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

17 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

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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