Cofactor Biogenesis in Cysteamine Dioxygenase: C-F Bond Cleavage with Genetically Incorporated Unnatural Tyrosine

Angewandte Chemie
Yifan WangAimin Liu

Abstract

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 (F2 -Tyr), specifically into Tyr222 of human ADO, an autocatalytic oxidative carbon-fluorine bond activation and fluoride release were identified by mass spectrometry and 19 F NMR 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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Citations

Jun 9, 2020·Chemical Society Reviews·Yifan Wang, Aimin Liu
Sep 2, 2020·Proceedings of the National Academy of Sciences of the United States of America·Mark D WhiteEmily Flashman
Nov 19, 2020·Journal of Structural Biology·Zhenzhen ChenChao Xu
Mar 19, 2021·Journal of the American Chemical Society·Yifan WangAimin Liu
Jun 9, 2020·Biochemistry·Rebeca L FernandezThomas C Brunold
Oct 23, 2020·Journal of the American Chemical Society·Jiasong LiAimin Liu
May 3, 2019·Biochemistry·Sekotilani AloiGuy N L Jameson
Aug 5, 2021·The FEBS Journal·Dona M GunawardanaEmily Flashman

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