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Journal article
Bioorthogonal pro-metabolites for profiling short chain fatty acylation
Chemical science (Cambridge), v 9(5), pp 1236-1241
07 Feb 2018
PMID: 29675169
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Short chain fatty acids (SCFAs) play a central role in health and disease. One function of these signaling molecules is to serve as precursors for short chain fatty acylation, a class of metabolically-derived posttranslational modifications (PTMs) that are established by lysine acetyltransferases (KATs) and lysine deacetylases (KDACs). Via this mechanism, short chain fatty acylation serves as an integrated reporter of metabolism as well as KAT and KDAC activity, and has the potential to illuminate the role of these processes in disease. However, few methods to study short chain fatty acylation exist. Here we report a bioorthogonal pro-metabolite strategy for profiling short chain fatty acylation in living cells. Inspired by the dietary component tributyrin, we synthesized a panel of ester-caged bioorthogonal short chain fatty acids. Cellular evaluation of these agents led to the discovery of an azido-ester that is metabolized to its cognate acyl-coenzyme A (CoA) and affords robust protein labeling profiles. We comprehensively characterize the metabolic dependence, toxicity, and histone deacetylase (HDAC) inhibitor sensitivity of these bioorthogonal pro-metabolites, and apply an optimized probe to identify novel candidate protein targets of short chain fatty acids in cells. Our studies showcase the utility of bioorthogonal pro-metabolites for unbiased profiling of cellular protein acylation, and suggest new approaches for studying the signaling functions of SCFAs in differentiation and disease.
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Details
- Title
- Bioorthogonal pro-metabolites for profiling short chain fatty acylation
- Creators
- Wilson R. Sinclair - National Cancer InstituteJonathan H. Shrimp - National Cancer InstituteThomas T. Zengeya - National Cancer InstituteRhushikesh A. Kulkarni - National Cancer InstituteJulie M. Garlick - National Cancer InstituteHans Luecke - National Institute of Diabetes and Digestive and Kidney DiseasesAndrew J. Worth - University of PennsylvaniaIan A. Blair - University of PennsylvaniaNathaniel W. Snyder - Drexel UniversityJordan L. Meier - National Cancer Institute
- Publication Details
- Chemical science (Cambridge), v 9(5), pp 1236-1241
- Publisher
- Royal Soc Chemistry
- Number of pages
- 6
- Grant note
- ZIABC011488 / NATIONAL CANCER INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) ZIA BC011488-04 / NIH, National Cancer Institute; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) T32ES019851 / NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Environmental Health Sciences (NIEHS)
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- A.J. Drexel Autism Institute
- Web of Science ID
- WOS:000424010600017
- Scopus ID
- 2-s2.0-85041327552
- Other Identifier
- 991019167724704721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Chemistry, Multidisciplinary