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Selective Covalent Protein Modification by 4‐Halopyridines through Catalysis
Author(s) -
Schardon Christopher L.,
Tuley Alfred,
Er Joyce A. V.,
Swartzel Jake C.,
Fast Walter
Publication year - 2017
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.201700104
Subject(s) - chemistry , covalent bond , cysteine , bioorthogonal chemistry , protonation , electrophile , combinatorial chemistry , pyridinium , reactivity (psychology) , reagent , chemical modification , iodoacetamide , stereochemistry , biochemistry , catalysis , organic chemistry , enzyme , medicine , ion , alternative medicine , pathology , click chemistry
We have investigated 4‐halopyridines as selective, tunable, and switchable covalent protein modifiers for use in the development of chemical probes. Nonenzymatic reactivity of 4‐chloropyridine with amino acids and thiols was ranked with respect to common covalent protein‐modifying reagents and found to have reactivity similar to that of acrylamide, but could be switched to a reactivity similar to that of iodoacetamide upon stabilization of the positively charged pyridinium. Diverse, fragment‐sized 4‐halopyridines inactivated human dimethylarginine dimethylaminohydrolase‐1 (DDAH1) through covalent modification of the active site cysteine, acting as quiescent affinity labels that required off‐pathway catalysis through stabilization of the protonated pyridinium by a neighboring aspartate residue. A series of 2‐fluoromethyl‐substituted 4‐chloropyridines demonstrated that the p K a and k inact / K I values could be predictably varied over several orders of magnitude. Covalent labeling of proteins in an Escherichia coli lysate was shown to require folded proteins, indicating that alternative proteins can be targeted, and modification is likely to be catalysisdependent. 4‐Halopyridines, and quiescent affinity labels in general, represent an attractive strategy to develop reagents with switchable electrophilicity as selective covalent protein modifiers.

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