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Synthesis and Evaluation of Non‐Hydrolyzable Phospho‐Lysine Peptide Mimics

The intrinsic lability of the phosphoramidate P−N bond in phosphorylated histidine (pHis), arginine (pHis) and lysine (pLys) residues is a significant challenge for the investigation of these post‐translational modifications (PTMs), which gained attention rather recently. While stable mimics of pHis...

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Autores principales: Hauser, Anett, Poulou, Eleftheria, Müller, Fabian, Schmieder, Peter, Hackenberger, Christian P. R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7898648/
https://www.ncbi.nlm.nih.gov/pubmed/32986895
http://dx.doi.org/10.1002/chem.202003947
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author Hauser, Anett
Poulou, Eleftheria
Müller, Fabian
Schmieder, Peter
Hackenberger, Christian P. R.
author_facet Hauser, Anett
Poulou, Eleftheria
Müller, Fabian
Schmieder, Peter
Hackenberger, Christian P. R.
author_sort Hauser, Anett
collection PubMed
description The intrinsic lability of the phosphoramidate P−N bond in phosphorylated histidine (pHis), arginine (pHis) and lysine (pLys) residues is a significant challenge for the investigation of these post‐translational modifications (PTMs), which gained attention rather recently. While stable mimics of pHis and pArg have contributed to study protein substrate interactions or to generate antibodies for enrichment as well as detection, no such analogue has been reported yet for pLys. This work reports the synthesis and evaluation of two pLys mimics, a phosphonate and a phosphate derivative, which can easily be incorporated into peptides using standard fluorenyl‐methyloxycarbonyl‐ (Fmoc‐)based solid‐phase peptide synthesis (SPPS). In order to compare the biophysical properties of natural pLys with our synthetic mimics, the pK (a) values of pLys and analogues were determined in titration experiments applying nuclear magnetic resonance (NMR) spectroscopy in small model peptides. These results were used to compute electrostatic potential (ESP) surfaces obtained after molecular geometry optimization. These findings indicate the potential of the designed non‐hydrolyzable, phosphonate‐based mimic for pLys in various proteomic approaches.
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spelling pubmed-78986482021-03-03 Synthesis and Evaluation of Non‐Hydrolyzable Phospho‐Lysine Peptide Mimics Hauser, Anett Poulou, Eleftheria Müller, Fabian Schmieder, Peter Hackenberger, Christian P. R. Chemistry Full Papers The intrinsic lability of the phosphoramidate P−N bond in phosphorylated histidine (pHis), arginine (pHis) and lysine (pLys) residues is a significant challenge for the investigation of these post‐translational modifications (PTMs), which gained attention rather recently. While stable mimics of pHis and pArg have contributed to study protein substrate interactions or to generate antibodies for enrichment as well as detection, no such analogue has been reported yet for pLys. This work reports the synthesis and evaluation of two pLys mimics, a phosphonate and a phosphate derivative, which can easily be incorporated into peptides using standard fluorenyl‐methyloxycarbonyl‐ (Fmoc‐)based solid‐phase peptide synthesis (SPPS). In order to compare the biophysical properties of natural pLys with our synthetic mimics, the pK (a) values of pLys and analogues were determined in titration experiments applying nuclear magnetic resonance (NMR) spectroscopy in small model peptides. These results were used to compute electrostatic potential (ESP) surfaces obtained after molecular geometry optimization. These findings indicate the potential of the designed non‐hydrolyzable, phosphonate‐based mimic for pLys in various proteomic approaches. John Wiley and Sons Inc. 2020-12-07 2021-02-01 /pmc/articles/PMC7898648/ /pubmed/32986895 http://dx.doi.org/10.1002/chem.202003947 Text en © 2020 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Full Papers
Hauser, Anett
Poulou, Eleftheria
Müller, Fabian
Schmieder, Peter
Hackenberger, Christian P. R.
Synthesis and Evaluation of Non‐Hydrolyzable Phospho‐Lysine Peptide Mimics
title Synthesis and Evaluation of Non‐Hydrolyzable Phospho‐Lysine Peptide Mimics
title_full Synthesis and Evaluation of Non‐Hydrolyzable Phospho‐Lysine Peptide Mimics
title_fullStr Synthesis and Evaluation of Non‐Hydrolyzable Phospho‐Lysine Peptide Mimics
title_full_unstemmed Synthesis and Evaluation of Non‐Hydrolyzable Phospho‐Lysine Peptide Mimics
title_short Synthesis and Evaluation of Non‐Hydrolyzable Phospho‐Lysine Peptide Mimics
title_sort synthesis and evaluation of non‐hydrolyzable phospho‐lysine peptide mimics
topic Full Papers
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7898648/
https://www.ncbi.nlm.nih.gov/pubmed/32986895
http://dx.doi.org/10.1002/chem.202003947
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