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An Error has occurred retrieving Wikidata item for infobox Thioredoxin is a class of small redox proteins known to be present in all organisms. It plays a role in many important biological processes, including redox signaling. In humans, thioredoxins are encoded by TXN and TXN2 genes.[1][2] Loss-of-function mutation of either of the two human thioredoxin genes is lethal at the four-cell stage of the developing embryo. Although not entirely understood, thioredoxin plays a central role in humans and is increasingly linked to medicine through their response to reactive oxygen species (ROS). In plants, thioredoxins regulate a spectrum of critical functions, ranging from photosynthesis to growth, flowering and the development and germination of seeds. They have also recently been found to play a role in cell-to-cell communication.[3]


Thioredoxins are proteins that act as antioxidants by facilitating the reduction of other proteins by cysteine thiol-disulfide exchange. Thioredoxins are found in nearly all known organisms and are essential for life in mammals.[4][5]

Thioredoxin is a 12-kD oxidoreductase enzyme containing a dithiol-disulfide active site. It is ubiquitous and found in many organisms from plants and bacteria to mammals. Multiple in vitro substrates for thioredoxin have been identified, including ribonuclease, choriogonadotropins, coagulation factors, glucocorticoid receptor, and insulin. Reduction of insulin is classically used as an activity test.[6]

Thioredoxins are characterized at the level of their amino acid sequence by the presence of two vicinal cysteines in a CXXC motif. These two cysteines are the key to the ability of thioredoxin to reduce other proteins. Thioredoxin proteins also have a characteristic tertiary structure termed the thioredoxin fold.

The thioredoxins are kept in the reduced state by the flavoenzyme thioredoxin reductase, in a NADPH-dependent reaction.[7] Thioredoxins act as electron donors to peroxidases and ribonucleotide reductase.[8] The related glutaredoxins share many of the functions of thioredoxins, but are reduced by glutathione rather than a specific reductase.

The benefit of thioredoxins to reduce oxidative stress is shown by transgenic mice that overexpress thioredoxin, are more resistant to inflammation, and live 35% longer[9] — supporting the free radical theory of aging. However, the controls of this study were short lived, which may have contributed to the apparent increase in longevity[10]. Trx1 can regulate non-redox post-translational modifications.[11]. In the mice with cardiac-specific overexpression of Trx1, the proteomics study found that SET and MYND domain-containing protein 1 (SMYD1), a lysine methyltransferase highly expressed in cardiac and other muscle tissues, is also upregulated. This suggests that Trx1 may also play an role in protein methylation via regulating SMYD1 expression, which is independent of its oxidoreductase activity.[12]

Plants have an unusually complex complement of Trxs composed of six well-defined types (Trxs f, m, x, y, h, and o) that reside in different cell compartments and function in an array of processes. In 2010 it was discovered for the first time that thioredoxin proteins are able to move from cell to cell, representing a novel form of cellular communication in plants.[3]

Mechanism of action

The primary function of Thioredoxin (Trx) is the reduction of oxidized cysteine residues and the cleavage of disulfide bonds.[13] For Trx1, this process begins by attack of Cys32, one of the residues conserved in the thioredoxin CXXC motif, onto the oxidized group of the substrate.[14] Almost immediately after this event Cys35, the other conserved Cys residue in Trx1, forms a disulfide bond with Cys32, thereby transferring 2 electrons to the substrate which is now in its reduced form. Oxidized Trx1 is then reduced by thioredoxin reductase, which in turn is reduced by NADPH as described above.[14]

Mechanism of Trx1 reducing a substrate


Thioredoxin has been shown to interact with:

Effect on cardiac hypertrophy

Trx1 has been shown to downregulate cardiac hypertrophy, the thickening of the walls of the lower heart chambers, by interactions with several different targets. Trx1 upregulates the transcriptional activity of nuclear respiratory factors 1 and 2 (NRF1 and NRF2) and stimulates the expression of peroxisome proliferator-activated receptor γ coactivator 1-α (PGC-1α).[25][26] Furthermore, Trx1 reduces two cysteine residues in histone deacetylase 4 (HDAC4), which allows HDAC4 to be imported from the cytosol, where the oxidized form resides,[27] into the nucleus.[28] Once in the nucleus, reduced HDAC4 downregulates the activity of transcription factors such as NFAT that mediate cardiac hypertrophy.[14] Trx 1 also controls microRNA levels in the heart and has been found to inhibit cardiac hypertrophy by upregulating miR-98/let-7.[29] Trx1 can regulate the expression level of SMYD1, thus may indirectly modulate protein methylation for purpose of cardiac protection.[30]

Thioredoxin in skin care

Thioredoxin is used in skin care products as an antioxidant in conjunction with glutaredoxin and glutathione.[citation needed]

See also


  1. "Cloning and expression of a cDNA for human thioredoxin". The Journal of Biological Chemistry 263 (30): 15506–12. October 1988. PMID 3170595. 
  2. "Entrez Gene: TXN2 thioredoxin 2". 
  3. 3.0 3.1 "A membrane-associated thioredoxin required for plant growth moves from cell to cell, suggestive of a role in intercellular communication". Proceedings of the National Academy of Sciences of the United States of America 107 (8): 3900–5. February 2010. doi:10.1073/pnas.0913759107. PMID 20133584. 
  4. "Thioredoxin and glutaredoxin systems". The Journal of Biological Chemistry 264 (24): 13963–6. August 1989. PMID 2668278. 
  5. "Reactive oxygen species, antioxidants, and the mammalian thioredoxin system". Free Radical Biology & Medicine 31 (11): 1287–312. December 2001. doi:10.1016/S0891-5849(01)00724-9. PMID 11728801. 
  6. "Entrez Gene: TXN thioredoxin". 
  7. "Thioredoxin reductase". The Biochemical Journal 346 (1): 1–8. February 2000. doi:10.1042/0264-6021:3460001. PMID 10657232. 
  8. "Physiological functions of thioredoxin and thioredoxin reductase". European Journal of Biochemistry 267 (20): 6102–9. October 2000. doi:10.1046/j.1432-1327.2000.01701.x. PMID 11012661. 
  9. "The involvement of thioredoxin and thioredoxin binding protein-2 on cellular proliferation and aging process". Annals of the New York Academy of Sciences 1055: 1–12. December 2005. doi:10.1196/annals.1323.002. PMID 16387713. 
  10. "Trends in oxidative aging theories". Free Radical Biology & Medicine 43 (4): 477–503. August 2007. doi:10.1016/j.freeradbiomed.2007.03.034. PMID 17640558. 
  11. "Master redox regulator Trx1 upregulates SMYD1 & modulates lysine methylation". Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics 1854 (12): 1816–1822. December 2015. doi:10.1016/j.bbapap.2015.09.006. PMID 26410624. 
  12. "Master redox regulator Trx1 upregulates SMYD1 & modulates lysine methylation". Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics 1854 (12): 1816–1822. December 2015. doi:10.1016/j.bbapap.2015.09.006. PMID 26410624. 
  13. "Redox regulation of cellular activation". Annual Review of Immunology 15 (1): 351–69. 1997-01-01. doi:10.1146/annurev.immunol.15.1.351. PMID 9143692. 
  14. 14.0 14.1 14.2 "Modulation of signaling mechanisms in the heart by thioredoxin 1". Free Radical Biology & Medicine 109: 125–131. December 2016. doi:10.1016/j.freeradbiomed.2016.12.020. PMID 27993729. 
  15. "Thioredoxin promotes ASK1 ubiquitination and degradation to inhibit ASK1-mediated apoptosis in a redox activity-independent manner". Circulation Research 90 (12): 1259–66. June 2002. doi:10.1161/01.res.0000022160.64355.62. PMID 12089063. 
  16. "Negative feedback regulation of ASK1 by protein phosphatase 5 (PP5) in response to oxidative stress". The EMBO Journal 20 (21): 6028–36. November 2001. doi:10.1093/emboj/20.21.6028. PMID 11689443. 
  17. "Mammalian thioredoxin is a direct inhibitor of apoptosis signal-regulating kinase (ASK) 1". The EMBO Journal 17 (9): 2596–606. May 1998. doi:10.1093/emboj/17.9.2596. PMID 9564042. 
  18. "C-propeptide region of human pro alpha 1 type 1 collagen interacts with thioredoxin". Biochemical and Biophysical Research Communications 295 (3): 663–7. July 2002. doi:10.1016/s0006-291x(02)00727-1. PMID 12099690. 
  19. "Direct association with thioredoxin allows redox regulation of glucocorticoid receptor function". The Journal of Biological Chemistry 274 (5): 3182–8. January 1999. doi:10.1074/jbc.274.5.3182. PMID 9915858. 
  20. "SENP1 mediates TNF-induced desumoylation and cytoplasmic translocation of HIPK1 to enhance ASK1-dependent apoptosis". Cell Death and Differentiation 15 (4): 739–50. April 2008. doi:10.1038/sj.cdd.4402303. PMID 18219322. 
  21. "Identification of thioredoxin-binding protein-2/vitamin D(3) up-regulated protein 1 as a negative regulator of thioredoxin function and expression". The Journal of Biological Chemistry 274 (31): 21645–50. July 1999. doi:10.1074/jbc.274.31.21645. PMID 10419473. 
  22. "Thioredoxin regulates the DNA binding activity of NF-kappa B by reduction of a disulphide bond involving cysteine 62". Nucleic Acids Research 20 (15): 3821–30. August 1992. doi:10.1093/nar/20.15.3821. PMID 1508666. 
  23. "AP-1 transcriptional activity is regulated by a direct association between thioredoxin and Ref-1" (in en). Proceedings of the National Academy of Sciences of the United States of America 94 (8): 3633–8. April 1997. doi:10.1073/pnas.94.8.3633. PMID 9108029. 
  24. "A redox-dependent mechanism for regulation of AMPK activation by Thioredoxin1 during energy starvation". Cell Metabolism 19 (2): 232–45. February 2014. doi:10.1016/j.cmet.2013.12.013. PMID 24506865. 
  25. "Thioredoxin1 upregulates mitochondrial proteins related to oxidative phosphorylation and TCA cycle in the heart". Antioxidants & Redox Signaling 8 (9–10): 1635–50. 2006. doi:10.1089/ars.2006.8.1635. PMID 16987018. 
  26. "Inhibition of endogenous thioredoxin in the heart increases oxidative stress and cardiac hypertrophy". The Journal of Clinical Investigation 112 (9): 1395–406. November 2003. doi:10.1172/JCI17700. PMID 14597765. 
  27. "Increased oxidative stress in the nucleus caused by Nox4 mediates oxidation of HDAC4 and cardiac hypertrophy" (in en). Circulation Research 112 (4): 651–63. February 2013. doi:10.1161/CIRCRESAHA.112.279760. PMID 23271793. 
  28. "A redox-dependent pathway for regulating class II HDACs and cardiac hypertrophy". Cell 133 (6): 978–93. June 2008. doi:10.1016/j.cell.2008.04.041. PMID 18555775. 
  29. "Thioredoxin 1 negatively regulates angiotensin II-induced cardiac hypertrophy through upregulation of miR-98/let-7" (in en). Circulation Research 108 (3): 305–13. February 2011. doi:10.1161/CIRCRESAHA.110.228437. PMID 21183740. 
  30. "Master redox regulator Trx1 upregulates SMYD1 & modulates lysine methylation". Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics 1854 (12): 1816–1822. December 2015. doi:10.1016/j.bbapap.2015.09.006. PMID 26410624. 

Further reading

External links