Thioredoxin reductases (TR, TrxR) () are enzymes that reduce thioredoxin (Trx). Two classes of thioredoxin reductase have been identified: one class in bacteria and some eukaryotes and one in animals. Bacterial TrxR also catalyzes the reduction of glutaredoxin like proteins known as NrdH. 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.
Cellular role
Thioredoxin reductases are enzymes that catalyze the reduction of thioredoxin 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.
[[File:CellularTrxR.png|thumb|center|500px|Schematic diagram of TrxR's cellular role Adapted from Holmgren et al.
Humans express three thioredoxin reductase isozymes: thioredoxin reductase 1 (TrxR1, cytosolic), thioredoxin reductase 2 (TrxR2, mitochondrial), thioredoxin reductase 3 (TrxR3, testis specific). Each isozyme is encoded by a separate gene:
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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. Each domain individually is very similar to the analogous domains in glutathione reductase and lipoamide dehydrogenase, but the relative orientation of these domains in ThxR is rotated by 66 degrees. 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. 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. The conserved active site residues in E. coli are -Cys-Ala-Thr-Cys-. Mafireyi synthesized the first diselenide probe that was applied in the detection of TrxR. 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. 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.
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.) This is especially true for Mycobacterium Haemophilum, and could be used for antibiotic resistant bacteria.