Details in the catalytic mechanism of mammalian thioredoxin reductase 1 revealed using point mutations and juglone-coupled enzyme activities

Free Radical Biology & Medicine
J XuElias S J Arnér

Abstract

The mammalian selenoprotein thioredoxin reductase 1 (TrxR1) is a key enzyme in redox regulation, antioxidant defense, and cellular growth. TrxR1 can catalyze efficient reduction of juglone (5-hydroxy-1,4-naphthoquinone; walnut toxin) in a reaction which, in contrast to reduction of most other substrates of TrxR1, is not dependent upon an intact selenocysteine (Sec, U) residue of the enzyme. Using a number of TrxR1 mutant variants, we here found that a sole Cys residue at the C-terminal tail of TrxR1 is required for high-efficiency juglone-coupled NADPH oxidase activity of Sec-deficient enzyme, occurring with mixed one- and two-electron reactions producing superoxide. The activity also utilizes the FAD and the N-terminal redox active disulfide/dithiol motif of TrxR1. If a sole Cys residue at the C-terminal tail of TrxR1, in the absence of Sec, was moved further towards the C-terminal end of the protein compared to its natural position at residue 497, juglone reduction was, surprisingly, further increased. Ala substitutions of Trp407, Asn418 and Asn419 in a previously described "guiding bar", thought to mediate interactions of the C-terminal tail of TrxR1 with the FAD/dithiol site at the N-terminal domain of the other subunit in ...Continue Reading

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Citations

Sep 12, 2018·Chemistry, an Asian Journal·Baoxin ZhangJianguo Fang
Apr 10, 2019·Antioxidants·Taseer Ahmad, Yuichiro J Suzuki
Dec 15, 2020·Expert Opinion on Drug Discovery·Jianqiang Xu, Jianguo Fang
Dec 27, 2017·Free Radical Biology & Medicine·Markus DagnellElias S J Arnér
Feb 13, 2020·Inorganic Chemistry·Ingrid J PickeringElias S J Arnér
Aug 28, 2021·Annual Review of Pharmacology and Toxicology·Radosveta Gencheva, Elias S J Arnér

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