Site-Selective Synthetic Acylation of a Target Protein in Living Cells Promoted by a Chemical Catalyst/Donor System

Site-Selective Synthetic Acylation of a Target Protein in Living Cells Promoted by a Chemical Catalyst/Donor System

Cell biology is tightly regulated by post-translational modifications of proteins. Methods to modulate post-translational modifications in living cells without relying on enzymes or genetic manipulation are, however, largely underexplored. We previously reported that a chemical catalyst (DSH) conjug...

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Bibliographic Details
Published in:ACS chemical biology Vol. 14; no. 6; pp. 1102 - 1109
Main Authors: Hamajima, Wataru, Fujimura, Akiko, Fujiwara, Yusuke, Yamatsugu, Kenzo, Kawashima, Shigehiro A, Kanai, Motomu
Format: Journal Article
Language:English
Published: United States American Chemical Society 21-06-2019
Subjects:
Acetylation
Acyl Coenzyme A - metabolism
Acylation
Catalysis
Cell Membrane Permeability
Escherichia coli - enzymology
HEK293 Cells
Humans
Ligands
Proteins - metabolism
Tetrahydrofolate Dehydrogenase - metabolism
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Summary:Cell biology is tightly regulated by post-translational modifications of proteins. Methods to modulate post-translational modifications in living cells without relying on enzymes or genetic manipulation are, however, largely underexplored. We previously reported that a chemical catalyst (DSH) conjugated with a nucleosome-binding ligand can activate an acyl-CoA and promote site-selective lysine acylation of histones in test tubes. In-cell acylation by this catalyst system is challenging, however, mainly due to the low cell permeability of acyl-CoA and the propensity of DSH to form inactive disulfide. Here, we report a new catalyst system effective for in-cell acylation, comprising a cell-permeable acyl donor and pro-drugged DSH. Using E. coli dihydrofolate reductase and trimethoprim as a model protein and ligand pair, the catalyst system enabled site-selective acylation of the target protein in living cells. The findings will lead to the development of useful chemical biology tools and new therapeutic strategies capable of synthetically modulating post-translational modifications.
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ISSN:1554-8929
1554-8937
DOI:10.1021/acschembio.9b00102