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Lookup NU author(s): Professor Tiago OuteiroORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2024 The Royal Society of Chemistry.Advanced glycation end products (AGEs) arise from the Maillard reaction between dicarbonyls and proteins, nucleic acids, or specific lipids. Notably, AGEs are linked to aging and implicated in various disorders, spanning from cancer to neurodegenerative diseases. While dicarbonyls like methylglyoxal preferentially target arginine residues, lysine-derived AGEs, such as N(6)-(1-carboxymethyl)lysine (CML) and N(6)-(1-carboxyethyl)lysine (CEL), are also abundant. Predicting protein glycation in vivo proves challenging due to the intricate nature of glycation reactions. In vitro, glycation is difficult to control, especially in proteins that harbor multiple glycation-prone amino acids. α-Synuclein (aSyn), pivotal in Parkinson's disease and synucleinopathies, has 15 lysine residues and is known to become glycated at multiple lysine sites. To understand the influence of glycation in specific regions of aSyn on its behavior, a strategy for site-specific glycated protein production is imperative. To fulfill this demand, we devised a synthetic route integrating solid-phase peptide synthesis, orthogonal protection of amino acid side-chain functionalities, and reductive amination strategies. This methodology yielded two disease-related N-terminal peptide fragments, each featuring five and six CML and CEL modifications, alongside a full-length aSyn protein containing a site-selective E46CEL modification. Our synthetic approach facilitates the broad introduction of glycation motifs at specific sites, providing a foundation for generating glycated forms of synucleinopathy-related and other disease-relevant proteins.
Author(s): Bosbach C, Gatzemeier LM, Bloch von Blottnitz KI, Konig A, Diederichsen U, Steinem C, Outeiro TF
Publication type: Article
Publication status: Published
Journal: Organic and Biomolecular Chemistry
Year: 2024
Volume: 22
Issue: 13
Pages: 2670-2676
Print publication date: 07/04/2024
Online publication date: 08/03/2024
Acceptance date: 08/03/2024
Date deposited: 02/04/2024
ISSN (electronic): 1477-0539
Publisher: Royal Society of Chemistry
URL: https://doi.org/10.1039/d4ob00225c
DOI: 10.1039/d4ob00225c
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