Thioredoxin (Trx) system proteins

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Thioredoxin (Trx) system proteins

Unless otherwise stated all data on this page refer to the human proteins. Gene information is provided for human (Hs), mouse (Mm) and rat (Rn).

Overview

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The thioredoxin antioxidant system acts to rapidly remove reactive oxygen and nitrogen species as a defense against oxidative stress. The system comprises NADPH, thioredoxin reductases (TrxR), and thioredoxins (Trx).
Trxs are monomeric enzymes that catalyses protein disulfide/dithiol change, with an active site disulfide within a conserved thioredoxin fold structure. The human genome encodes two Trx genes, TXN and TXN2. Three TrxRs are found in mammalian cells: TrxR1 (cytosolic; TXNRD1), TrxR2 (mitochondrial; TXNRD2) and TrxR3 (testis-specific; TXNRD3). Overexpression of TrxR1 in nonsmall cell lung cancer (NSCLC) has led to its recognition as a novel therapeutic target for this cancer.

Enzymes

thioredoxin reductase 1 Show summary »« Hide summary

Target Id

3302

Nomenclature

thioredoxin reductase 1

Genes

TXNRD1 (Hs), Txnrd1 (Mm), Txnrd1 (Rn)

Ensembl ID

ENSG00000198431 (Hs), ENSMUSG00000020250 (Mm), ENSRNOG00000009088 (Rn)

UniProtKB AC

Q16881 (Hs), Q9JMH6 (Mm), O89049 (Rn)

Inhibitors

TrxR1 inhibitor 6a (Binding) pK_d 5.1 [4]

parthenolide pIC₅₀ ~5.5 [1] - Rat

micheliolide pIC₅₀ 5.2 [5]

xanthatin [2]

Comment

Thioredoxin reductase 1 (TrxR1) is a homodimeric selenocysteine-containing flavoenzyme that contains conserved FAD and NADPH binding domains and N-terminal active site motif CVNVGC. It is one component of the thioredoxin antioxidant system that protects cells and tissues from oxidative stress and free radical damage by maintaining cellular redox homeostasis.
Overexpression of TrxR1 is assocaited with resistance to therapies and poor prognosis in several types of cancer. These discoveries have led to recognition of TrxR1 as a novel oncology drug target. Inhibition of enzyme activity drastically disrupts redox homeostasis, elevates ROS production and leads to ER stress, apoptosis and ferroptosis [3-4,6].

References

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1. Duan D, Zhang J, Yao J, Liu Y, Fang J. (2016) Targeting Thioredoxin Reductase by Parthenolide Contributes to Inducing Apoptosis of HeLa Cells. J Biol Chem, 291 (19): 10021-31. [PMID:27002142]

2. Liu R, Shi D, Zhang J, Li X, Han X, Yao X, Fang J. (2018) Xanthatin Promotes Apoptosis via Inhibiting Thioredoxin Reductase and Eliciting Oxidative Stress. Mol Pharm, 15 (8): 3285-3296. [PMID:29939757]

3. Nikitjuka A, Ozola M, Krims-Davis K, Žalubovskis R. (2024) Design, Synthesis, and Bioactivity Evaluations of 3-Methylenechroman-2-one Derivatives as Thioredoxin Reductase (TrxR) Inhibitors. ChemMedChem, 19 (3): e202300504. [PMID:38063319]

4. Ren H, Wang YJ, Wang XY, Li X, Han Z, Zhang G, Gu L, Bai M, Yao GD, Liu Q et al.. (2025) Design of ROS-Triggered Sesquiterpene Lactone SC Prodrugs as TrxR1 Covalent Inhibitors for the Treatment of Non-Small Cell Lung Cancer. J Med Chem, [Epub ahead of print]. [PMID:39869029]

5. Xu Z, Xu J, Sun S, Lin W, Li Y, Lu Q, Li F, Yang Z, Lu Y, Liu W. (2022) Mecheliolide elicits ROS-mediated ERS driven immunogenic cell death in hepatocellular carcinoma. Redox Biol, 54: 102351. [PMID:35671636]

6. Zheng P, Xia Y, Shen X, Lu H, Chen Y, Xu C, Qiu C, Zhang Y, Zou P, Cui R et al.. (2024) Combination of TrxR1 inhibitor and lenvatinib triggers ROS-dependent cell death in human lung cancer cells. Int J Biol Sci, 20 (1): 249-264. [PMID:38164168]

How to cite this family page

Database page citation:

Thioredoxin (Trx) system proteins. Accessed on 25/04/2025. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=1105.

Concise Guide to PHARMACOLOGY citation:

Alexander SPH, Fabbro D, Kelly E, Mathie AA, Peters JA, Veale EL, Armstrong JF, Faccenda E, Harding SD, Davies JA et al. (2023) The Concise Guide to PHARMACOLOGY 2023/24: Enzymes. Br J Pharmacol. 180 Suppl 2:S289-373.