Proteins are biopolymers consisting of 20 amino acids. The amino acids are sequentially elongated in the ribosome via translation and transcription from genetic information to synthesize polypeptide chains. In many cases, the synthesized polypeptides undergo oxidative folding in the endoplasmic reticulum (ER), during which cross-linking of the disulfide (SS) linkage(s) between cysteine (Cys; C) residues in the peptides is coupled with the formation of a unique three-dimensional structure (i.e., conformational folding) to exert biological functions¹  (path a in Figure 25.1). It is well known that polypeptides can fold spontaneously to some extent under oxidative conditions in vitro according to the primary sequence information.²  In vivo, various enzymes cooperatively promote oxidative folding and regulate unfolding and subsequent degradation to effectively maintain proteostasis.³  The most representative ER-resident enzymes are protein disulfide isomerase (PDI) and more than 20 types of family proteins (PDIs).⁴  Although the detailed functions and molecular mechanisms of many of them are still unknown, they all consist of thioredoxin (Trx)-like domains with a redox quartet sequence called the CXXC motif as the active center, which regulates folding and unfolding while promoting SS-related reactions (i.e., SS-formation, SS-reduction, SS-isomerization, see Figure 25.10 in Section 25.4.1) in the substrate proteins.