Thioredoxin reductase

Abstract

The mammalian thioredoxin reductases (TrxRs) are a family of selenium-containing pyridine nucleotide-disulphide oxidoreductases with mechanistic and sequence identity, including a conserved -Cys-Val-Asn-Val-Gly-Cys- redox catalytic site, to glutathione reductases. TrxRs catalyse the NADPH-dependent reduction of the redox protein thioredoxin (Trx), as well as of other endogenous and exogenous compounds. The broad substrate specificity of mammalian TrxRs is due to a second redox-active site, a C-terminal -Cys-SeCys- (where SeCys is selenocysteine), that is not found in glutathione reductase or Escherichia coli TrxR. There are currently two confirmed forms of mammalian TrxRs, TrxR1 and TrxR2, and it is possible that other forms will be identified. The availability of Se is a key factor determining TrxR activity both in cell culture and in vivo, and the mechanism(s) for the incorporation of Se into TrxRs, as well as the regulation of TrxR activity, have only recently begun to be investigated. The importance of Trx to many aspects of cell function make it likely that TrxRs also play a role in protection against oxidant injury, cell growth and transformation, and the recycling of ascorbate from its oxidized form. Since TrxRs are able to reduce a number of substrates other than Trx, it is likely that additional biological effects will be discovered for TrxR. Furthermore, inhibiting TrxR with drugs may lead to new treatments for human diseases such as cancer, AIDS and autoimmune diseases.

Emerging roles of thioredoxin cycle enzymes in the central nervous system

“…The first report on a mammalian Trx-Trx reductase system was published in 1967 [55]. The disulfide state of Trx is regenerated by a Trx reductase (TrxR), which is the only type of enzyme known so far to reduce back the inactive disulfide form of Trx [46,56]. Acting together, these two enzymes constitute a highly efficient system for reducing cystine disulfide bridges to cysteines [17,36,37].…”

“…The Trx reductases (TrxRs) belong to the flavoprotein family of pyridine nucleotide disulfide oxydo-reductases [38,46]. They are homodimeric proteins in which each monomer includes two prosthetic flavin adenine dinucleotide (FAD) groups and a NADPH binding site.…”

“…This review will mainly focus on the emerging role of these antioxidant enzymes in the CNS. For basic knowledge on the structure and function of Trx system enzymes, the reader is referred to excellent previous reviews [17,37,38,[46][47][48][49][50][51][52][53].…”

Discovery of anti-cancer activity for benzo[1,2,4]triazin-7-ones: Very strong correlation to pleurotin and thioredoxin reductase inhibition

“…13,15 TrxR is a flavoprotein homodimer with each monomer containing a FAD prosthetic group, NADPH binding domain, and a redox-active selenothiol active site. 16,17 TrxR is the only known enzyme to reduce Trx protein, which in turn provides reducing equivalents for a number of essential redox-dependent cellular processes, such as H 2 O 2 metabolism, sulfate assimilation, and signal transduction. 18 Trx protein is, however, over-expressed in a number of cancers, and is associated with increased cell proliferation, inhibition of apoptosis, and decreased patient survival.…”

Mechanisms by which selenium influences immune responses

“…These enzymes regenerate reduced thioredoxin (TRX), which is used for regenerating cellular antioxidant systems, activating signaling molecules, reducing ribonucleotides to deoxyribonucleotides for synthesis of DNA, and regulating the activity of transcription factors [1]. The different TR enzymes have different localizations, including the cytoplasm and nucleus (TR-1), mitochondria (TR-2), and sperm (TR-3) [2,61]. Both TR-1 and -2 are widely distributed throughout tissues and each of the knockouts in mice are embryonic lethal, emphasizing their essential biological role [23,44].…”