Thioredoxin reductase

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Thioredoxin reductase
Identifiers
Symbol?
InterPro IPR005982
PROSITE PS00573
SCOP2 1zof / SCOPe / SUPFAM

Thioredoxin reductases (TR, TrxR) (EC 1.8.1.9) are enzymes that reduce thioredoxin (Trx). [1] Two classes of thioredoxin reductase have been identified: one class in bacteria and some eukaryotes and one in animals. In bacteria TrxR also catalyzes the reduction of glutaredoxin like proteins known as NrdH. [2] [3] [4] Both classes are flavoproteins which function as homodimers. Each monomer contains a FAD prosthetic group, a NADPH binding domain, and an active site containing a redox-active disulfide bond. [5]

Contents

Cellular role

Thioredoxin reductases are enzymes that catalyze the reduction of thioredoxin [1] and hence they are a central component in the thioredoxin system. Together with thioredoxin (Trx) and NADPH this system's most general description is as a system for reducing disulfide bonds in cells. Electrons are taken from NADPH via TrxR and are transferred to the active site of Trx, which goes on to reduce protein disulfides or other substrates. [6] The Trx system exists in all living cells and has an evolutionary history tied to DNA as a genetic material, defense against oxidative damage due to oxygen metabolism, and redox signaling using molecules like hydrogen peroxide and nitric oxide. [7] [8]

Schematic diagram of TrxR's cellular role Adapted from Holmgren et al. CellularTrxR.png
Schematic diagram of TrxR's cellular role Adapted from Holmgren et al.

Diversity

Two classes of thioredoxin reductase have evolved independently:

These two classes of TrxR have only ~20% sequence identity in the section of primary sequence where they can be reliably aligned. [5] The net reaction of both classes of TrxR is identical but the mechanism of action of each is distinct. [9]

Humans express three thioredoxin reductase isozymes: thioredoxin reductase 1 (TrxR1, cytosolic), thioredoxin reductase 2 (TrxR2, mitochondrial), thioredoxin reductase 3 (TrxR3, testis specific). [10] Each isozyme is encoded by a separate gene:

thioredoxin reductase 1
Identifiers
Symbol TXNRD1
NCBI gene 7296
HGNC 12437
OMIM 601112
RefSeq NM_003330
UniProt Q16881
Other data
EC number 1.8.1.9
Locus Chr. 12 q23-q24.1
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Structures Swiss-model
Domains InterPro
thioredoxin reductase 2
Identifiers
SymbolTXNRD2
NCBI gene 10587
HGNC 18155
OMIM 606448
RefSeq NM_006440
UniProt Q9NNW7
Other data
EC number 1.8.1.9
Locus Chr. 22 q11.21
Search for
Structures Swiss-model
Domains InterPro
thioredoxin reductase 3
Identifiers
SymbolTXNRD3
NCBI gene 114112
HGNC 20667
OMIM 606235
RefSeq XM_051264
UniProt Q86VQ6
Other data
EC number 1.8.1.9
Locus Chr. 3 p13-q13.33
Search for
Structures Swiss-model
Domains InterPro

Structure

E. coli

In E. coli ThxR there are two binding domains, one for FAD and another for NADPH. The connection between these two domains is a two-stranded anti-parallel β-sheet. [11] Each domain individually is very similar to the analogous domains in glutathione reductase, and lipoamide dehydrogenase but they relative orientation of these domains in ThxR is rotated by 66 degrees. [11] This becomes significant in the enzyme mechanism of action which is described below. ThxR homo-dimerizes with the interface between the two monomers formed by three alpha-helices and two loops. [11] Each monomer can separately bind a molecule of thioredoxin.

Mammalian

Mammalian TrxR structure is similar to E. coli. It contains a FAD and NADPH binding domain, and an interface between two monomer subunits. In mammalian ThxR there is an insertion in the FAD binding domain between two alpha helices which forms a small pair of beta strands. [12] The active disulfide in the enzyme is located on one of these helices and thus the active disulfide bond is located in the FAD domain and not the NADPH domain as in E. coli and other prokaryotes. [12]

Mechanism

Proposed mechanism in mammals and presumably humans: Starting from the completely oxidized form, the reaction begins with the reduction of the selenenylsulfide to the selenolate anion (Se(-1)) with electrons received from NADPH via FAD (Step A). Due to the low pKa value of the selenol the selenolate anion is the predominant form under physiological conditions. A second electron transfer from a second molecule of NADPH reduces the active site tihiol bonds with one Cys residue stabilized by an interaction with FAD (Step B). The selenolate anion then attacks the disulfide bonds of Trx and the resulting enzyme-Trx mixed selenenylsulfide (Step C), which is then subsequently attacked by the neighboring Cys residue to regenerate the selenenylsulfide (Step D). This selenenylsulfide is then reduced by the active-site thiolate from the other subunit (Step E). Adapted from Zhong et al. Consistent with findings that (2,2':6',2''-terpyridine)platinum(II) complexes inhibit human TrxR. HumanTrxRRxnMech.jpg
Proposed mechanism in mammals and presumably humans: Starting from the completely oxidized form, the reaction begins with the reduction of the selenenylsulfide to the selenolate anion (Se(-1)) with electrons received from NADPH via FAD (Step A). Due to the low pKa value of the selenol the selenolate anion is the predominant form under physiological conditions. A second electron transfer from a second molecule of NADPH reduces the active site tihiol bonds with one Cys residue stabilized by an interaction with FAD (Step B). The selenolate anion then attacks the disulfide bonds of Trx and the resulting enzyme-Trx mixed selenenylsulfide (Step C), which is then subsequently attacked by the neighboring Cys residue to regenerate the selenenylsulfide (Step D). This selenenylsulfide is then reduced by the active-site thiolate from the other subunit (Step E). Adapted from Zhong et al. Consistent with findings that (2,2‘:6‘,2‘‘-terpyridine)platinum(II) complexes inhibit human TrxR.

E. coli

In E. coli ThxR the spatial orientation of the FAD and NADPH domains are such that the redox-active rings of FAD and NADPH are not in close proximity to each other. [1] When the FAD domain of E. coli is rotated 66 degrees with the NADPH domain remaining fixed the two prosthetic groups move into close contact allowing electrons to pass from NADPH to FAD and then to the active site disulfide bond. [1] [15] The conserved active site residues in E. coli are -Cys-Ala-Thr-Cys-. [1]

Mammalian

Mammalian TrxRs have a much higher sequence homology with glutathione reductase than E. coli. [1] The active-site Cys residues in the FAD domain and bound NADPH domain are in close proximity removing the necessity for a 66 degree rotation for electron transfer found in E. coli. An additional feature of the mammalian mechanism is the presence of a selenocysteine residue at the C-terminal end of the protein which is required for catalytic activity. The conserved residues in mammalian active site are -Cys-Val-Asn-Val-Gly-Cys-. [1]

Detection methods

Thioredoxin reductase can be quantified by various methods such as the DTNB assay using Ellman's reagent. The disulfide-based TRFS series of fluorescent probes have shown selective detection of TrxR. [16] [17] [18] [19] Mafireyi synthesized the first diselenide probe that was applied in the detection of TrxR. [20] [21] Other detection methods include immunological techniques and the selenocystine-thioredoxin reductase assay (SC-TR assay).

Clinical significance

Cancer treatment

Since the activity of this enzyme is essential for cell growth and survival, it is a good target for anti-tumor therapy. Furthermore, the enzyme is upregulated in several types of cancer, including malignant mesothelioma. [22] [23] For example, motexafin gadolinium (MGd) is a new chemotherapeutic agent that selectively targets tumor cells, leading to cell death and apoptosis via inhibition of thioredoxin reductase and ribonucleotide reductase.

Cardiomyopathy

Dilated cardiomyopathy (DCM) is a common diagnosis in cases of congestive heart failure. Thioredoxin reductases are essential proteins for regulating cellular redox balance and mitigating the damage caused by reactive oxygen species generated via oxidative phosphorylation in the mitochondria. Inactivation of mitochondrial TrxR2 in mice results in thinning of the ventricular heart walls and neonatal death. [10] Furthermore two mutations in the TrxR2 gene are found in patients diagnosed with DCM and not in a control population. It is hypothesized that the pathological impact of these mutations is an impaired ability to control oxidative damage in cardiac myocytes. [24]

Antibiotic

There has recently been some research to show that low molecular weight thioredoxin reductase could be a target for novel antibiotics (such as auranofin or Ebselen. [25] ) This is especially true for Mycobacterium Haemophilum, and could be used for antibiotic resistant bacteria. [26]

Related Research Articles

In molecular biology a selenoprotein is any protein that includes a selenocysteine amino acid residue. Among functionally characterized selenoproteins are five glutathione peroxidases (GPX) and three thioredoxin reductases, (TrxR/TXNRD) which both contain only one Sec. Selenoprotein P is the most common selenoprotein found in the plasma. It is unusual because in humans it contains 10 Sec residues, which are split into two domains, a longer N-terminal domain that contains 1 Sec, and a shorter C-terminal domain that contains 9 Sec. The longer N-terminal domain is likely an enzymatic domain, and the shorter C-terminal domain is likely a means of safely transporting the very reactive selenium atom throughout the body.

<span class="mw-page-title-main">Protein disulfide-isomerase</span> Class of enzymes

Protein disulfide isomerase, or PDI, is an enzyme in the endoplasmic reticulum (ER) in eukaryotes and the periplasm of bacteria that catalyzes the formation and breakage of disulfide bonds between cysteine residues within proteins as they fold. This allows proteins to quickly find the correct arrangement of disulfide bonds in their fully folded state, and therefore the enzyme acts to catalyze protein folding.

<span class="mw-page-title-main">Thioredoxin</span> Class of reduction–oxidation proteins

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. 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 is 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. Thioredoxins play a role in cell-to-cell communication.

<span class="mw-page-title-main">Flavin adenine dinucleotide</span> Redox-active coenzyme

In biochemistry, flavin adenine dinucleotide (FAD) is a redox-active coenzyme associated with various proteins, which is involved with several enzymatic reactions in metabolism. A flavoprotein is a protein that contains a flavin group, which may be in the form of FAD or flavin mononucleotide (FMN). Many flavoproteins are known: components of the succinate dehydrogenase complex, α-ketoglutarate dehydrogenase, and a component of the pyruvate dehydrogenase complex.

<span class="mw-page-title-main">Glutathione disulfide</span> Chemical compound

Glutathione disulfide (GSSG) is a disulfide derived from two glutathione molecules.

<span class="mw-page-title-main">Glutathione reductase</span> Enzyme

Glutathione reductase (GR) also known as glutathione-disulfide reductase (GSR) is an enzyme that in humans is encoded by the GSR gene. Glutathione reductase catalyzes the reduction of glutathione disulfide (GSSG) to the sulfhydryl form glutathione (GSH), which is a critical molecule in resisting oxidative stress and maintaining the reducing environment of the cell. Glutathione reductase functions as dimeric disulfide oxidoreductase and utilizes an FAD prosthetic group and NADPH to reduce one molar equivalent of GSSG to two molar equivalents of GSH:

<span class="mw-page-title-main">Glutaredoxin</span>

Glutaredoxins are small redox enzymes of approximately one hundred amino-acid residues that use glutathione as a cofactor. In humans this oxidation repair enzyme is also known to participate in many cellular functions, including redox signaling and regulation of glucose metabolism. Glutaredoxins are oxidized by substrates, and reduced non-enzymatically by glutathione. In contrast to thioredoxins, which are reduced by thioredoxin reductase, no oxidoreductase exists that specifically reduces glutaredoxins. Instead, glutaredoxins are reduced by the oxidation of glutathione. Reduced glutathione is then regenerated by glutathione reductase. Together these components compose the glutathione system.

<span class="mw-page-title-main">Peroxiredoxin</span> Family of antioxidant enzymes

Peroxiredoxins are a ubiquitous family of antioxidant enzymes that also control cytokine-induced peroxide levels and thereby mediate signal transduction in mammalian cells. The family members in humans are PRDX1, PRDX2, PRDX3, PRDX4, PRDX5, and PRDX6. The physiological importance of peroxiredoxins is indicated by their relative abundance. Their function is the reduction of peroxides, specifically hydrogen peroxide, alkyl hydroperoxides, and peroxynitrite.

Arsenate reductase (glutaredoxin) (EC 1.20.4.1) is an enzyme that catalyzes the chemical reaction

In enzymology, a ferredoxin-NADP+ reductase (EC 1.18.1.2) abbreviated FNR, is an enzyme that catalyzes the chemical reaction

Adenylyl-sulfate reductase (thioredoxin) is an enzyme that catalyzes the chemical reaction

<span class="mw-page-title-main">GLRX2</span> Protein-coding gene in the species Homo sapiens

Glutaredoxin 2 (GLRX2) is an enzyme that in humans encoded by the GLRX2 gene. GLRX2, also known as GRX2, is a glutaredoxin family protein and a thiol-disulfide oxidoreductase that maintains cellular thiol homeostasis. This gene consists of four exons and three introns, spanned 10 kilobase pairs, and localized to chromosome 1q31.2–31.3.

<span class="mw-page-title-main">TXN2</span> Protein-coding gene in the species Homo sapiens

Thioredoxin, mitochondrial also known as thioredoxin-2 is a protein that in humans is encoded by the TXN2 gene on chromosome 22. This nuclear gene encodes a mitochondrial member of the thioredoxin family, a group of small multifunctional redox-active proteins. The encoded protein may play important roles in the regulation of the mitochondrial membrane potential and in protection against oxidant-induced apoptosis.

The ascorbate-glutathione cycle, sometimes Foyer-Halliwell-Asada pathway, is a metabolic pathway that detoxifies hydrogen peroxide (H2O2), a reactive oxygen species that is produced as a waste product in metabolism. The cycle involves the antioxidant metabolites: ascorbate, glutathione and NADPH and the enzymes linking these metabolites.

Thioredoxins are small disulfide-containing redox proteins that have been found in all the kingdoms of living organisms. Thioredoxin serves as a general protein disulfide oxidoreductase. It interacts with a broad range of proteins by a redox mechanism based on reversible oxidation of 2 cysteine thiol groups to a disulfide, accompanied by the transfer of 2 electrons and 2 protons. The net result is the covalent interconversion of a disulfide and a dithiol.

<span class="mw-page-title-main">Ars operon</span>

In molecular biology, the ars operon is an operon found in several bacterial taxon. It is required for the detoxification of arsenate, arsenite, and antimonite. This system transports arsenite and antimonite out of the cell. The pump is composed of two polypeptides, the products of the arsA and arsB genes. This two-subunit enzyme produces resistance to arsenite and antimonite. Arsenate, however, must first be reduced to arsenite before it is extruded. A third gene, arsC, expands the substrate specificity to allow for arsenate pumping and resistance. ArsC is an approximately 150-residue arsenate reductase that uses reduced glutathione (GSH) to convert arsenate to arsenite with a redox active cysteine residue in the active site. ArsC forms an active quaternary complex with GSH, arsenate, and glutaredoxin 1 (Grx1). The three ligands must be present simultaneously for reduction to occur.

<span class="mw-page-title-main">Ferredoxin-thioredoxin reductase</span>

Ferredoxin-thioredoxin reductase EC 1.8.7.2, systematic name ferredoxin:thioredoxin disulfide oxidoreductase, is a [4Fe-4S] protein that plays an important role in the ferredoxin/thioredoxin regulatory chain. It catalyzes the following reaction:

Oxidation response is stimulated by a disturbance in the balance between the production of reactive oxygen species and antioxidant responses, known as oxidative stress. Active species of oxygen naturally occur in aerobic cells and have both intracellular and extracellular sources. These species, if not controlled, damage all components of the cell, including proteins, lipids and DNA. Hence cells need to maintain a strong defense against the damage. The following table gives an idea of the antioxidant defense system in bacterial system.

Thiol oxidoreductases are proteins that redox control by utilizing catalytic cysteine (Cys) residues for oxidation or reduction of their substrates. Examples of such proteins include thioredoxin, thioredoxin reductase, glutathione reductase, glutaredoxin, glutathione peroxidase, and peroxiredoxin.

<span class="mw-page-title-main">Selenosulfide</span>

In chemistry, a selenosulfide refers to distinct classes of inorganic and organic compounds containing sulfur and selenium. The organic derivatives contain Se-S bonds, whereas the inorganic derivatives are more variable.

References

  1. 1 2 3 4 5 6 7 Mustacich D, Powis G (February 2000). "Thioredoxin reductase". The Biochemical Journal. 346 Pt 1 (1): 1–8. doi:10.1042/0264-6021:3460001. PMC   1220815 . PMID   10657232.
  2. ↑ Jordan A, Aslund F, Pontis E, Reichard P, Holmgren A (July 1997). "Characterization of Escherichia coli NrdH. A glutaredoxin-like protein with a thioredoxin-like activity profile". The Journal of Biological Chemistry. 272 (29): 18044–50. doi: 10.1074/jbc.272.29.18044 . PMID   9218434.
  3. ↑ Phulera S, Mande SC (June 2013). "The crystal structure of Mycobacterium tuberculosis NrdH at 0.87 Å suggests a possible mode of its activity". Biochemistry. 52 (23): 4056–65. doi:10.1021/bi400191z. PMID   23675692.
  4. ↑ Phulera S, Akif M, Sardesai AA, Mande SC (2014-01-01). "Redox Proteins of Mycobacterium tuberculosis". Journal of the Indian Institute of Science. 94 (1): 127–138. ISSN   0970-4140.
  5. 1 2 3 4 Hirt RP, Müller S, Embley TM, Coombs GH (July 2002). "The diversity and evolution of thioredoxin reductase: new perspectives". Trends in Parasitology. 18 (7): 302–8. doi:10.1016/S1471-4922(02)02293-6. PMID   12379950.
  6. 1 2 Holmgren A, Lu J (May 2010). "Thioredoxin and thioredoxin reductase: current research with special reference to human disease". Biochemical and Biophysical Research Communications. 396 (1): 120–4. doi:10.1016/j.bbrc.2010.03.083. PMID   20494123.
  7. ↑ Meyer Y, Buchanan BB, Vignols F, Reichheld JP (2009). "Thioredoxins and glutaredoxins: unifying elements in redox biology". Annual Review of Genetics. 43: 335–67. doi:10.1146/annurev-genet-102108-134201. PMID   19691428.
  8. ↑ Lillig CH, Holmgren A (Jan 2007). "Thioredoxin and related molecules--from biology to health and disease". Antioxidants & Redox Signaling. 9 (1): 25–47. doi:10.1089/ars.2007.9.25. PMID   17115886.
  9. ↑ Arscott LD, Gromer S, Schirmer RH, Becker K, Williams CH (Apr 1997). "The mechanism of thioredoxin reductase from human placenta is similar to the mechanisms of lipoamide dehydrogenase and glutathione reductase and is distinct from the mechanism of thioredoxin reductase from Escherichia coli". Proceedings of the National Academy of Sciences of the United States of America. 94 (8): 3621–6. Bibcode:1997PNAS...94.3621A. doi: 10.1073/pnas.94.8.3621 . PMC   20490 . PMID   9108027.
  10. 1 2 Conrad M, Jakupoglu C, Moreno SG, Lippl S, Banjac A, Schneider M, Beck H, Hatzopoulos AK, Just U, Sinowatz F, Schmahl W, Chien KR, Wurst W, Bornkamm GW, Brielmeier M (Nov 2004). "Essential role for mitochondrial thioredoxin reductase in hematopoiesis, heart development, and heart function". Molecular and Cellular Biology. 24 (21): 9414–23. doi:10.1128/MCB.24.21.9414-9423.2004. PMC   522221 . PMID   15485910.
  11. 1 2 3 Williams CH (Oct 1995). "Mechanism and structure of thioredoxin reductase from Escherichia coli". FASEB Journal. 9 (13): 1267–76. doi:10.1096/fasebj.9.13.7557016. hdl: 2027.42/154540 . PMID   7557016. S2CID   26055087.
  12. 1 2 Sandalova T, Zhong L, Lindqvist Y, Holmgren A, Schneider G (Aug 2001). "Three-dimensional structure of a mammalian thioredoxin reductase: implications for mechanism and evolution of a selenocysteine-dependent enzyme". Proceedings of the National Academy of Sciences of the United States of America. 98 (17): 9533–8. Bibcode:2001PNAS...98.9533S. doi: 10.1073/pnas.171178698 . PMC   55487 . PMID   11481439.
  13. ↑ Zhong L, Arnér ES, Holmgren A (May 2000). "Structure and mechanism of mammalian thioredoxin reductase: the active site is a redox-active selenolthiol/selenenylsulfide formed from the conserved cysteine-selenocysteine sequence". Proceedings of the National Academy of Sciences of the United States of America. 97 (11): 5854–9. Bibcode:2000PNAS...97.5854Z. doi: 10.1073/pnas.100114897 . PMC   18523 . PMID   10801974.
  14. ↑ Becker K, Herold-Mende C, Park JJ, Lowe G, Schirmer RH (Aug 2001). "Human thioredoxin reductase is efficiently inhibited by (2,2':6',2' '-terpyridine)platinum(II) complexes. Possible implications for a novel antitumor strategy". Journal of Medicinal Chemistry. 44 (17): 2784–92. doi:10.1021/jm001014i. PMID   11495589.
  15. ↑ Lennon BW, Williams CH (Aug 1997). "Reductive half-reaction of thioredoxin reductase from Escherichia coli". Biochemistry. 36 (31): 9464–77. doi:10.1021/bi970307j. PMID   9235991.
  16. ↑ Li X, Zhang B, Yan C, Li J, Wang S, Wei X, et al. (June 2019). "A fast and specific fluorescent probe for thioredoxin reductase that works via disulphide bond cleavage". Nature Communications. 10 (1): 2745. Bibcode:2019NatCo..10.2745L. doi: 10.1038/s41467-019-10807-8 . PMC   6588570 . PMID   31227705.
  17. ↑ Ma H, Zhang J, Zhang Z, Liu Y, Fang J (October 2016). "A fast response and red emission probe for mammalian thioredoxin reductase". Chemical Communications. 52 (81): 12060–12063. doi:10.1039/C6CC04984B. PMID   27709154.
  18. ↑ Zhao J, Qu Y, Gao H, Zhong M, Li X, Zhang F, et al. (November 2020). "Loss of thioredoxin reductase function in a mouse stroke model disclosed by a two-photon fluorescent probe". Chemical Communications. 56 (90): 14075–14078. doi:10.1039/D0CC05900E. PMID   33107534. S2CID   225082279.
  19. ↑ Liu Y, Ma H, Zhang L, Cui Y, Liu X, Fang J (February 2016). "A small molecule probe reveals declined mitochondrial thioredoxin reductase activity in a Parkinson's disease model". Chemical Communications. 52 (11): 2296–9. doi:10.1039/c5cc09998f. PMID   26725656.
  20. ↑ Mafireyi TJ, Laws M, Bassett JW, Cassidy PB, Escobedo JO, Strongin RM (August 2020). "A Diselenide Turn-On Fluorescent Probe for the Detection of Thioredoxin Reductase". Angewandte Chemie. 59 (35): 15147–15151. doi:10.1002/ange.202004094. PMC   9438933 . PMID   32449244. S2CID   229142596.
  21. ↑ Mafireyi TJ, Escobedo JO, Strongin RM (2021-03-29). "Fluorogenic probes for thioredoxin reductase activity". Results in Chemistry. 3: 100127. doi: 10.1016/j.rechem.2021.100127 . ISSN   2211-7156.
  22. ↑ Nilsonne G, Sun X, Nyström C, Rundlöf AK, Potamitou Fernandes A, Björnstedt M, Dobra K (Sep 2006). "Selenite induces apoptosis in sarcomatoid malignant mesothelioma cells through oxidative stress". Free Radical Biology & Medicine. 41 (6): 874–85. doi:10.1016/j.freeradbiomed.2006.04.031. hdl: 10616/47514 . PMID   16934670.
  23. ↑ Kahlos K, Soini Y, Säily M, Koistinen P, Kakko S, Pääkkö P, Holmgren A, Kinnula VL (May 2001). "Up-regulation of thioredoxin and thioredoxin reductase in human malignant pleural mesothelioma". International Journal of Cancer. 95 (3): 198–204. doi: 10.1002/1097-0215(20010520)95:3<198::AID-IJC1034>3.0.CO;2-F . PMID   11307155.
  24. ↑ Sibbing D, Pfeufer A, Perisic T, Mannes AM, Fritz-Wolf K, Unwin S, Sinner MF, Gieger C, Gloeckner CJ, Wichmann HE, Kremmer E, Schäfer Z, Walch A, Hinterseer M, Näbauer M, Kääb S, Kastrati A, Schömig A, Meitinger T, Bornkamm GW, Conrad M, von Beckerath N (May 2011). "Mutations in the mitochondrial thioredoxin reductase gene TXNRD2 cause dilated cardiomyopathy". European Heart Journal. 32 (9): 1121–33. doi: 10.1093/eurheartj/ehq507 . hdl: 11858/00-001M-0000-0024-1F10-3 . PMID   21247928.
  25. ↑ Marshall AC, Kidd SE, Lamont-Friedrich SJ, Arentz G, Hoffmann P, Coad BR, Bruning JB (March 2019). "Aspergillus fumigatus Thioredoxin Reductase". Antimicrobial Agents and Chemotherapy. 63 (3). doi:10.1128/AAC.02281-18. PMC   6395915 . PMID   30642940.
  26. ↑ Harbut MB, Vilchèze C, Luo X, Hensler ME, Guo H, Yang B, et al. (April 2015). "Auranofin exerts broad-spectrum bactericidal activities by targeting thiol-redox homeostasis". Proceedings of the National Academy of Sciences of the United States of America. 112 (14): 4453–8. Bibcode:2015PNAS..112.4453H. doi: 10.1073/pnas.1504022112 . PMC   4394260 . PMID   25831516.
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