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Thioredoxin
TrxR enzymes are essential components of the Trx system, which contains NADPH, Trx, and TrxR. This highly conserved system is ubiquitous and present in all levels of life – from plants to archaea and humans – and plays a pivotal role in maintaining a reduced intracellular environment and regulating multiple cellular redox signaling pathways, ranging from antioxidant defense and selenium metabolism to regulation of gene transcription. TrxR enzymes are homodimeric proteins and belong to the flavoprotein family of pyridine nucleotide-disulfide oxidoreductases that have an FAD prosthetic group, an NADPH binding site, and a redox active site containing a dithiol/disulfide motif. In addition to TrxR, members of this family include glutathione reductase (GR), lipoamide dehydrogenase, trypanothione reductase, and mercury reductase.
The Trx system plays an important role in antioxidant defense by either direct neutralization of ROS or by indirect effects through recycling small-molecule antioxidants, such as DHA, LA, ebselen, and UQ, and supplying electrons to other antioxidant enzymes. Apoptosis signaling kinase 1 (ASK1) is a MAP kinase kinase kinase that leads to the activation of the JNK and p38 MAP kinase pathways. Reduced Trx, but not oxidized Trx, may bind to ASK1 to inhibit its activation. In addition, binding of reduced Trx to ASK1 further directs the kinase for ubiquitin-mediated degradation. The tumor-suppressor phosphatase and tensin homolog (PTEN) is a negative regulator of the PI3K–Akt pathway. Inactivation of PTEN results in elevated Akt activity and abnormal growth regulation. Trx1 directly binds to the C2 domain of PTEN and inhibits its lipid phosphatase activity. Thus, the increased level of TrxR/Trx may serve to stimulate the proliferation of cancer cells. In addition, the Trx system activates several transcription factors that are generally related to cell growth, cell survival, and angiogenesis, including p53, nuclear factor kB (NF-kB), activating protein 1 (AP-1), hypoxia-inducible factor 1a (HIF-1a), and histone deacetylase (HDAC). Many molecules targeting the Trx system are being developed as potential therapeutic agents for cancer treatments or as adjuncts to existing anticancer therapy
References
1.Zhang J, et al. Trends Pharmacol Sci. 2017;38(9):794–808.
The Trx system plays an important role in antioxidant defense by either direct neutralization of ROS or by indirect effects through recycling small-molecule antioxidants, such as DHA, LA, ebselen, and UQ, and supplying electrons to other antioxidant enzymes. Apoptosis signaling kinase 1 (ASK1) is a MAP kinase kinase kinase that leads to the activation of the JNK and p38 MAP kinase pathways. Reduced Trx, but not oxidized Trx, may bind to ASK1 to inhibit its activation. In addition, binding of reduced Trx to ASK1 further directs the kinase for ubiquitin-mediated degradation. The tumor-suppressor phosphatase and tensin homolog (PTEN) is a negative regulator of the PI3K–Akt pathway. Inactivation of PTEN results in elevated Akt activity and abnormal growth regulation. Trx1 directly binds to the C2 domain of PTEN and inhibits its lipid phosphatase activity. Thus, the increased level of TrxR/Trx may serve to stimulate the proliferation of cancer cells. In addition, the Trx system activates several transcription factors that are generally related to cell growth, cell survival, and angiogenesis, including p53, nuclear factor kB (NF-kB), activating protein 1 (AP-1), hypoxia-inducible factor 1a (HIF-1a), and histone deacetylase (HDAC). Many molecules targeting the Trx system are being developed as potential therapeutic agents for cancer treatments or as adjuncts to existing anticancer therapy
References
1.Zhang J, et al. Trends Pharmacol Sci. 2017;38(9):794–808.
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