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Chemical proteomic analysis of palmostatin beta-lactone analogs that affect N-Ras palmitoylation.
- Source :
-
Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2021 Dec 01; Vol. 53, pp. 128414. Date of Electronic Publication: 2021 Oct 16. - Publication Year :
- 2021
-
Abstract
- S-Palmitoylation is a reversible post-translational lipid modification that regulates protein trafficking and signaling. The enzymatic depalmitoylation of proteins is inhibited by the beta-lactones Palmostatin M and B, which have been found to target several serine hydrolases. In efforts to better understand the mechanism of action of Palmostatin M, we describe herein the synthesis, chemical proteomic analysis, and functional characterization of analogs of this compound. We identify Palmostatin M analogs that maintain inhibitory activity in N-Ras depalmitoylation assays while displaying complementary reactivity across the serine hydrolase class as measured by activity-based protein profiling. Active Palmostatin M analogs inhibit the recently characterized ABHD17 subfamily of depalmitoylating enzymes, while sparing other candidate depalmitoylases such as LYPLA1 and LYPLA2. These findings improve our understanding of the structure-activity relationship of Palmostatin M and refine the set of serine hydrolase targets relevant to the compound's effects on N-Ras palmitoylation dynamics.<br /> (Copyright © 2021. Published by Elsevier Ltd.)
- Subjects :
- Humans
Lactones metabolism
Lactones pharmacology
Molecular Structure
Propiolactone analysis
Propiolactone metabolism
Propiolactone pharmacology
Sulfones metabolism
Sulfones pharmacology
ras Proteins antagonists & inhibitors
ras Proteins chemistry
Lactones analysis
Propiolactone analogs & derivatives
Proteomics
Sulfones analysis
ras Proteins metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1464-3405
- Volume :
- 53
- Database :
- MEDLINE
- Journal :
- Bioorganic & medicinal chemistry letters
- Publication Type :
- Academic Journal
- Accession number :
- 34666187
- Full Text :
- https://doi.org/10.1016/j.bmcl.2021.128414