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.
Keywords: aggregation; catalyst; chaperone; enzyme model; oxidative folding; selenium.