Issue 39, 2023
From the journal:

Chemical Science

Masked cerulenin enables a dual-site selective protein crosslink†

Ziran Jiang, ORCID logo a   Aochiu Chen,a   Jeffrey Chen,a   Arman Sekhon,a   Gordon V. Louie, ORCID logo b   Joseph P. Noel, ORCID logo b   James J. La Clair ORCID logo a  and  Michael D. Burkart ORCID logo *a  

* Corresponding authors

a Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, CA 92093-0358, USA
E-mail: mburkart@ucsd.edu

b The Salk Institute for Biological Studies, Jack H. Skirball Center for Chemical Biology and Proteomics, La Jolla, CA, USA

Abstract

Protein-reactive natural products such as the fungal metabolite cerulenin are recognized for their value as therapeutic candidates, due to their ability to selectively react with catalytic residues within a protein active site or a complex of protein domains. Here, we explore the development of fatty-acid and polyketide-synthase probes by synthetically modulating cerulenin's functional moieties. Using a mechanism-based approach, we reveal unique reactivity within cerulenin and adapt it for fluorescent labeling and crosslinking of fatty-acid and iterative type-I polyketide synthases. We also describe two new classes of silylcyanohydrin and silylhemiaminal masked crosslinking probes that serve as new tools for activity and structure studies of these biosynthetic pathways.

Graphical abstract: Masked cerulenin enables a dual-site selective protein crosslink

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Article information

DOI
https://doi.org/10.1039/D3SC02864J
Article type
Edge Article
Submitted
05 Jun 2023
Accepted
02 Sep 2023
First published
08 Sep 2023
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY-NC license

Chem. Sci., 2023,14, 10925-10933

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Masked cerulenin enables a dual-site selective protein crosslink

Z. Jiang, A. Chen, J. Chen, A. Sekhon, Gordon V. Louie, J. P. Noel, J. J. La Clair and M. D. Burkart, Chem. Sci., 2023, 14, 10925 DOI: 10.1039/D3SC02864J

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