Abnormal Enhancement of Protein Disulfide Isomerase-like Activity of a Cyclic Diselenide Conjugated with a Basic Amino Acid by Inserting a Glycine Spacer

Abstract

In a previous study, we reported that (S)-1,2-diselenane-4-amine (1) catalyzes oxidative protein folding through protein disulfide isomerase (PDI)-like catalytic mechanisms and that the direct conjugation of a basic amino acid (Xaa: His, Lys, or Arg) via an amide bond improves the catalytic activity of 1 by increasing its diselenide (Se–Se) reduction potential (E′°). In this study, to modulate the Se–Se redox properties and the association of the compounds with a protein substrate, new catalysts, in which a Gly spacer was inserted between 1 and Xaa, were synthesized. Exhaustive comparison of the PDI-like catalytic activities and E′° values among 1, 1-Xaa, and 1-Gly-Xaa showed that the insertion of a Gly spacer into 1-Xaa either did not change or slightly reduced the PDI-like activity and the E′° values. Importantly, however, only 1-Gly-Arg deviated from this generality and showed obviously increased E°′ value and PDI-like activity compared to the corresponding compound with no Gly spacer (1-Arg); on the contrary, its catalytic activity was the highest among the diselenide compounds employed in this study, while this abnormal enhancement of the catalytic activity of 1-Gly-Arg could not be fully explained by the thermodynamics of the Se–Se bond and its association ability with protein substrates.

Modeling Type‐1 Iodothyronine Deiodinase with Peptide‐Based Aliphatic Diselenides: Potential Role of Highly Conserved His and Cys Residues as a General Acid Catalyst

“…Therefore, we evaluated the deiodination activity of an analog (compound 5 [14] ) with glycine (Gly) as a spacer amino acid residue. Instead of Aze and Pro in compounds 3 and 4 , respectively, Gly provides flexibility to the peptide backbone and prohibits the formation of a turn structure [15c] . As a result, substituting Aze and Pro spacers with Gly significantly decreased the ID‐1‐like activity, indicating that the formation of the γ‐turn in the ring‐opened state is essential for promoting deiodination.…”

Functions and mechanisms of protein disulfide isomerase family in cancer emergence

“…Since then, the family has been expanded to include new members with different structural features, sizes and functions but having the capability to assist in protein folding especially vis-à-vis disulfide bond formation. Owing to this capability, artificial mini proteins have been developed to resemble the PDI-like catalytic activity for promoting the folding process in preparations of peptide-based drugs [ 186 ]. Though PDI proteins are crucial in the normal physiology of the ER by ensuring proper folding and maturation of substrate proteins before they are exported to their destined locations, it has been found that several members of the PDI play roles in cancer as discussed in the review.…”