Thioredoxin reductase (TrxR) is similar in activity to glutathione reductase (GR), catalyzing the reduction of GSSG to GSH, and is one of the key enzymes of the glutathione redox cycle.
TrxR is a dimeric flavoproteinase, a member of the pyridine nucleotide disulfide reductase family, widely expressed in cells of all levels of organisms from prokaryotes to humans. The three isozymes are named thioredoxin R1 (TrxR1) (cytoplasmic type), TrxR2 (mitochondrial type) and an isozyme TrxR3 (TGR) expressed mainly in the testis due to their different distribution regions. Cytoplasmic TrxR1 was the first to be discovered and is more widely distributed, and is the most studied isozyme to date.
In most eukaryotes, there are mainly two independent antioxidant systems, one is the thioredoxin system and the other is the glutathione system. The thioredoxin system includes NADPH, thioredoxin reductase (TrxR) and thioredoxin (Trx); the glutathione system includes NADPH, glutathione reductase (GR) and glutaredoxin (Grx) ). In these two systems, GR and TrxR catalyze the transfer of electrons from NADPH to GSSG and thioredoxin, respectively, turning them into a reduced state, thereby participating in various subsequent reactions that maintain redox balance. It is an important detoxification mechanism that protects cells from reactive oxygen species.
Mammalian thioredoxin reductase (TrxR) enzymes are a family of selenoproteins with a unique but essential selenocysteine (Sec) residue at their C-terminal redox center. TrxR, mainly by donating electrons from NADPH to maintain the endogenous substrate thioredoxin (Trx) protein in a reduced state, regulates various redox-based signaling pathways involved in antioxidant defense, protein repair and transcriptional regulation.
Physiological Function
Regulation of redox homeostasis
Studies have demonstrated the role of TrxR and its catalyzed Trx in counteracting oxidative stress. Superoxide anions (O2-) produced by physiological processes such as mitochondrial aerobic respiration generate large amounts of hydrogen peroxide (H2O2) through superoxide dismutase (SOD)-catalyzed or spontaneous disproportionation reactions. Increased oxidative stress was found in rheumatoid arthritis (RA) synoviocytes by measuring intracellular reactive oxygen species (ROS), and upregulation of TrxR1 protein in RA synoviocytes was also found. Further analysis showed that cells were protected against oxidative stress by inhibiting hydrogen peroxide and RA synoviocyte apoptosis by upregulating TrxR1.
Regulation of cell growth and apoptosis
Inhibition of TrxR activity below normal levels produces inhibition of cell growth. Nucleotide reductase is an enzyme specifically expressed in replicating cells or rapidly growing tumor cells, and treatment of cells with TrxR inhibition and compounds such as adriamycin results in inhibition of nucleotide reductase and inhibition of cell growth.
Regulation of early embryonic development
Marcus et al. used embryos generated from mouse mutants deficient in mitochondrial TrxR1 and showed that TrxR2-deficient embryos were smaller, extremely anemic and showed increased apoptosis in the liver and dramatically reduced hematopoietic colonies in in vitro culture compared to controls.
Involved in the regulation of other physiological processes
TrxR can catalyze selenite to produce selenide, which indirectly inhibits inflammation.
The development of efficient and reliable tools is crucial for exploring fundamental biological processes. A particularly useful tool is small-molecule fluorescent probes, which has led to increasing attention to the design and development of various chemical probes for biological macromolecules, inorganic ions, biological small molecules, and various reactive signaling species. In general, the quality of probes is critical for probing complex biological systems and for drawing convincing conclusions from experimental observations, as poor-quality probes may yield ambiguous or even misleading results and conclusions. The desired probe should recognize the target of interest with an appropriate response rate and high specificity, which will ensure that the probe is applied with confidence to give an accurate and real-time dissection of a specific biological event. Previous studies have reported a series of TrxR fluorescent probes, including TRFS-green, TRFS-red and Mito-TRFS.
