Jump to main content
Jump to site search


Bioorthogonal pro-metabolites for profiling short chain fatty acylation

Author affiliations

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.

Graphical abstract: Bioorthogonal pro-metabolites for profiling short chain fatty acylation

Back to tab navigation

Supplementary files

Publication details

The article was received on 17 Jan 2017, accepted on 07 Dec 2017 and first published on 08 Dec 2017


Article type: Edge Article
DOI: 10.1039/C7SC00247E
Citation: Chem. Sci., 2018, Advance Article
  • Open access: Creative Commons BY license
  •   Request permissions

    Bioorthogonal pro-metabolites for profiling short chain fatty acylation

    W. R. Sinclair, J. H. Shrimp, T. T. Zengeya, R. A. Kulkarni, Julie M. Garlick, H. Luecke, A. J. Worth, I. A. Blair, N. W. Snyder and J. L. Meier, Chem. Sci., 2018, Advance Article , DOI: 10.1039/C7SC00247E

    This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. Material from this article can be used in other publications provided that the correct acknowledgement is given with the reproduced material.

    Reproduced material should be attributed as follows:

    • For reproduction of material from NJC:
      [Original citation] - Published by The Royal Society of Chemistry (RSC) on behalf of the Centre National de la Recherche Scientifique (CNRS) and the RSC.
    • For reproduction of material from PCCP:
      [Original citation] - Published by the PCCP Owner Societies.
    • For reproduction of material from PPS:
      [Original citation] - Published by The Royal Society of Chemistry (RSC) on behalf of the European Society for Photobiology, the European Photochemistry Association, and RSC.
    • For reproduction of material from all other RSC journals:
      [Original citation] - Published by The Royal Society of Chemistry.

    Information about reproducing material from RSC articles with different licences is available on our Permission Requests page.

Search articles by author

Spotlight

Advertisements