Thioredoxin, thioredoxin reductase and NADPH, the thioredoxin system, is ubiquitous from Archea to man. Thioredoxins, with a dithiol/disulfide active site (CGPC) are the major cellular protein disulfide reductases; they therefore also serve as electron donors for enzymes such as ribonucleotide reductases, thioredoxin peroxidases (peroxiredoxins) and methionine sulfoxide reductases. Glutaredoxins catalyze glutathione-disulfide oxidoreductions overlapping the functions of thioredoxins and using electrons from NADPH via glutathione reductase. Thioredoxin isoforms are present in most organisms and mitochondria have a separate thioredoxin system. Plants have chloroplast thioredoxins, which via ferredoxin±thioredoxin reductase regulates photosynthetic enzymes by light. Thioredoxins are critical for redox regulation of protein function and signaling via thiol redox control. A growing number of transcription factors including NF-kB or the Ref-1-dependent AP1 require thioredoxin reduction for DNA binding. The cytosolic mammalian thioredoxin, lack of which is embryonically lethal, has numerous functions in defense against oxidative stress, control of growth and apoptosis, but is also secreted and has co-cytokine and chemokine activities. Thioredoxin reductase is a specific dimeric 70-kDa flavoprotein in bacteria, fungi and plants with a redox active site disulfide/dithiol. In contrast, thioredoxin reductases of higher eukaryotes are larger (112±130 kDa), selenium-dependent dimeric flavoproteins with a broad substrate specificity that also reduce nondisulfide substrates such as hydroperoxides, vitamin C or selenite. All mammalian thioredoxin reductase isozymes are homologous to glutathione reductase and contain a conserved C-terminal elongation with a cysteine±selenocysteine sequence forming a redox-active selenenylsulfide/selenolthiol active site and are inhibited by goldthioglucose (aurothioglucose) and other clinically used drugs.Keywords: thioredoxin; thioredoxin reductase; redox regulation; redox active disulfide; selenocysteine; electron transport; enzyme mechanisms; enzyme evolution. I N T R O D U C T I O NProteins in the extracellular environment or on the cell surface are rich in stabilizing disulfides, reflecting oxidizing conditions. In contrast, the inside of the cell is kept reduced and proteins contain many free sulfhydryl groups and disulfides are rare [1]. The major ubiquitous disulfide reductase responsible for maintaining proteins in their reduced state is thioredoxin, which is reduced by electrons from NADPH via thioredoxin reductase [2]. The other major factor generally responsible for the low redox potential and high free SH level inside cells is glutathione (GSH) present in millimolar concentrations and kept reduced by NADPH and glutathione reductase [1,3]. GSHdependent disulfide reductions are catalyzed by glutaredoxins overlapping the functions of thioredoxins, but also uniquely reactive with GSH-mixed disulfides [4].Thiol±disulfide exchange reactions via redox active disulfides are efficient for el...

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The requirement of the trace element selenium for life and its beneficial role in human health has been known for several decades. This is attributed to low molecular weight selenium compounds, as well as to its presence within at least 25 proteins, named selenoproteins, in the form of the amino acid selenocysteine (Sec). Incorporation of Sec into selenoproteins employs a unique mechanism that involves decoding of the UGA codon. This process requires multiple features such as the selenocysteine insertion sequence (SECIS) element and several protein factors including a specific elongation factor EFSec and the SECIS binding protein 2, SBP2. The function of most selenoproteins is currently unknown; however, thioredoxin reductases (TrxR), glutathione peroxidases (GPx) and thyroid hormone deiodinases (DIO) are well characterised selenoproteins involved in redox regulation of intracellular signalling, redox homeostasis and thyroid hormone metabolism. Recent evidence points to a role for selenium compounds as well as selenoproteins in the prevention of some forms of cancer. A number of clinical trials are either underway or being planned to examine the effects of selenium on cancer incidence. In this review we describe some of the recent progress in our understanding of the mechanism of selenoprotein synthesis, the role of selenoproteins in human health and disease and the therapeutic potential of some of these proteins.