3926414

Masked cerulenin enables a dual-site selective protein crosslink

Date
August 13, 2023
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In the current study of polyketide and non-ribosomal peptide biosynthesis, a major goal has been the structural elucidation of the megasynthases that produce them. We have been developing chemical biology tools to study these enzyme systems, with a focus on dual site-selective crosslinking probes. Protein-reactive natural products such as the fungal metabolite cerulenin are recognized for their value as therapeutic leads due to the ability to selectively react with catalytic residues within a protein active site or protein complex. Here, we explore the development of fatty-acid and polyketide synthase probes by synthetically adapting the reactive functionalities of cerulenin. Using a mechanism-based approach, we further develop and reveal unique reactivity within cerulenin and adapt it for fluorescent labeling and crosslinking select proteins within fatty acid and iterative type I polyketide synthases. Inclusive in this study are two new classes of silylether cyanohydrin and hemiaminal masked crosslinking probes, which offer new tools for activity and structural studies of these pathways.

Presenter

Speaker Image for Michael Burkart
Professor, Chemistry and Biochemistry, University of California San Diego

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