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. PMCID PMC7709968. doi:10.1021/acscatal.0c01888. https://resolver.caltech.edu/CaltechAUTHORS:20200608-115355402

	PDF - Accepted Version See Usage Policy. 1MB
	PDF (PubMed Central) - Accepted Version See Usage Policy. 385kB
	PDF (Materials and experimental methods, compound characterization data) - Supplemental Material See Usage Policy. 2MB
	MS Excel (Full nucleotide and amino-acid sequences for all reported enzyme variants) - Supplemental Material See Usage Policy. 23kB
	Crystallographic Info File (CIF) (X-ray crystallographic information file for (1R,2S)-4) - Supplemental Material See Usage Policy. 962kB

Use this Persistent URL to link to this item: https://resolver.caltech.edu/CaltechAUTHORS:20200608-115355402

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:

URL	URL Type	Description
https://doi.org/10.1021/acscatal.0c01888	DOI	Article
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7709968/	PubMed Central	Article

ORCID:

Author	ORCID
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. Jennifer	0000-0001-6371-8042
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 Agency	Grant Number
NSF	MCB-1513007
NSF	IIP-1738308
NIH	R35GM118191-01
NIH Predoctoral Fellowship	T32 GM112592
NIH Predoctoral Fellowship	T32 GM07616
NSF Graduate Research Fellowship	DGE-1144469

Subject Keywords:

biocatalysis, cyclopropanation, carbene transfer, diastereodivergence, diversity-oriented synthesis

Issue or Number:

PubMed Central ID:

PMC7709968

DOI:

10.1021/acscatal.0c01888

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:

09 Feb 2022 17:48

Repository Staff Only: item control page