiv.org/articles/Engineered_Biosynthesis_of_-Alkyl_Tryptophan_Analogs/6813446arXivDiscussion Paper
ORCID:
AuthorORCID
Boville, Christina E.0000-0002-2577-9343
Brinkmann-Chen, Sabine0000-0002-5419-4192
Buller, Andrew R.0000-0002-9635-4844
Arnold, Frances H.0000-0002-4027-364X
Additional Information:© 2018 Wiley‐VCH Verlag GmbH & Co. KGaA, Weinheim. Manuscript received: July 15, 2018; Accepted manuscript online: September 14, 2018; Version of record online: October 12, 2018. We thank Dr. David Romney, Patrick Almhjell, Dr. Christopher Prier, Nathaniel Goldberg, and Ella Watkins for helpful discussions and comments on the manuscript. We thank Dr. Jens Kaiser of the Caltech Molecular Observatory, 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 research was funded by the Rothenberg Innovation Initiative. C.E.B. was supported by a postdoctoral fellowship from the Resnick Sustainability Institute. R.A.S. was supported by funding from the University of Groningen. Conflict of interest: The enzyme variants and tryptophan analogues in this manuscript are the subject of a patent application submitted by the authors and Caltech.
Group:Resnick Sustainability Institute
Funders:
Funding AgencyGrant Number
Rothenberg Innovation Initiative (RI2)UNSPECIFIED
Resnick Sustainability InstituteUNSPECIFIED
University of GroningenUNSPECIFIED
Subject Keywords:Biocatalysis; tryptophan synthase; β-branched amino acid
Issue or Number:45
Record Number:CaltechAUTHORS:20180723-111237018
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20180723-111237018
Official Citation:C. E. Boville, R. A. Scheele, P. Koch, S. Brinkmann-Chen, A. R. Buller, F. H. Arnold, Angew. Chem. Int. Ed. 2018, 57, 14764
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:88128
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:23 Jul 2018 18:27
Last Modified:14 Oct 2019 18:01

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