Epimeric modulation of post-translational modifications
- 1Department of Chemistry & Biochemistry
- 2University of Texas at Arlington
Abstract
2 Abstract Dysregulated PTMs are widely implicated in many diseases both directly and as biomarkers. Investigations into the diverse mechanistic aspects leading to their formation are complex and consequential. Although reports on the prevalence and importance of amino acid epimers in biological systems and therapeutics have escalated, their effect on subsequent posttranslational modifications (PTMs) has been overlooked. We show that such epimeric modifications can have profound effects through a form of hierarchical crosstalk, termed bottomup crosstalk. We examined how D-serine and D-aspartic acid residues within biologically and therapeutically important peptides affect subsequent enzymatic phosphorylation and glycosylation. D-Ser was found to inhibit phosphorylation and/or direct phosphorylation to different sites within the peptide. Surprisingly, the D-Ser6 epimer and L-Ser5 residue of atrial natriuretic peptide were phosphorylated. Asp epimers and isomers produced widely different effects in all peptides examined. Epimers reduced the degree of O-glycosylated products and often altered the glycosylation sites. Epimers also affected enzymatic hydrolysis of the peptide main chain. However, they did not affect higher order PTMs such as extending glycosylation of existing groups. Epimeric modifications often caused negative crosstalk, such as residue competition and site redirection, when the modification was within one or two amino acids of the existing PTM.
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BibTeX
@misc{armstrong2026epimeric,
title = {{Epimeric modulation of post-translational modifications}},
author = {Daniel W. Armstrong and Angel Covarrubias and Umang Dhaubhadel and Arzoo Patel and Amanda Razo-Smith},
howpublished = {ChemRxiv},
year = {2026},
month = oct,
doi = {10.26434/chemrxiv.15010376/v1},
url = {https://chemrxiv.org/doi/full/10.26434/chemrxiv.15010376/v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Epimeric modulation of post-translational modifications
AU - Daniel W. Armstrong
AU - Angel Covarrubias
AU - Umang Dhaubhadel
AU - Arzoo Patel
AU - Amanda Razo-Smith
PY - 2026
DA - 2026/10/13
PB - ChemRxiv
DO - 10.26434/chemrxiv.15010376/v1
UR - https://chemrxiv.org/doi/full/10.26434/chemrxiv.15010376/v1
AB - 2 Abstract Dysregulated PTMs are widely implicated in many diseases both directly and as biomarkers. Investigations into the diverse mechanistic aspects leading to their formation are complex and consequential. Although reports on the prevalence and importance of amino acid epimers in biological systems and therapeutics have escalated, their effect on subsequent posttranslational modifications (PTMs) has been overlooked. We show that such epimeric modifications can have profound effects through a form of hierarchical crosstalk, termed bottomup crosstalk. We examined how D-serine and D-aspartic acid residues within biologically and therapeutically important peptides affect subsequent enzymatic phosphorylation and glycosylation. D-Ser was found to inhibit phosphorylation and/or direct phosphorylation to different sites within the peptide. Surprisingly, the D-Ser6 epimer and L-Ser5 residue of atrial natriuretic peptide were phosphorylated. Asp epimers and isomers produced widely different effects in all peptides examined. Epimers reduced the degree of O-glycosylated products and often altered the glycosylation sites. Epimers also affected enzymatic hydrolysis of the peptide main chain. However, they did not affect higher order PTMs such as extending glycosylation of existing groups. Epimeric modifications often caused negative crosstalk, such as residue competition and site redirection, when the modification was within one or two amino acids of the existing PTM.
ER -