Journal
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
Volume 57, Issue 27, Pages 8149-8153Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.201803907
Keywords
amino acids; C-H activation; dioxygenases; fluorine; proteins
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Funding
- National Institutes of Health (NIH) [GM107529, GM108988]
- National Science Foundation [CHE-1623856]
- Lutcher Brown Distinguished Chair Endowment fund
- National Institutes of Health [G12MD007591]
- National Science Foundation (NSF) [1625963]
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Cysteamine dioxygenase (ADO) is a thiol dioxygenase whose study has been stagnated by the ambiguity as to whether or not it possesses an anticipated protein-derived cofactor. Reported herein is the discovery and elucidation of a Cys-Tyr cofactor in human ADO, crosslinked between Cys220 and Tyr222 through a thioether (C-S) bond. By genetically incorporating an unnatural amino acid, 3,5-difluoro-tyrosine (F-2-Tyr), specifically into Tyr222 of human ADO, an autocatalytic oxidative carbon-fluorine bond activation and fluoride release were identified by mass spectrometry and (FNMR)-F-19 spectroscopy. These results suggest that the cofactor biogenesis is executed by a powerful oxidant during an autocatalytic process. Unlike that of cysteine dioxygenase, the crosslinking results in a minimal structural change of the protein and it is not detectable by routine low-resolution techniques. Finally, a new sequence motif, C-X-Y-Y(F), is proposed for identifying the Cys-Tyr crosslink.
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