Properties and Biological Activities of Thioredoxins

Abstract

The mammalian thioredoxins are a family of small (approximately 12 kDa) redox proteins that undergo NADPH-dependent reduction by thioredoxin reductase and in turn reduce oxidized cysteine groups on proteins. The two main thioredoxins are thioredoxin- 1, a cytosolic and nuclear form, and thioredoxin-2, a mitochondrial form. Thioredoxin-1 has been studied more. It performs many biological actions including the supply of reducing equivalents to thioredoxin peroxidases and ribonucleotide reductase, the regulation of transcription factor activity, and the regulation of enzyme activity by heterodimer formation. Thioredoxin-1 stimulates cell growth and is an inhibitor of apoptosis. Thioredoxins may play a role in a variety of human diseases including cancer. An increased level of thioredoxin-1 is found in many human tumors, where it is associated with aggressive tumor growth. Drugs are being developed that inhibit thioredoxin and that have antitumor activity.

Oxidoreductase regulation of Kv currents in rat ventricle

“…Trx and Grx are each part of an integrated system that controls the transfer of electrons from NADPH to oxidized proteins. In the thioredoxin system, the function of Trx depends on the upstream activity of thioredoxin reductase (TrxR), which uses NADPH as cofactor to convert the oxidized, inactive form of Trx to its reduced active form [8,9,10]. For the glutaredoxin system, electrons are transferred from NADPH to glutathione reductase (GR), then to glutathione (GSH) which converts oxidized Grx to its active form [1,2,11].…”

“…For the glutaredoxin system, electrons are transferred from NADPH to glutathione reductase (GR), then to glutathione (GSH) which converts oxidized Grx to its active form [1,2,11]. While both Trx and Grx reduce oxidized thiols, they display unique substrate specificities [1,2,10]. In general, reduced Trx catalyzes the reduction of intra-or intermolecular protein disulfides [8,9,12] and possibly other thiol intermediates such as sulfenic acid and S-nitrosothiols [10].…”

“…While both Trx and Grx reduce oxidized thiols, they display unique substrate specificities [1,2,10]. In general, reduced Trx catalyzes the reduction of intra-or intermolecular protein disulfides [8,9,12] and possibly other thiol intermediates such as sulfenic acid and S-nitrosothiols [10]. By comparison, Grx mainly catalyzes the reduction of protein-mixed disulfides [1,2,11,13].…”

Cytotoxic and antiangiogenic activity of AW464 (NSC 706704), a novel thioredoxin inhibitor: an in vitro study

“…COMPARE analysis indicates possible interaction with thioredoxin/thioredoxin reductase signalling. The proposed molecular target of AW464, thioredoxin, belongs to a family of small 12 kDa redox proteins that undergo NADPH dependent reduction by the enzyme thioredoxin reductase and in turn reduces oxidised cysteine group on proteins (reviewed by Powis and Montfort, 2001;Hirota et al, 2002). AW464 has been proposed to crosslink irreversibly to cysteine residues 32 and 35 of the thioredoxin active site via its two b-carbon atoms; the first link is reversible, whereas the second crosslink is thought to be irreversible.…”

“…The effects of thioredoxin in the cell are pleiotropic, viz increasing cell proliferation through ribonucleotide reductase (Mau and Powis, 1992), prevention of apoptosis by inhibiting ASK-1 (Saitoh et al, 1998) and protection against oxidative stress through the activity of thioredoxin peroxidases (Powis and Montfort, 2001). Therefore, inhibition of thioredoxin can have antiproliferative and proapoptotic effects (Pallis et al, 2003).…”