Copper-Mediated Selenazolidine Deprotection Enables One-Pot Chemical Synthesis of Challenging Proteins

Zhenguang Zhao, Norman Metanis*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

14 Scopus citations


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, CuII-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.

Original languageAmerican English
Pages (from-to)14610-14614
Number of pages5
JournalAngewandte Chemie - International Edition
Issue number41
StatePublished - 7 Oct 2019

Bibliographical note

Funding Information:
We would like to thank Dr. Shailesh Kumar and Ms. Reem Mousa for technical assistance and helpful discussions. We also thank Mrs. Ricki Notis Dardashti for input on the manuscript. Z.Z. is grateful for a CSC fellowship. N.M. acknowledges the financial support of Israel Science Foundation (783/18) and ICRF Acceleration Grant.

Publisher Copyright:
© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim


  • chemical protein synthesis
  • native chemical ligation
  • selenocysteine
  • selenoproteins
  • thiosulfate:glutathione sulfurtransferase


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