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Thioredoxin reductase (TrXR) is a ubiquitous enzyme which reduces the thioredoxin protein by a disulfide oxidoreductase activity ^[1]. This enzyme belongs to the flavoprotein family which needs cofactors to catalyze the NADPH dependent reaction. NADPH cofactor allows electrons transmission during the reaction via FAD from enzyme to oxidized protein. The thioredoxin system is thus composed of thioredoxin reductase, NADPH and thioredoxin with the following reaction:

TrxR1 belongs to one of the two forms of mammalian TrxR enzymes mostly present in cytosol contrary to TrxR2 which is only mitochondrial. TrxR1 is heterogeneous protein which is present in most tissues and she is specific of the small thioredoxin 1 protein (Trx1) ^[2]. Its capacity to reduce oxidized Trx1 is important to maintain the active site of Trx1. The redox activity of Trx1 reduced is the key of its biological activity ^[3]. TrxR1 can thus regulate Trx1 activities by its NADPH dependent reduction specificity.

Structure

Catalytic mechanism

Biological function

Biological functions of TrxR1 depend directly of thioredoxin activities ^[4]. Trx1 can interact with many partners in different cellular compartments. Its biological function is cellular localisation dependent. Reductase activity of Trx1 can regulate cell growth or apoptosis for example but in the nucleus, Trx can bind to different transcription factors. The key role of Trx is its capacity to defence against oxidative damage.

A central role for oxidative stress

Oxidative stress is the balance between oxidative and reducing species and several mediators can alternate this redox potential. Most of the time, pro-oxidative species derived from di-oxygen (O2) or nitrogen monoxide (NO) in high concentration cause oxidative damages. Reactive species have at list signaling functions and their increased levels are stimuli for cells. This response engages cells into a program to change their characteristics: as in differentiation or apoptosis.

Reductase activity of Trx1 can neutralize the reactive species to equilibrate the oxidative drift by mediating the reduction of proteins involved in scavenging reactive oxygen species (ROS) ^[5]. Trx1 is an important hydrogen donor to ribonucleotide reductase which has an intracellular antioxidant activity. Trx acts thus as an important regulator of the oxidative stress.

Regulation of signal transduction pathways

Some cellular pathways are affected by increase of the levels of oxidizing species below those inducing damage. Several of these pathways rely on transcriptional responses by activation of redox-sensitive transcription factors such as p53, AP-1 or NF-κB in cytoplasm ^{[6] [7]}. These transcription factors are then activated by Trx in nucleus. This enzyme over-expressed can thus bind redox-sensitive transcription factors and activates them. That leads to modulate their DNA-binding activity on the promoter region of several genes. Transcription factors regulate in this way expression of genes which leads to cellular activation and regulates apoptosis ^[8]. For example, the tumour suppressor protein p53 stimulates reporter gene expression involved in cellular function such as mitosis or apoptosis. He is the guardian of the genome in prevent mutations by inducing expression of various genes as redox related genes, apoptosis related genes and many other ^[9]. In addition, Trx can also regulate the transcription factor NF-κB which is involved in the control of several processes as cell growth, immune response or even inflammation ^[10].

And its impact of immune system

Thioredoxin was first identified as a cytokine like factor in virus transformed cells ^[11]. Indeed, the Trx protein allows reduce NF-κB by its binding to this transcription factor. NF-κB factor can be thus a redox sensitive factor by regulation of gene expression of cytokines or other immune response genes. Trx allows directly regulation of pro-inflammatory cytokines expression and demonstrates several anti-inflammatory effects ^[12].

Diseases