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 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.
Department of Chemistry, University of California, Berkeley, CA, USA.
Shixian
0000-0001-9718-9986
S
Lin
Department of Chemistry, University of California, Berkeley, CA, USA.|School of Physical Science and Technology, ShanghaiTech University, Shanghai, China.
Xiaoyu
0000-0002-0756-0671
X
Yang
Department of Chemistry, University of California, Berkeley, CA, USA.
Shang
0000-0001-6285-8959
S
Jia
Department of Pharmaceutical Chemistry, University of California, San Francisco, CA, USA.
Amy M
0000-0003-4700-8256
AM
Weeks
Department of Pharmaceutical Chemistry, University of California, San Francisco, CA, USA.
Michael
0000-0002-2304-9961
M
Hornsby
Department of Pharmaceutical Chemistry, University of California, San Francisco, CA, USA.
Peter S
0000-0002-8745-4034
PS
Lee
California Institute for Quantitative Biosciences, University of California, Berkeley, CA, USA.
Rita V
0000-0001-6917-8147
RV
Nichiporuk
California Institute for Quantitative Biosciences, University of California, Berkeley, CA, USA.
Anthony T
AT
Iavarone
Department of Pharmaceutical Chemistry, University of California, San Francisco, CA, USA.|Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA, USA.
James A
0000-0001-8267-5519
JA
Wells
Department of Chemistry, University of California, Berkeley, CA, USA. chrischang@berkeley.edu fdtoste@berkeley.edu.|Chemical Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA.
F Dean
0000-0001-8018-2198
FD
Toste
Department of Chemistry, University of California, Berkeley, CA, USA. chrischang@berkeley.edu fdtoste@berkeley.edu.|Department of Molecular and Cell Biology, University of California, Berkeley, CA, USA.|Howard Hughes Medical Institute, University of California, Berkeley, CA, USA.|Chemical Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA.
Christopher J
0000-0001-5732-9497
CJ
Chang
D000199:Actins / Q000737:chemistry; D001388:Aziridines / Q000737:chemistry*; D003545:Cysteine / Q000737:chemistry*; D000072669:Gene Editing; D055786:Gene Knockout Techniques; D018796:Immunoconjugates / Q000737:chemistry*; D008715:Methionine / Q000032:analysis / Q000737:chemistry*; D009154:Mutation; D010084:Oxidation-Reduction; D010751:Phosphopyruvate Hydratase / Q000235:genetics; D000072417:Protein Domains; D011506:Proteins / Q000737:chemistry; D040901:Proteomics / Q000379:methods; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000201:enzymology / Q000235:genetics / Q000254:growth & development; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics; D012973:Sodium Hypochlorite / Q000494:pharmacology
D000199:Actins; D001388:Aziridines; D018796:Immunoconjugates; D011506:Proteins; D029701:Saccharomyces cerevisiae Proteins; D008715:Methionine; D012973:Sodium Hypochlorite; C521376:ENO1 protein, S cerevisiae; D010751:Phosphopyruvate Hydratase; D003545:Cysteine