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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.
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