Disulfide-bond A oxidoreductase-like protein (DsbA-L) is the enzyme, which used to be called glutathione S-transferase kappa 1 (GSTK1) in humans and belongs to superfamily of enzymes glutathione S-transferases (GST), which are mainly known for cellular detoxification. GSTK1 enzyme is a homodimer, molecular weight of each subunit being 27 kDa, and shares high sequence and secondary structure homology with bacterial DsbA. Based on this finding, the enzyme GSTK1 was renamed to DsbA-L.
Bacterial DsbA catalyzes disulfide bond formation during folding of secreted proteins and therefore DsbA-L might also have the ability to catalyze disulfide bond formation during protein assembling. DsbA-L is expressed in a number of mouse tissues such as liver, kidney, pancreas, heart and lung; the highest DsbA-L expression was observed in the adipose tissue. It has been shown that DsbA-L expression in adipocytes is negatively correlated with obesity in mice and humans. DsbA-L in adipocytes plays a critical role in regulation of adiponectin secretion and multimerization to form high molecular weight (HMW) complex. This HMW form of adiponectin is the active form of the hormone and has a relevant role in enhancing insulin sensitivity and in protecting against diabetes. Impairment in adiponectin multimerization leads to defects in adiponectin secretion and function and is associated with diabetes. These findings suggest that increasing the ratio of the HMW form rather than the total levels of adiponectin might provide an effective alternative therapeutic strategy.
Transgenic mice overexpressing DsbA-L in fat exhibited increased levels of total and HMW adiponectin compared with wild type mice. These mice also displayed suppression of diet-induced obesity, insulin resistance and hepatic steatosis compared with wild type mice; thus, upregulation of DsbA-L may be a new therapeutic approach to treatment of obesity and associated metabolic disorders.
Originally, DsbA-L was identified as a mitochondrial enzyme but recent investigation provides evidence that DsbA-L is also localized in endoplasmic reticulum (ER). In obesity, increased demands on ER function (protein folding) lead to ER stress which in turn downregulates cellular levels and secretion of adiponectin in 3T3-L1 adipocytes. Experiments with 3T3-L1 adipocytes have shown that DsbA-L localization in ER is critical for its promoting effect on adiponectin biosynthesis in adipocytes and for suppressing the negative effects of ER stress.
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