Department of Molecular, Cell and Cancer Biology
Amino Acids, Peptides, and Proteins | Enzymes and Coenzymes | Medicinal Chemistry and Pharmaceutics | Medicinal-Pharmaceutical Chemistry
Most known probes for activity-based protein profiling (ABPP) use electrophilic groups that tag a single type of nucleophilic amino acid to identify cases in which its hyper-reactivity underpins function. Much important biochemistry derives from electrophilic enzyme cofactors, transient intermediates, and labile regulatory modifications, but ABPP probes for such species are underdeveloped. Here, we describe a versatile class of probes for this less charted hemisphere of the proteome. The use of an electron-rich hydrazine as the common chemical modifier enables covalent targeting of multiple, pharmacologically important classes of enzymes bearing diverse organic and inorganic cofactors. Probe attachment occurs by both polar and radicaloid mechanisms, can be blocked by molecules that occupy the active sites, and depends on the proper poise of the active site for turnover. These traits will enable the probes to be used to identify specific inhibitors of individual members of these multiple enzyme classes, making them uniquely versatile among known ABPP probes.
Iron, Peptides and proteins, Labeling, Inhibitors, Probes
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Copyright © 2021 The Authors. Published by American Chemical Society. Permits non-commercial access and re-use, provided that author attribution and integrity are maintained; but does not permit creation of adaptations or other derivative works (https://creativecommons.org/licenses/by-nc-nd/4.0/).
DOI of Published Version
Lin Z, Wang X, Bustin KA, Shishikura K, McKnight NR, He L, Suciu RM, Hu K, Han X, Ahmadi M, Olson EJ, Parsons WH, Matthews ML. Activity-Based Hydrazine Probes for Protein Profiling of Electrophilic Functionality in Therapeutic Targets. ACS Cent Sci. 2021 Sep 22;7(9):1524-1534. doi: 10.1021/acscentsci.1c00616. Epub 2021 Aug 19. PMID: 34584954; PMCID: PMC8461768. Link to article on publisher's site
ACS central science
Lin Z, Wang X, Bustin KA, Shishikura K, McKnight NR, He L, Suciu RM, Hu K, Han X, Ahmadi M, Olson EJ, Parsons WH, Matthews ML. (2021). Activity-Based Hydrazine Probes for Protein Profiling of Electrophilic Functionality in Therapeutic Targets. Open Access Publications by UMass Chan Authors. https://doi.org/10.1021/acscentsci.1c00616. Retrieved from https://escholarship.umassmed.edu/oapubs/4866
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This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.