Basic Amino Acid Conjugates of 1,2-Diselenan-4-amine with Protein Disulfide Isomerase-like Functions as a Manipulator of Protein Quality Control

Abstract

Protein disulfide isomerase (PDI) can assist immature proteins to correctly fold by controlling cysteinyl disulfide (SS)-relating reactions (i. e., SS-formation, SS-cleavage, and SS-isomerization). PDI controls protein quality by suppressing protein aggregation, as well as functions as an oxidative folding catalyst. Following the amino acid sequence of the active center in PDI, basic amino acid conjugates of 1,2-diselenan-4-amine (1), which show oxidoreductase- and isomerase-like activities for SS-relating reactions, were designed as a novel PDI model compound. By conjugating the amino acids, the diselenide reduction potential of compound 1 was significantly increased, causing improvement of the catalytic activities for all SS-relating reactions. Furthermore, these compounds, especially histidine-conjugated one, remarkably suppressed protein aggregation even at low concertation (0.3 mM∼). Thus, it was demonstrated that the conjugation of basic amino acids into 1 simultaneously achieves the enhancement of the redox reactivity and the capability to suppress protein aggregation.

Keywords: Aggregation; Catalyst; Enzyme model; Protein folding; Selenium.