Thioredoxins, Glutaredoxins, and Peroxiredoxins—Molecular Mechanisms and Health Significance: from Cofactors to Antioxidants to Redox Signaling

Hanschmann, Eva-Maria; Godoy, José R.; Berndt, Carsten; Hudemann, Christoph; Lillig, Christopher Horst

doi:10.1089/ars.2012.4599

Cited by 574 publications

(527 citation statements)

References 850 publications

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“…Monothiol GRXs function primarily both in the biosynthesis of FeS proteins and Fe homeostasis 164. GRX1 is mainly localized in the cytosol but can be found in the MIS; it can be translocated into the nucleus and exported from the cell 159. GRX2 is expressed in the mitochondria,165 GRX3 in the cytosolic and nuclear compartment, and monothiol GRX5 has a mitochondrial translocation signal and shares the active site motif of GRX3 166.…”

Section: Regulatory Reactive Oxygen and Nitrogen Species Enzymes Exprmentioning

confidence: 99%

Redox homeostasis and age‐related deficits in neuromuscular integrity and function

Sakellariou

Lightfoot

Earl

et al. 2017

J cachexia sarcopenia muscle

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Skeletal muscle is a major site of metabolic activity and is the most abundant tissue in the human body. Age‐related muscle atrophy (sarcopenia) and weakness, characterized by progressive loss of lean muscle mass and function, is a major contributor to morbidity and has a profound effect on the quality of life of older people. With a continuously growing older population (estimated 2 billion of people aged >60 by 2050), demand for medical and social care due to functional deficits, associated with neuromuscular ageing, will inevitably increase. Despite the importance of this ‘epidemic’ problem, the primary biochemical and molecular mechanisms underlying age‐related deficits in neuromuscular integrity and function have not been fully determined. Skeletal muscle generates reactive oxygen and nitrogen species (RONS) from a variety of subcellular sources, and age‐associated oxidative damage has been suggested to be a major factor contributing to the initiation and progression of muscle atrophy inherent with ageing. RONS can modulate a variety of intracellular signal transduction processes, and disruption of these events over time due to altered redox control has been proposed as an underlying mechanism of ageing. The role of oxidants in ageing has been extensively examined in different model organisms that have undergone genetic manipulations with inconsistent findings. Transgenic and knockout rodent studies have provided insight into the function of RONS regulatory systems in neuromuscular ageing. This review summarizes almost 30 years of research in the field of redox homeostasis and muscle ageing, providing a detailed discussion of the experimental approaches that have been undertaken in murine models to examine the role of redox regulation in age‐related muscle atrophy and weakness.

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Section: Regulatory Reactive Oxygen and Nitrogen Species Enzymes Exprmentioning

confidence: 99%

Redox homeostasis and age‐related deficits in neuromuscular integrity and function

Sakellariou

Lightfoot

Earl

et al. 2017

J cachexia sarcopenia muscle

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“…Such redox regulation is achieved by a combination of (a) cysteine oxidation by hydrogen peroxide or other reactive oxygen species and (b) reduction of by cellular redoxin systems (1)(2)(3). The oxidation products are mostly disulfides, including mixed disulfides with GSH (4).…”

mentioning

confidence: 99%

Glutathionylation of the Active Site Cysteines of Peroxiredoxin 2 and Recycling by Glutaredoxin

Peskin

Pace

Behring

et al. 2016

Journal of Biological Chemistry

102

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Peroxiredoxin 2 (Prx2) is a thiol protein that functions as an antioxidant, regulator of cellular peroxide concentrations, and sensor of redox signals. Its redox cycle is widely accepted to involve oxidation by a peroxide and reduction by thioredoxin/ thioredoxin reductase. Interactions of Prx2 with other thiols are not well characterized. Here we show that the active site Cys residues of Prx2 form stable mixed disulfides with glutathione (GSH). Glutathionylation was reversed by glutaredoxin 1 (Grx1), and GSH plus Grx1 was able to support the peroxidase activity of Prx2. Prx2 became glutathionylated when its disulfide was incubated with GSH and when the reduced protein was treated with H 2 O 2 and GSH. The latter reaction occurred via the sulfenic acid, which reacted sufficiently rapidly (k ‫؍‬ 500 M ؊1 s ؊1 ) for physiological concentrations of GSH to inhibit Prx disulfide formation and protect against hyperoxidation to the sulfinic acid. Glutathionylated Prx2 was detected in erythrocytes from Grx1 knock-out mice after peroxide challenge. We conclude that Prx2 glutathionylation is a favorable reaction that can occur in cells under oxidative stress and may have a role in redox signaling. GSH/Grx1 provide an alternative mechanism to thioredoxin and thioredoxin reductase for Prx2 recycling.

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“…A large, mostly hydrophobic groove harbors a redox activesite motif CPWC, typical of the thioredoxin superfamily of oxidoreductases (13)(14)(15)(16). Using a combination of x-ray crystallography, small angle x-ray scattering, limited proteolysis, circular dichroism, site-directed mutagenesis and activity measurements, we show that Rv2466c undergoes significant conformational changes upon formation of its oxidized state, providing unprecedented insight into the molecular mechanism of TP053 activation.…”

Section: Among Infectious Human Diseases Tuberculosis (Tb)mentioning

confidence: 98%

The Redox State Regulates the Conformation of Rv2466c to Activate the Antitubercular Prodrug TP053

Albesa‐Jové

Comino

Tersa

et al. 2015

Journal of Biological Chemistry

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Rv2466c is a key oxidoreductase that mediates the reductive activation of TP053, a thienopyrimidine derivative that kills replicating and non-replicating Mycobacterium tuberculosis, but whose mode of action remains enigmatic. Rv2466c is a homodimer in which each subunit displays a modular architecture comprising a canonical thioredoxin-fold with a Cys 19 -Pro 20 -Trp 21 -Cys 22 motif, and an insertion consisting of a four ␣-helical bundle and a short ␣-helical hairpin. Strong evidence is provided for dramatic conformational changes during the Rv2466c redox cycle, which are essential for TP053 activity. Strikingly, a new crystal structure of the reduced form of Rv2466c revealed the binding of a C-terminal extension in ␣-helical conformation to a pocket next to the active site cysteine pair at the interface between the thioredoxin domain and the helical insertion domain. The ab initio low-resolution envelopes obtained from small angle x-ray scattering showed that the fully reduced form of Rv2466c adopts a "closed" compact conformation in solution, similar to that observed in the crystal structure. In contrast, the oxidized form of Rv2466c displays an "open" conformation, where tertiary structural changes in the ␣-helical subdomain suffice to account for the observed conformational transitions. Altogether our structural, biochemical, and biophysical data strongly support a model in which the formation of the catalytic disulfide bond upon TP053 reduction triggers local structural changes that open the substrate binding site of Rv2466c allowing the release of the activated, reduced form of TP053. Our studies suggest that similar structural changes might have a functional role in other members of the thioredoxin-fold superfamily. Among infectious human diseases, tuberculosis (TB)3 is the second greatest killer worldwide due to a single infectious agent, and remains a major challenge to human health care. In 2013, there were about 9 million new cases and 1.5 million deaths from TB, with an estimated one-third of the human population carrying a latent infection (1). First-line treatment for drug-susceptible TB requires the administration of a combination of four drugs during a period of 6 months: isoniazid, rifampicin, ethambutol, and pyrazinamide. Lengthy treatment regimens, unpleasant side effects, and patient noncompliance have provided conditions for the generation of multidrug-resistant and extensively drug-resistant cases of TB (2). Thus, the discovery and development of novel anti-TB drugs with bactericidal mechanisms different from those of currently available agents has become an urgent need. In that context, bedaquiline, a diarylquinoline that inhibits the c subunit of ATP synthase from Mycobacterium tuberculosis, has been recently approved by the Food and Drug Administration (FDA) for the treatment of multidrug-resistant TB in adults (3-5). Moreover, several candidate molecules are currently in preclinical studies, phase II and III clinical trials (6, 7). However, up to date, only a few drugs are capable of e...

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Thioredoxins, Glutaredoxins, and Peroxiredoxins—Molecular Mechanisms and Health Significance: from Cofactors to Antioxidants to Redox Signaling

Cited by 574 publications

References 850 publications

Redox homeostasis and age‐related deficits in neuromuscular integrity and function

Redox homeostasis and age‐related deficits in neuromuscular integrity and function

Glutathionylation of the Active Site Cysteines of Peroxiredoxin 2 and Recycling by Glutaredoxin

The Redox State Regulates the Conformation of Rv2466c to Activate the Antitubercular Prodrug TP053

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