Thioredoxin reductase as a pathophysiological factor and drug target

Human cytosolic thioredoxin reductase (TrxR), a homodimeric protein contain ing 1 selenocysteine and 1 FAD per subunit of 55 kDa, catalyses the NADPH-d ependent reduction of thioredoxin disulfide and of numerous other oxidized cell constituents. As a general reducing enzyme with little substrate speci ficity, it also contributes to redox homeostasis and is involved in prevent ion, intervention and repair of damage caused by H2O2-based oxidative stres s. Being a selenite-reducing enzyme as well as a selenol-containing enzyme, hu man TrxR plays a central role in selenium (patho)physiology. Both dietary s elenium deficiency and selenium oversupplementation, a lifestyle phenomenon of our time, appear to interfere with the activity of TrxR. Selenocysteine 496 of human TrxR is a major target of the anti-rheumatic gold-containing drug auranofin, the formal K-i for the stoichiometric inhibition being 4 nm . The hypothesis that TrxR and extracellular thioredoxin play a pathophysio logic role in chronic diseases such as rheumatoid arthritis, Sjogren's synd rom, AIDS, and certain malignancies, is substantiated by biochemical, virol ogical, and clinical evidence. Reduced thioredoxin acts as an autocrine gro wth factor in various tumour diseases, as a chemoattractant, and it synergi ses with interleukins 1 and 2. The effects of anti-tumour drugs such as car mustine and cisplatin can be explained in part by the inhibition of TrxR. C onsistently, high levels of the enzyme can support drug resistance. TrxRs from different organisms such as Escherichia coli, Mycobacterium lepr ae, Plasmodium falciparum, Drosophila melanogaster, and man show a surprisi ng diversity in their chemical mechanism of thioredoxin reduction. This is the basis for attempts to develop specific TrxR inhibitors as drugs against bacterial infections like leprosy and parasitic diseases like amebiasis an d malaria.