Increasing evidence supports an important role for misfolded proteins in the pathogenesis of numerous diseases including diabetes, Alzheimer disease, Parkinson disease, and both alcoholic and non-alcoholic liver disease.

Understanding the mechanisms of protein-folding, specifically thiol-disulfide exchange, may lead to development of a novel class of therapeutics that would help alleviate a wide range of diseases by targeting the UPR. Over the past decade, UPR has become a very attractive therapeutic target for multiple pathologies including Alzheimer disease, Parkinson disease, alcoholic and non-alcoholic liver disease, and type-2 diabetes. Given their vital role in protein-folding, loss of PDI activity has been associated with the pathogenesis of numerous disease states, most commonly related to the unfolded protein response (UPR). To date, the PDI gene family contains 21 members, varying in domain composition, molecular weight, tissue expression, and cellular processing. Subcellular localization and the presence of a TRX domain, however, comprise the short list of distinguishing features required for gene family classification. As members of the PDI family of proteins, all proteins contain a TRX-like structural domain and are predominantly expressed in the endoplasmic reticulum. These proteins are part of a larger superfamily of proteins known as the thioredoxin protein family (TRX).

The enzymes primarily responsible for facilitating thiol-disulfide exchange are members of an expanding family of proteins known as protein disulfide isomerases (PDIs). Enzyme-mediated disulfide bond formation is a highly conserved process affecting over one-third of all eukaryotic proteins.

Pdi p22884