Physiological functions of thioredoxin and thioredoxin reductase

Thioredoxin, thioredoxin reductase and NADPH, the thioredoxin system, is ub iquitous from Archea to man. Thioredoxins, with a dithiol/disulfide active site (CGPC) are the major cellular protein disulfide reductases; they there fore also serve as electron donors for enzymes such as ribonucleotide reduc tases, thioredoxin peroxidases (peroxiredoxins) and methionine sulfoxide re ductases. Glutaredoxins catalyze glutathione-disulfide oxidoreductions over lapping the functions of thioredoxins and using electrons from NADPH via gl utathione reductase. Thioredoxin isoforms are present in most organisms and mitochondria have a separate thioredoxin system. Plants have chloroplast t hioredoxins, which via ferredoxin-thioredoxin reductase regulates photosynt hetic enzymes by light. Thioredoxins are critical for redox regulation of p rotein function and signaling via thiol redox control. A growing number of transcription factors including NF-kappa B or the Ref-1-dependent AP1 requi re thioredoxin reduction for DNA binding. The cytosolic mammalian thioredox in, lack of which is embryonically lethal, has numerous functions in defens e against oxidative stress, control of growth and apoptosis, but is also se creted and has co-cytokine and chemokine activities. Thioredoxin reductase is a specific dimeric 70-kDa flavoprotein in bacteria, fungi and plants wit h a redox active site disulfide/dithiol. In contrast, thioredoxin reductase s of higher eukaryotes are larger (112-130 kDa), selenium-dependent dimeric flavoproteins with a broad substrate specificity that also reduce nondisul fide substrates such as hydroperoxides, vitamin C or selenite. All mammalia n thioredoxin reductase isozymes are homologous to glutathione reductase an d contain a conserved C-terminal elongation with a cysteine-selenocysteine sequence forming a redox-active selenenylsulfide/selenolthiol active site a nd are inhibited by goldthioglucose (aurothioglucose) and other clinically used drugs.