Thioredoxin Reductase 1 (TR1, Protein tyrosine phosphatase (PTP))

The mammalian thioredoxin reductases(TrxRs) are a family of selenocysteine-containing pyridine nucleotide-disulfide oxido-reductases. Three different TrxR isoenzymes, TrxR1 as cytosolic, TrxR2 as mitochondrial, and TrxR3 as testis-specific thiol regulator are known. All the mammalian TrxRs are homologous to glutathione reductase with respect to primary structure including the conserved redox catalytic site (-Cys-Val-Asn-Val-Gly-Cys-) but distinctively with a C-terminal extension containing a catalytically active penultimate selenocysteine(Se­Cys) residue in the conserved sequence(-Gly-Cys-SeCys-Gly). TrxR is homodimeric protein in which each monomer includes an FAD prosthetic group, a NADPH binding site and a redox catalytic site. Electrons are transferred from NADPH via FAD and the active-site disulfide to C-terminal SeCys-containing redox center, which then reduces the substrate like thioredoxin. The members of TrxR family are 55–58 kDa in molecular size and composed of three isoforms including cytosolic TrxR1, mitochondrial TrxR2, and TrxR3, known as Trx and GSSG reductase(TGR). TrxR plays a key role in protection of cells against oxidative stress and redox-regulatory mechanism of transcription factors and various biological phenomena. Many tumor cells have elevated TrxR levels and TrxR has been shown to play a major role in drug resistance. Inhibition of TrxR and its related redox reactions may thus contribute to a successful single, combinatory or adjuvant cancer therapy. A great number of effective natural and synthetic TrxR inhibitors are now available possessing antitumor potential ranging from induction of oxidative stress to cell cycle arrest and apoptosis.