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Publication Detail

Title: Discovering Targets of Non-enzymatic Acylation by Thioester Reactivity Profiling.

Authors: Kulkarni, Rhushikesh A; Worth, Andrew J; Zengeya, Thomas T; Shrimp, Jonathan H; Garlick, Julie M; Roberts, Allison M; Montgomery, David C; Sourbier, Carole; Gibbs, Benjamin K; Mesaros, Clementina; Tsai, Yien Che; Das, Sudipto; Chan, King C; Zhou, Ming; Andresson, Thorkell; Weissman, Allan M; Linehan, W Marston; Blair, Ian A; Snyder, Nathaniel W; Meier, Jordan L

Published In Cell Chem Biol, (2017 Feb 16)

Abstract: Non-enzymatic protein modification driven by thioester reactivity is thought to play a major role in the establishment of cellular lysine acylation. However, the specific protein targets of this process are largely unknown. Here we report an experimental strategy to investigate non-enzymatic acylation in cells. Specifically, we develop a chemoproteomic method that separates thioester reactivity from enzymatic utilization, allowing selective enrichment of non-enzymatic acylation targets. Applying this method to cancer cell lines identifies numerous candidate targets of non-enzymatic acylation, including several enzymes in lower glycolysis. Functional studies highlight malonyl-CoA as a reactive thioester metabolite that can modify and inhibit glycolytic enzyme activity. Finally, we show that synthetic thioesters can be used as novel reagents to probe non-enzymatic acylation in living cells. Our studies provide new insights into the targets and drivers of non-enzymatic acylation, and demonstrate the utility of reactivity-based methods to experimentally investigate this phenomenon in biology and disease.

PubMed ID: 28163016 Exiting the NIEHS site

MeSH Terms: Acyl Coenzyme A/chemistry; Acyl Coenzyme A/metabolism; Acylation; Esters/chemistry; Esters/metabolism*; Humans; Models, Molecular; Molecular Structure; Proteomics; Sulfhydryl Compounds/chemistry; Sulfhydryl Compounds/metabolism*; Tumor Cells, Cultured

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