Thioredoxin as a key molecule in redox signaling.

Abstract

as a hydrogen donor for ribonucleotide reductase, an essential enzyme for DNA synthesis (5). The thioredoxin system is composed of NADPH, thioredoxin reductase, and thioredoxin (4). Oxidized thioredoxin is reversibly reduced by NADPH and thioredoxin reductase. Mammalian thioredoxin reductase contains selenocysteine in the conserved C-terminal sequence and has broad substrate specificity. It reduces many substrates in addition to oxidized thioredoxin. Mammalian cells contain three isoforms of thioredoxin reductase. Rundlof and Arner review the roles of thioredoxin reductase in this Forum (13). Peroxiredoxin is a thioredoxindependent peroxidase and mammalian cells contain at least six isoforms of peroxiredoxin. Therefore, thioredoxin-related proteins function as antioxidants. The terminology of “reduction/oxidation (redox) regulation” was originally defined as the thiol-dependent modulation in the DNA binding activity of a transcriptional factor for a gene expression. Now “redox regulation” is widely used to mean the biological responses maintaining the homeostasis against oxidative stresses. Oxidative stresses caused by chemical, physical, or biological stimuli generate reactive oxygen species (ROS) in the cells, and the cellular responses against oxidative stresses transduce the signals to maintain the cellular redox balance. A small amount of hydrogen peroxide by itself plays a crucial role as a second messenger in the signal transduction, and antioxidants such as superoxide dismutase, catalase, and glutathione-dependent enzymes also regulate the redox balance by scavenging ROS. As antioxidants, glutathione-dependent enzymes play major roles in the cells. This is because the intracellular amounts of glutathione are in the millimolar range, whereas intracellular amounts of thioredoxin are in the micromolar range. However, thioredoxin plays a crucial role in the redox regulation of gene expression. This is because the reducing activity of thioredoxin for transcriptional factors such as nuclear factor–kB and activator protein-1 is >1,000-fold higher than that of glutathione. Therefore, thioredoxin is a key molecule in redox signaling. Redox regulation by thioredoxin is deeply involved in the activation of transcriptional factors for the expressions of cellular re-