Redox-based reagents for chemoselective methionine bioconjugation

Cysteine can be specifically functionalized by a myriad of acid-base conjugation strategies for applications ranging from probing protein function to antibody-drug conjugates and proteomics. In contrast, selective ligation to the other sulfur-containing amino acid, methionine, has been precluded by...

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Bibliographic Details
Published in:Science (American Association for the Advancement of Science) 2017-02, Vol.355 (6325), p.597-602
Main Authors: Lin, Shixian, Yang, Xiaoyu, Jia, Shang, Weeks, Amy M., Hornsby, Michael, Lee, Peter S., Nichiporuk, Rita V., Iavarone, Anthony T., Wells, James A., Toste, F. Dean, Chang, Christopher J.
Format: Article
Language:English
Subjects:
Acids
Actins - chemistry
Amino acids
Antibodies
Aziridines - chemistry
BASIC BIOLOGICAL SCIENCES
Biocompatibility
Conjugates
Conjugation
Cysteine
Cysteine - chemistry
Gene Editing
Gene Knockout Techniques
Hydrophobicity
Immunoconjugates - chemistry
INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY
Methionine
Methionine - analysis
Methionine - chemistry
Mutation
Oxidation-Reduction
Oxidizing agents
Payloads
Phosphopyruvate Hydratase - genetics
Protein Domains
Proteins
Proteins - chemistry
Proteomics
Proteomics - methods
Reagents
Residues
Saccharomyces cerevisiae - drug effects
Saccharomyces cerevisiae - enzymology
Saccharomyces cerevisiae - genetics
Saccharomyces cerevisiae - growth & development
Saccharomyces cerevisiae Proteins - genetics
Sodium Hypochlorite - pharmacology
Strategy
Sulfur
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Summary:Cysteine can be specifically functionalized by a myriad of acid-base conjugation strategies for applications ranging from probing protein function to antibody-drug conjugates and proteomics. In contrast, selective ligation to the other sulfur-containing amino acid, methionine, has been precluded by its intrinsically weaker nucleophilicity. Here, we report a strategy for chemoselective methionine bioconjugation through redox reactivity, using oxaziridine-based reagents to achieve highly selective, rapid, and robust methionine labeling under a range of biocompatible reaction conditions. We highlight the broad utility of this conjugation method to enable precise addition of payloads to proteins, synthesis of antibody-drug conjugates, and identification of hyperreactive methionine residues in whole proteomes.
ISSN:0036-8075
1095-9203
DOI:10.1126/science.aal3316