Towards the Synthesis of Well-Defined O-ADP-Ribosylated Peptides

PS1 Poster session 1 Odd numbers
Location (hall): 
Start/end time: 
Monday, July 1, 2019 - 15:45 to 17:15

Jim Voorneveld1, Hermen Overkleeft1, Gijsbert A. van der Marel1, Dmitri Filippov1

1Leiden University, Leiden Institute of Chemistry, Bio-Organic Synthesis Group, Leiden, The Netherlands

The sites of intracellular ADP-ribosylation were generally believed to be either acidic Asp and Glu residues1 or, less frequently, Arg2. In case of arginine the ADPr moiety is connected to the peptide through an N-glycosidic linkage, while the acidic residues are O-ADP-ribosylated. With the recent discovery that serine is not only a possible but also abundant acceptor of ADPr3, transferred to it by the PARP1-HPF1 complex4, a renewed scientific interest arose in O-linked ADPr-Ser and by extension ADPr-Tyr and ADPr-Thr.

This work shows the synthesis of well-defined Ser-ADP-ribosylated peptides and the corresponding 5-phosphate-ribose intermediates as well as the ability to obtain these peptides in quantities sufficient for biological experimentation. To demonstrate the utility of the ADPr-peptides prepared by organic synthesis we set out to confirm the stereochemistry of the glycosidic linkage in the native ADPr-Ser bond by means of preparation both α- and β-configured ADPr-Ser-peptides. To this end, Fmoc-Ser-OH building blocks decorated with orthogonally protected α- and β-5-phosphate-ribose were synthesized. Such building blocks are compatible with solid-phase peptide synthesis and enable access to a variety of Ser-ADP-ribosylated peptides.

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  2. Lu, B.; Bu, M.; Eckei, L.; Krieg, S.; Verheugd, P.; Shilton, B. H. ADP-Ribosylation , a Multifaceted Posttranslational Modi Fi Cation Involved in the Control of Cell Physiology in Health and Disease. DOI: 10.1021/acs.chemrev.7b00122
  3. Leidecker, O.; Bonfiglio, J. J.; Colby, T.; Zhang, Q.; Atanassov, I.; Zaja, R.; Palazzo, L.; Stockum, A.; Ahel, I.; Matic, I. Serine Is a New Target Residue for Endogenous ADP-Ribosylation on Histones. Nat. Chem. Biol. 2016, 12, 998–1000.
  4. Bonfiglio, J. J.; Fontana, P.; Zhang, Q.; Colby, T.; Gibbs-Seymour, I.; Atanassov, I.; Bartlett, E.; Zaja, R.; Ahel, I.; Matic, I. Serine ADP-Ribosylation Depends on HPF1. Mol. Cell 2017, 65 (5), 932–940.