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Copper‐Mediated Selenazolidine Deprotection Enables One‐Pot Chemical Synthesis of Challenging Proteins
Author(s) -
Zhao Zhenguang,
Metanis Norman
Publication year - 2019
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201909484
Subject(s) - selenocysteine , chemistry , cysteine , native chemical ligation , chemical synthesis , combinatorial chemistry , glutathione , biochemistry , bioorthogonal chemistry , selenium , organic chemistry , enzyme , click chemistry , in vitro
While chemical protein synthesis has granted access to challenging proteins, the synthesis of longer proteins is often limited by low abundance or non‐strategic placement of cysteine residues, which are essential for native chemical ligations, as well as multiple purification and isolation steps. We describe the one‐pot total synthesis of human thiosulfate:glutathione sulfurtransferase (TSTD1). WT‐TSTD1 was synthesized in a C‐to‐N synthetic approach involving multiple NCL reactions, Cu II ‐mediated deprotection of selenazolidine (Sez), and chemoselective deselenization. The seleno‐analog Se‐TSTD1, in which the active site Cys is replaced with selenocysteine, was also synthesized with a kinetically controlled ligation with an N‐to‐C synthetic approach. The catalytic activity of the two proteins indicated that Se‐TSTD1 possessed only four‐fold lower activity than WT‐TSTD1, thus suggesting that selenoproteins can have physiologically comparable sulfutransferase activity to their cysteine counterparts.