The protein disulfide isomerase (PDI) family, found in the endoplasmic reticulum (ER) of the eukaryotic cell, catalyzes the formation and cleavage of disulfide bonds and thereby helps in protein folding. A decrease in PDI activity under ER stress conditions leads to protein misfolding, which is responsible for the progression of various human diseases, such as Alzheimer's, Parkinson's, diabetes mellitus, and atherosclerosis. Here we report that water-soluble cyclic diselenides mimic the multifunctional activity of the PDI family by facilitating oxidative folding, disulfide formation/reduction, and repair of the scrambled disulfide bonds in misfolded proteins.

At the redox-active centero ft hioredoxin reductase (TrxR), as elenenyl sulfide( SeÀS) bond is formed between Cys497 and Sec498, which is activated into the thiolselenolate state ([SH,Se À ]) by reactingw ith an earby dithiol motif ([SH Cys59 ,SH Cys64 ]) presenti nt he other subunit. This process is achievedt hrough two reversible steps:a na ttack of a cysteinyl thiol of Cys59 at the Se atom of the SeÀSb ond and as ubsequenta ttack of ar emaining thiol at the Sa tom of the generated mixed SeÀSi ntermediate. However,i ti s not clearh ow the kinetically unfavorable second step pro-gresses smoothly in the catalytic cycle. Am odel study that used synthetic selenenyl sulfides, which mimic the active site structure of human TrxR comprising Cys497, Sec498, and His472, suggested that His472 can play ak ey role by forming ah ydrogen bond with the Se atom of the mixed SeÀS intermediate to facilitatet he seconds tep. In addition, the selenenyl sulfides exhibited ad efensive ability against H 2 O 2induced oxidative stress in cultured cells, which suggests the possibility for medicinal applications to control the redox balance in cells.[a] Dr.

A model study using synthetic selenenyl sulfides revealed that the basic His472 would accelerate the reduction of the Se−S bond in the catalytic cycle of thioredoxin reductase (TrxR). More information can be found in the Full Paper by G. Mugesh, M. Iwaoka, et al. on page 12751.