Chemical Synthesis of Human Selenoprotein F and Elucidation of Its Thiol-Disulfide Oxidoreductase Activity

04 February 2022, Version 1
This content is a preprint and has not undergone peer review at the time of posting.


Selenoprotein F (SelF) is an endoplasmic reticulum-residing eukaryotic protein that contains a selenocysteine (Sec) residue. It has been suggested to be involved in a number of physiological processes by acting as a thiol-disulfide oxidoreductase, but the exact role has remained unclear due to the lack of a reliable production method. We document herein a robust synthesis of the human SelF through a three-segment two-ligation semisynthesis strategy. Highlighted in this synthetic route are the use of a mild desulfurization process to protect the side-chain of the Sec residue from being affected and the simultaneous removal of acetamidomethyl and p-methoxybenzyl protection groups by PdCl2, thus facilitating the synthesis of multi-milligram of homogenous SelF. The reduction potential of SelF was determined and the thiol-disulfide oxidoreductase activity was further supported by its ability to catalyze the reduction and isomerization of disulfide bonds.


selenoprotein F
chemical protein synthesis
thioredoxin-like domain
selenenylsulfide bond
thiol-disulfide oxidoreductase

Supplementary materials

Chemical Synthesis of Human Selenoprotein F--Supporting information
The chemical synthesis of the 134-residue human selenoprotein F (SelF) was accomplished on multi-milligram scale. The synthetic SelF exhibits typical thiol-disulfide oxidoreductase activity.


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