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Diversity-Oriented Enzymatic Synthesis of Cyclopropane Building Blocks

Wittmann, Bruce J. and Knight, Anders M. and Hofstra, Julie L. and Reisman, Sarah E. and Kan, S. B. Jennifer and Arnold, Frances H. (2020) Diversity-Oriented Enzymatic Synthesis of Cyclopropane Building Blocks. ACS Catalysis, 10 (13). pp. 7112-7116. ISSN 2155-5435. https://resolver.caltech.edu/CaltechAUTHORS:20200608-115355402

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Abstract

While biocatalysis is increasingly incorporated into drug development pipelines, it is less commonly used in the early stages of drug discovery. By engineering a protein to produce a chiral motif with a derivatizable functional handle, biocatalysts can be used to help generate diverse building blocks for drug discovery. Here we show the engineering of two variants of Rhodothermus marinus nitric oxide dioxygenase (RmaNOD) to catalyze the formation of cis- and trans-diastereomers of a pinacolboronate-substituted cyclopropane which can be readily derivatized to generate diverse stereopure cyclopropane building blocks.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1021/acscatal.0c01888DOIArticle
ORCID:
AuthorORCID
Wittmann, Bruce J.0000-0001-8144-9157
Knight, Anders M.0000-0001-9665-8197
Hofstra, Julie L.0000-0001-9558-4317
Reisman, Sarah E.0000-0001-8244-9300
Kan, S. B. Jennifer0000-0001-6371-8042
Arnold, Frances H.0000-0002-4027-364X
Additional Information:© 2020 American Chemical Society. Received: April 28, 2020; Revised: June 4, 2020; Published: June 4, 2020. This work was supported by NSF MCB (grant 1513007 to F.H.A.), NSF STTR (grant 1738308 to F.H.A.), and the NIH (grant R35GM118191-01 to S.E.R.). Graduate student support from NIH T32 training grants GM112592 (A.M.K.) and GM07616 (B.J.W.), and the NSF Graduate Research Fellowship Program (A.M.K. and J.L.H., DGE-1144469), is acknowledged. The authors thank Mr. Lawrence M. Henling for assistance with small-molecule X-ray crystallography, as well as Dr. Mona Shahgholi and Naseem Torian for assistance with mass spectrometry measurements. Crystallography experiments were supported by Jens Kaiser and the Caltech Molecular Observatory. The authors thank Jingzhou Wang for technical assistance, David Rozzell, Nathaniel Goldberg, Ferdinand Huber, Nicholas Porter, and Kari Hernandez for valuable discussions, and Sabine Brinkmann-Chen and Zhen Liu for critical reading of the manuscript. Author Contributions: B.J.W., A.M.K.: These authors contributed equally. The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. The authors declare the following competing financial interest(s): A provisional patent, on which A.M.K., B.J.W., and S.B.J.K. are inventors, has been filed through the California Institute of Technology based on the results presented here.
Funders:
Funding AgencyGrant Number
NSFMCB-1513007
NSFIIP-1738308
NIHR35GM118191-01
NIH Predoctoral FellowshipT32 GM112592
NIH Predoctoral FellowshipT32 GM07616
NSF Graduate Research FellowshipDGE-1144469
Subject Keywords:biocatalysis, cyclopropanation, carbene transfer, diastereodivergence, diversity-oriented synthesis
Issue or Number:13
Record Number:CaltechAUTHORS:20200608-115355402
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20200608-115355402
Official Citation:Diversity-Oriented Enzymatic Synthesis of Cyclopropane Building Blocks Bruce J. Wittmann, Anders M. Knight, Julie L. Hofstra, Sarah E. Reisman, S. B. Jennifer Kan, and Frances H. Arnold. ACS Catalysis 2020 10 (13), 7112-7116; DOI: 10.1021/acscatal.0c01888
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:103768
Collection:CaltechAUTHORS
Deposited By: George Porter
Deposited On:08 Jun 2020 19:40
Last Modified:08 Jul 2020 17:08

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