Issue 8, 2025

Regioselective rapid ene-type reaction (RRER) enables bioconjugation of histone serotonylation

Abstract

Triazolinedione (TAD) derivatives have been commonly utilized as protection and labeling reagents for indole and phenol moieties via a reversible ene-type reaction. Previous studies showed that the TAD probes could selectively modify tyrosine and tryptophan side-chains within proteins and peptides under distinct pH conditions. Here, we report a pH-controlled regioselective rapid ene-type reaction (RRER) between TAD and 5-hydroxyindole, where the modification occurs on the C4 position rather than the C3 of inactivated indole rings. Employing this unique reaction, we have performed the selective bioconjugation of serotonylation occurring on the fifth amino acid residue, glutamine, of histone H3 (H3Q5), which does not contain any tryptophan in its protein sequence. Finally, RRER was applied to determine the H3Q5 serotonylation levels in cultured cells and tissue samples, which served as a newly developed powerful tool for in vitro and in vivo histone monoaminylation analysis. Overall, our findings in this research expanded the chemical biology toolbox for investigating histone monoaminylation and facilitated the understandings of TAD-mediated ene-type reactions.

Graphical abstract: Regioselective rapid ene-type reaction (RRER) enables bioconjugation of histone serotonylation

Supplementary files

Article information

Article type
Communication
Submitted
16 Jun 2025
Accepted
16 Jul 2025
First published
17 Jul 2025
This article is Open Access
Creative Commons BY-NC license

RSC Chem. Biol., 2025,6, 1278-1283

Regioselective rapid ene-type reaction (RRER) enables bioconjugation of histone serotonylation

J. Wu, H. Li, A. R. Lovato, A. Symasek, Z. Lin and Q. Zheng, RSC Chem. Biol., 2025, 6, 1278 DOI: 10.1039/D5CB00159E

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