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

In a previous study, we reported that ()-1,2-diselenane-4-amine () 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 by increasing its diselenide (Se-Se) reduction potential ('°). 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 and Xaa, were synthesized. Exhaustive comparison of the PDI-like catalytic activities and '° values among , -Xaa, and -Gly-Xaa showed that the insertion of a Gly spacer into -Xaa either did not change or slightly reduced the PDI-like activity and the '° values. Importantly, however, only -Gly-Arg deviated from this generality and showed obviously increased °' value and PDI-like activity compared to the corresponding compound with no Gly spacer (-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 -Gly-Arg could not be fully explained by the thermodynamics of the Se-Se bond and its association ability with protein substrates.