Molecular Tools for the Study of ADP-Ribosylation: A Unified and Versatile Method to Synthesise Native Mono-ADP-Ribosylated Peptides
| Autor: | Ivan Ahel, Qiang Liu, Luke van Gijlswijk, Johannes Gregor Matthias Rack, Nico J. Meeuwenoord, Dmitri V. Filippov, Gijsbert A. van der Marel, Jim Voorneveld, Herman S. Overkleeft |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
DNA Repair
DNA damage Poly ADP ribose polymerase Hot Paper 010402 general chemistry 01 natural sciences Catalysis Serine chemistry.chemical_compound ADP-Ribosylation (ADP-ribosyl) hydrolase Hydrolase Threonine poly(ADP-ribose) polymerases Full Paper 010405 organic chemistry Chemistry Organic Chemistry General Chemistry Full Papers 0104 chemical sciences post-translational modification Biochemistry ADP-ribosylation solid-phase peptide synthesis Bioisostere Peptides Protein Processing Post-Translational Cysteine |
| Zdroj: | CHEM-EUR J, 27(41), 10621-10627. WILEY-V C H VERLAG GMBH CHEM-EUR J Chemistry-a European Journal, 27(41), 10621-10627. WILEY-V C H VERLAG GMBH Chemistry (Weinheim an Der Bergstrasse, Germany) |
| Popis: | ADP‐ribosylation (ADPr), as a post‐translational modification, plays a crucial role in DNA‐repair, immunity and many other cellular and physiological processes. Serine is the main acceptor for ADPr in DNA damage response, whereas the physiological impact of less common ADPr‐modifications of cysteine and threonine side chains is less clear. Generally, gaining molecular insights into ADPr recognition and turn‐over is hampered by the availability of homogeneous, ADP‐ribosylated material, such as mono‐ADP‐ribosylated (MARylated) peptides. Here, a new and efficient solid‐phase strategy for the synthesis of Ser‐, Thr‐ and Cys‐MARylated peptides is described. ADP‐ribosylated cysteine, apart from being a native post‐translational modification in its own right, proved to be suitable as a stabile bioisostere for ADP‐ribosylated serine making it a useful tool to further biochemical research on serine ADP‐ribosylation. In addition, it was discovered that the Streptococcus pyogenes encoded protein, SpyMacroD, acts as a Cys‐(ADP‐ribosyl) hydrolase. ADP‐ribosylated peptides: A universal approach to synthesise mono‐ADP‐ribosylated peptides is presented. These peptides can provide a valuable tool for studying ADP‐ribosylation. This is demonstrated by the synthesis of a variety of ADP‐ribosylated peptides modified on Ser‐, Thr‐ or Cys‐residues, the latter of which can act as a stable isostere for Ser‐ADPr as Cys‐ADPr is not reversed by the Ser‐ADPr hydrolase ARH3. Furthermore, in using these peptides, the first hydrolase capable of hydrolysing Cys‐ADPr was identified. |
| Databáze: | OpenAIRE |
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