Lysine iminylation derived from ω-3 polyunsaturated fatty acids
5 affiliations
- 1Boyce Thompson Institute, Cornell University, Ithaca, NY 14853
- 2Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY 14853
- 3Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14853
- 4Department of Biomedical Sciences, Cornell University, Ithaca, NY 14853
- 5Department of Molecular Medicine, Cornell University, Ithaca, NY 14853
Abstract
Protein posttranslational modifications (PTMs) play a central role for regulating protein function and cellular processes, with many PTMs arising from reactions with electrophilic metabolites. Here we extend the known landscape of PTMs with the identification of “lysine C3-iminylation,” the conjugation of protein lysine residues with propionaldehyde. To stabilize iminylation for mass spectrometric analyses and distinguish it from other isomeric PTMs, we developed a fixation and stable-isotope labeling approach based on parallel reduction of proteome with sodium borohydride and borodeuteride. Analyses of protein hydrolysates confirmed the presence of C3-iminylation in Caenorhabditis elegans and mouse. Additionally, proteomics results demonstrated specificity of this PTM in vitro and in vivo and revealed C3-iminylation in proteins related to critical metabolic pathways. Importantly, collective evidence from isotope tracing as well as genetic, dietary, and pharmacological manipulation experiments uncovered that C3-iminylation originates from cytochrome P450 (CYP)-mediated oxidation of omega-3 fatty acids. Correspondingly, C3-iminylation levels were elevated in C. elegans daf-2(e1370) mutants, an aging model, in which CYP activity is generally increased. These findings not only expand our understanding of the biochemical diversity of PTMs but also underscore the complex interplay between lipid metabolism and protein modifications, enabling further exploration of their biological and clinical implications.
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BibTeX
@article{zhang2026lysine,
title = {{Lysine iminylation derived from ω-3 polyunsaturated fatty acids}},
author = {Bingsen Zhang and Yu-Heng Hsieh and Tyler R. Bales and Scott D. Butler and Destiny B. Van and James J. Mullmann and Robert S. Weiss and Frank C. Schroeder},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
year = {2026},
month = sep,
doi = {10.1073/pnas.2525618123},
url = {https://doi.org/10.1073/pnas.2525618123},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - Lysine iminylation derived from ω-3 polyunsaturated fatty acids
AU - Bingsen Zhang
AU - Yu-Heng Hsieh
AU - Tyler R. Bales
AU - Scott D. Butler
AU - Destiny B. Van
AU - James J. Mullmann
AU - Robert S. Weiss
AU - Frank C. Schroeder
PY - 2026
DA - 2026/09/04
JO - Proceedings of the National Academy of Sciences of the United States of America
DO - 10.1073/pnas.2525618123
UR - https://doi.org/10.1073/pnas.2525618123
AB - Protein posttranslational modifications (PTMs) play a central role for regulating protein function and cellular processes, with many PTMs arising from reactions with electrophilic metabolites. Here we extend the known landscape of PTMs with the identification of “lysine C3-iminylation,” the conjugation of protein lysine residues with propionaldehyde. To stabilize iminylation for mass spectrometric analyses and distinguish it from other isomeric PTMs, we developed a fixation and stable-isotope labeling approach based on parallel reduction of proteome with sodium borohydride and borodeuteride. Analyses of protein hydrolysates confirmed the presence of C3-iminylation in Caenorhabditis elegans and mouse. Additionally, proteomics results demonstrated specificity of this PTM in vitro and in vivo and revealed C3-iminylation in proteins related to critical metabolic pathways. Importantly, collective evidence from isotope tracing as well as genetic, dietary, and pharmacological manipulation experiments uncovered that C3-iminylation originates from cytochrome P450 (CYP)-mediated oxidation of omega-3 fatty acids. Correspondingly, C3-iminylation levels were elevated in C. elegans daf-2(e1370) mutants, an aging model, in which CYP activity is generally increased. These findings not only expand our understanding of the biochemical diversity of PTMs but also underscore the complex interplay between lipid metabolism and protein modifications, enabling further exploration of their biological and clinical implications.
SN - 0027-8424
SN - 1091-6490
ER -