Mammalian Selenoprotein Thioredoxin-glutathione Reductase

Su, Dan; Novoselov, Sergey V.; Sun, Qi; Moustafa, Mohamed E.; Zhou, You; Oko, Richard; Hatfield, Dolph L.; Gladyshev, Vadim N.

doi:10.1074/jbc.m503638200

Cited by 176 publications

(68 citation statements)

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“…Functional analysis performed on SmTGR and on different TGRs proved that the penultimate Sec is essential for the reduction of thioredoxin and the glutaredoxin domain (6,12,15). Reduction of glutathione under physiological conditions is probably dependent on the redox exchange with glutaredoxin and thus is also inhibited in Sec-lacking enzymes, even though we observed residual GR activity in a C-terminally truncated variant of SmTGR (17).…”

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confidence: 66%

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Mapping the Catalytic Cycle of Schistosoma mansoni Thioredoxin Glutathione Reductase by X-ray Crystallography

Angelucci¹,

Dimastrogiovanni²,

Boumis

et al. 2010

Journal of Biological Chemistry

115

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Schistosomiasis is the second most widespread human parasitic disease. It is principally treated with one drug, praziquantel, that is administered to 100 million people each year; less sensitive strains of schistosomes are emerging. One of the most appealing drug targets against schistosomiasis is thioredoxin glutathione reductase (TGR). This natural chimeric enzyme is a peculiar fusion of a glutaredoxin domain with a thioredoxin selenocysteine (U)-containing reductase domain. Selenocysteine is located on a flexible C-terminal arm that is usually disordered in the available structures of the protein and is essential for the full catalytic activity of TGR. In this study, we dissect the catalytic cycle of Schistosoma mansoni TGR by structural and functional analysis of the U597C mutant. The crystallographic data presented herein include the following: the oxidized form (at 1.9 Å resolution); the NADPH-and GSH-bound forms (2.3 and 1.9 Å , respectively); and a different crystal form of the (partially) reduced enzyme (3.1 Å ), showing the physiological dimer and the entire C terminus of one subunit. Whenever possible, we determined the rate constants for the interconversion between the different oxidation states of TGR by kinetic methods. By combining the crystallographic analysis with computer modeling, we were able to throw further light on the mechanism of action of S. mansoni TGR. In particular, we hereby propose the putative functionally relevant conformational change of the C terminus after the transfer of reducing equivalents from NADPH to the redox sites of the enzyme.

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confidence: 66%

“…Characterization of mouse TGR demonstrated that the enzyme can reduce components of both mammalian Trx and GSH systems. In mammals, TGR exerts a wide range of catalytic activities though its selective overexpression in testis after puberty suggests its involvement in very specific functions related with sperm maturation (12).…”

mentioning

confidence: 99%

Mapping the Catalytic Cycle of Schistosoma mansoni Thioredoxin Glutathione Reductase by X-ray Crystallography

Angelucci¹,

Dimastrogiovanni²,

Boumis

et al. 2010

Journal of Biological Chemistry

115

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“…73 However, the physiological role that TrxRs play in the reduction of most of these substrates is still unknown. Some of the most likely functions for TrxRs are summarized in Fig.…”

Section: Thioredoxin Reductasesmentioning

confidence: 99%

“…This enzyme is mainly expressed in the male germ cells and has been suggested to play a role in sperm maturation by influencing the formation of disulfide bonds in structural proteins. 73 …”

Section: Thioredoxin Reductasesmentioning

confidence: 99%

Selenium biochemistry and its role for human health

Roman¹,

Jitaru²,

Barbante³

2014

Metallomics

657

451

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Despite its very low level in humans, selenium plays an important and unique role among the (semi)metal trace essential elements because it is the only one for which incorporation into proteins is genetically encoded, as the constitutive part of the 21st amino acid, selenocysteine. Twenty-five selenoproteins have been identified so far in the human proteome. The biological functions of some of them are still unknown, whereas for others there is evidence for a role in antioxidant defence, redox state regulation and a wide variety of specific metabolic pathways. In relation to these functions, the selenoproteins emerged in recent years as possible biomarkers of several diseases such as diabetes and several forms of cancer. Comprehension of the selenium biochemical pathways under normal physiological conditions is therefore an important requisite to elucidate its preventing/therapeutic effect for human diseases. This review summarizes the most recent findings on the biochemistry of active selenium species in humans, and addresses the latest evidence on the link between selenium intake, selenoproteins functionality and beneficial health effects. Primary emphasis is given to the interpretation of biochemical mechanisms rather than epidemiological/observational data. In this context, the review includes the following sections: (1) brief introduction; (2) general nutritional aspects of selenium; (3) global view of selenium metabolic routes; (4) detailed characterization of all human selenoproteins; (5) detailed discussion of the relation between selenoproteins and a variety of human diseases.

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“…Two redox-related proteins, glutathione peroxidase 4 and thioredoxin-glutathione reductase, have been studied extensively in association with spermiogenesis (17,18,25). Glutathione peroxidase 4 is highly expressed in spermatogenic cells and becomes oxidatively cross-linked to structural components of the sperm midpiece during spermiogenesis (18).…”

Section: Cellular Localization Of Prx Iv-s and Prx Iv-l In Mousementioning

confidence: 99%