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.