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Human Mitochondrial Glutaredoxin Reduces S-Glutathionylated Proteins with High Affinity Accepting Electrons from Either Glutathione or Thioredoxin Reductase
Open accessAbstract
Glutaredoxins catalyze glutathione-dependent thiol disulfide oxidoreductions via a GSH-binding site and active cysteines. Recently a second human glutaredoxin (Grx2), which is targeted to either mitochondria or the nucleus, was cloned. Grx2 contains the active site sequence CSYC, which is different from the conserved CPYC motif present in the cytosolic Grx1. Here we have compared the activity of Grx2 and Grx1 using glutathionylated substrates and active site mutants. The kinetic studies showed that Grx2 catalyzes the reduction of glutathionylated substrates with a lower rate but higher affinity compared with Grx1, resulting in almost identical catalytic efficiencies (k(cat)/K(m)). Permutation of the active site motifs of Grx1 and Grx2 revealed that the CSYC sequence of Grx2 is a prerequisite for its high affinity toward glutathionylated proteins, which comes at the price of lower k(cat). Furthermore Grx2 was a substrate for NADPH and thioredoxin reductase, which efficiently reduced both the active site disulfide and the GSH-glutaredoxin intermediate formed in the reduction of glutathionylated substrates. Using this novel electron donor pathway, Grx2 reduced low molecular weight disulfides such as CoA but with particular high efficiency glutathionylated substrates including GSSG. These results suggest an important role for Grx2 in protection and recovery from oxidative stress.
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“reduction of the oxidized form of Grx2 can be mediated by GSH or NADH and thioredoxin reductase (TrxR) (195)”
From Redox regulation of mitochondrial function (2012) · cites this paper as [195]
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InfluentialSelf-citationGlutathione-Related Enzymes and Proteins: A Review
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InfluentialGlutaredoxin: Discovery, redox defense and much more
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InfluentialDisruption of mitochondrial redox circuitry in oxidative stress
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Self-citationThe Incomplete Glutathione Puzzle: Just Guessing at Numbers and Figures?
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Glutathione, Glutaredoxins, and Iron
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Kinetic and Thermodynamic Aspects of Cellular Thiol–Disulfide Redox Regulation
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Selenium Cytotoxicity in Cancer
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“In addition, it has been shown that Grx2a can be reduced by TrxR2 [185] and also the occurrence of glutathionylation of thioredoxin has been demonstrated in vitro [186].”
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“, FTR and NTR), depending on the redox potential and catalytic mechanism of the specific GRX (145, 246, 578).”
BackgroundS-glutathionylation reactions in mitochondrial function and disease
Mailloux, R. J., & Willmore, W. G. (2014) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2014.00068 · Cited by 130
“An exception here is that the Grx2-SSG intermediate can also be reduced by thioredoxin reductase (TrxR) in an NADPH-dependent fashion (Johansson et al., 2004).”
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Michelet, L., Zaffagnini, M., Massot, V., Keryer, E., Vanacker, H., Miginiac-Maslow, M., Issakidis-Bourguet, E., & Lemaire, S. (2006) · Photosynthesis Research · doi:10.1007/s11120-006-9096-2 · Cited by 120
“Moreover, this GRX can be reactivated directly by TRX reductase as well as GSH, suggesting that human GRX2 could operate in an oxidative cell environment (Johansson et al. 2004).”
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“Mitochondrial thiols that maintain redox reactions mainly include GSH and thioredoxin-2 (Trx2) and the associated enzymes—glutathione reductase (GR) and thioredoxin reductase (TrxR)—supporting the activities of glutathione peroxidase, glutaredoxin-2 (Grx2), and peroxiredoxin-3 (Prx3) and - 5 (Prx5) (34, 70, 148).”
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Self-citationThe roles of glutaredoxins ligating Fe–S clusters: Sensing, transfer or repair functions?
Couturier, J., Przybyla‐Toscano, J., Roret, T., Claude Didierjean, B., & Rouhier, N. (2014) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2014.09.018 · Cited by 126
Rackham, O., Shearwood, A.-M. J., Thyer, R. T., McNamara, E. L., Davies, S. M. K., Callus, B. A., Miranda‐Vizuete, A., Berners‐Price, S. J., Cheng, Q., Arnér, E. S. J., et al. (2010) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2010.12.015 · Cited by 121
“Although mammalian TrxR1 and TrxR2 have some substrates in common, the different subcellular localizations of the isoenzymes have probably given rise to some differences, including specific protein substrates such as Trx2, glutaredoxin 2, and cytochrome c for TrxR2 [24,25] and thioredoxin-related protein 14 for TrxR1…”
BackgroundRuszkiewicz, J. A., & Albrecht, J. (2015) · Neurochemistry International · doi:10.1016/j.neuint.2014.12.012 · Cited by 125
The biological roles of glutaredoxins
Ströher, E., & Millar, A. H. (2012) · Biochemical Journal · doi:10.1042/bj20112131 · Cited by 121
Saleh, M., Bartual, S. G., Abdullah, M. R., Jensch, I., Asmat, T. M., Petruschka, L., Pribyl, T. M., Gellert, M., Lillig, C. H., Antelmann, H., et al. (2013) · EMBO Molecular Medicine · doi:10.1002/emmm.201202435 · Cited by 115
“ROS are able to react with all cellular macromolecules, such as proteins, lipids, carbohydrates and nucleotides (Gutteridge & Halliwell, 2000; Johansson et al, 2004).”
Self-citationHanschmann, E.-M., Lönn, M. E., Schütte, L. D., Funke, M., Godoy, J. R., Eitner, S., Hudemann, C., & Lillig, C. H. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.185827 · Cited by 112
Self-citationPapp, L. V., Lu, J., Striebel, F., Kennedy, D. D., Holmgren, A., & Khanna, K. K. (2006) · Molecular and Cellular Biology · doi:10.1128/mcb.02284-05 · Cited by 112
“human Grx1 was measured as described previously (36).”
MethodSelf-citationCouturier, J., Ströher, E., Albetel, A., Roret, T., Muthuramalingam, M., Tarrago, L., Seidel, T., Tsan, P., Jacquot, J., Johnson, M. K., et al. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.228726 · Cited by 112
The relationships between cytochromes P450 and H 2 O 2 : Production, reaction, and inhibition
Albertolle, M. E., & Guengerich, F. P. (2018) · Journal of Inorganic Biochemistry · doi:10.1016/j.jinorgbio.2018.05.014 · Cited by 114
Zhang, P., Wu, J., Xiao, F., Zhao, D., & Luan, Y. (2018) · Medicinal Research Reviews · doi:10.1002/med.21485 · Cited by 108
Gnanaprakasam, J. R., Wu, R., & Wang, R. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.01075 · Cited by 108
Tan, S., Greetham, D., Raeth, S., Grant, C. M., Dawes, I. W., & Perrone, G. G. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.062844 · Cited by 106
Rigobello, M., Folda, A., Baldoin, M. C., Scutari, G., & Bindoli, A. (2005) · Free radical research · doi:10.1080/10715760500135391 · Cited by 103
“To the glutathione system is also associated the dithiolcontaining protein glutaredoxin able to catalyze the reduction of S-glutathionylated substrates or to act as a disulfide reductase [13].”
BackgroundLourenço dos Santos, S., Petropoulos, I., & Friguet, B. (2018) · Antioxidants · doi:10.3390/antiox7120191 · Cited by 109
“An exception was observed with the Grx2 isoenzyme, which was shown to be reduced by Trx2 in mitochondria [4].”
BackgroundBonilla, M., Denicola, A., Novoselov, S. V., Turanov, A. A., Protasio, A. V., Izmendi, D., Gladyshev, V. N., & Salinas, G. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m710609200 · Cited by 103
Oxidation and S-Nitrosylation of Cysteines in Human Cytosolic and Mitochondrial Glutaredoxins
Hashemy, S. I., Johansson, C., Berndt, C., Lillig, C. H., & Holmgren, A. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m700927200 · Cited by 103
Self-citationHow Does Iron–Sulfur Cluster Coordination Regulate the Activity of Human Glutaredoxin 2?
Berndt, C., Hudemann, C., Hanschmann, E.-M., Axelsson, R., Holmgren, A., & Lillig, C. H. (2006) · Antioxidants and Redox Signaling · doi:10.1089/ars.2007.9.151 · Cited by 101
“However, Grx2 is clearly more adopted to accommodate an iron–sulfur cluster, because the Ser still able to bind the cluster in vitro .”
Self-citationMailloux, R. J., Xuan, J. Y., McBride, S., Maharsy, W. M., Thorn, S., Holterman, C. E., Kennedy, C., Rippstein, P. U., deKemp, R. A., da Silva, J., et al. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.550574 · Cited by 101
“The catalytic cycle of Grx2 is also quite similar to Grx1 except that the Grx2-SSG intermediate can be reduced by NADPH and thioredoxin reductase (20).”
BackgroundMolina‐Navarro, M. M., Bellı́, G., de la Torre-Ruiz, M. Á., Rodríguez‐Manzaneque, M. T., & Herrero, E. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m410219200 · Cited by 100
Pai, H. V., Starke, D. W., Lesnefsky, E. J., Hoppel, C. L., & Mieyal, J. J. (2007) · Antioxidants and Redox Signaling · doi:10.1089/ars.2007.1642 · Cited by 99
“Nevertheless, GRx2 does possess specific catalytic deglutathionylase activity like GRx1 (17), and it operates via a double-displacement catalytic mechanism like GRx1 (12).”
The A to Z of modulated cell patterning by mammalian thioredoxin reductases
Dagnell, M., Schmidt, E. E., & Arnér, E. S. J. (2017) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2017.12.029 · Cited by 101
“Either TrxR or GSH can in turn reactivate Grx2 through reduction [64,69,70].”
Lönn, M. E., Hudemann, C., Berndt, C., Cherkasov, V., Capani, F., Holmgren, A., & Lillig, C. H. (2007) · Antioxidants and Redox Signaling · doi:10.1089/ars.2007.1821 · Cited by 99
“Grx2 efficiently catalyzes the reduction of GSH-mixed disulfides (19).”
Self-citationThe Pancreatic β-Cell: A Bioenergetic Perspective
Nicholls, D. G. (2016) · Physiological Reviews · doi:10.1152/physrev.00009.2016 · Cited by 100
Structural and evolutionary aspects of thioredoxin reductases in photosynthetic organisms
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Buchmeier, N. A., Newton, G. L., & Fahey, R. C. (2006) · Journal of Bacteriology · doi:10.1128/jb.00393-06 · Cited by 97
“In systems where glutathione is the dominant thiol, glutaredoxins play an important role in reducing mixed disulfides of Cys and glutathione with glutathione as a cofactor (7).”
BackgroundRedox Control of Neural Function: Background, Mechanisms, and Significance
Maher, P. A. (2006) · Antioxidants and Redox Signaling · doi:10.1089/ars.2006.8.1941 · Cited by 92
“JNK is generally thought to be activated through a pathway involving small GTP-binding proteins and a series of protein kinases terminating but via inactivation of the phosphatases, which generally maintain this kinase in a dephosphorylated and therefore inactive state”
Metadata
- Authors
- Johansson, C., Lillig, C. H., & Holmgren, A.
- Affiliations
- Karolinska Institutet (SE)
- Corresponding author
- Holmgren, Arne
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2004-02
- Volume
- 279
- Issue
- 9
- Pages
- 7537-7543
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2103665725
- Cited by
- 320
- References
- 81
- Citations by year
- 2026: 6 · 2025: 8 · 2024: 7 · 2023: 12 · 2022: 10 · 2021: 10 · 2020: 8 · 2019: 11 · 2018: 16 · 2017: 14 · 2016: 8 · 2015: 14 · 2014: 16 · 2013: 14 · 2012: 18
- FWCI
- 6.87
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Wenner-Gren Foundation
- Cancerfonden
- Knut och Alice Wallenbergs Stiftelse
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Glutathione Transferases and Polymorphisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Sulfur Compounds in Biology
- Keywords
- glutaredoxin 2, glutaredoxin 1, glutathione, thioredoxin reductase, NADPH, catalytic efficiency, glutathione disulfide, antioxidant defense
- MeSH terms
- Amino Acid Sequence, Animals, Binding Sites, Catalysis, Cattle, Cytosol, Disulfides, Glutathione, Humans, Mitochondria, Molecular Sequence Data, NADP, Oxidation-Reduction, Oxidoreductases, Proteins, Recombinant Proteins, Structure-Activity Relationship, Substrate Specificity, Thioredoxin-Disulfide Reductase, Mutagenesis, Site-Directed, Sequence Alignment, Conserved Sequence, Oxidative Stress, Glutaredoxins
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