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Molecular Mechanisms of Thioredoxin and Glutaredoxin as Hydrogen Donors for Mammalian S Phase Ribonucleotide Reductase
Open accessAbstract
Ribonucleotide reductase (RNR) catalyzes the rate-limiting step in deoxyribonucleotide synthesis essential for DNA replication and repair. RNR in S phase mammalian cells comprises a weak cytosolic complex of the catalytic R1 protein containing redox active cysteine residues and the R2 protein harboring the tyrosine free radical. Each enzyme turnover generates a disulfide in the active site of R1, which is reduced by C-terminally located shuttle dithiols leaving a disulfide to be reduced. Electrons for reduction come ultimately from NADPH via thioredoxin reductase and thioredoxin (Trx) or glutathione reductase, glutathione, and glutaredoxin (Grx), but the mechanism has not been clarified for mammalian RNR. Using recombinant mouse RNR, we found that Trx1 and Grx1 had similar catalytic efficiency (k(cat)/K(m)). With 4 mm GSH, Grx1 showed a higher affinity (apparent K(m) value, 0.18 microm) compared with Trx1 which displayed a higher apparent k(cat), suggesting its major role in S phase DNA replication. Surprisingly, Grx activity was strongly dependent on GSH concentrations (apparent K(m) value, 3 mm) and a Grx2 C40S mutant was active despite only one cysteine residue in the active site. This demonstrates a GSH-mixed disulfide mechanism for glutaredoxin catalysis in contrast to the dithiol mechanism for thioredoxin. This may be an advantage with the low levels of RNR for DNA repair or in tumor cells with high RNR and no or low Trx expression. Our results demonstrate mechanistic differences between the mammalian and canonical Escherichia coli RNR enzymes, which may offer an explanation for the nonconserved shuttle dithiol sequences in the C terminus of the R1.
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“The thioredoxin (Trx) and glutaredoxin (Grx) systems are important as antioxidants for maintaining cellular redox balance and providing electrons for thiol-dependent reactions like those catalyzed by ribonucleotide reductase and peroxiredoxins (Prxs).”
From Inhibition of the glutaredoxin and thioredoxin systems and ribonucleotide reductase by mutant p53-targeting compound APR-246 (2018) · cites this paper as [21]
In the citing paper
“These systems are present in all mammalian cells19,20, and are required for the activity of ribonucleotide reductase (RNR) which provides deoxyribonucleotides for DNA replication and repair.”
From Inhibition of the glutaredoxin and thioredoxin systems and ribonucleotide reductase by mutant p53-targeting compound APR-246 (2018) · cites this paper as [21]
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Thioredoxin and thioredoxin reductase: Current research with special reference to human disease
Holmgren, A., & Lu, J. (2010) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2010.03.083 · Cited by 577
Self-citationThe human selenoproteome: recent insights into functions and regulation
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ATM activates the pentose phosphate pathway promoting anti‐oxidant defence and DNA repair
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Thioredoxin and Thioredoxin Target Proteins: From Molecular Mechanisms to Functional Significance
Lee, S., Kim, S. M., & Lee, R. T. (2012) · Antioxidants and Redox Signaling · doi:10.1089/ars.2011.4322 · Cited by 455
Metadata
- Authors
- Avval, F. Z., & Holmgren, A.
- Affiliations
- Karolinska Institutet (SE)
- Corresponding author
- Holmgren, Arne
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2009-03
- Volume
- 284
- Issue
- 13
- Pages
- 8233-8240
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC2659180
- OpenAlex
- W2095557093
- Cited by
- 169
- References
- 62
- Citations by year
- 2026: 7 · 2025: 5 · 2024: 10 · 2023: 6 · 2022: 10 · 2021: 13 · 2020: 7 · 2019: 6 · 2018: 11 · 2017: 12 · 2016: 9 · 2015: 7 · 2014: 9 · 2013: 5 · 2012: 11
- FWCI
- 6.92
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- 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
- Physical Sciences › Chemistry › Inorganic Chemistry › Metal-Catalyzed Oxygenation Mechanisms
- Keywords
- ribonucleotide reductase, thioredoxin, glutaredoxin, glutathione, disulfide bond reduction, hydrogen donors, NADPH, DNA repair, cancer cells, enzyme kinetics
- MeSH terms
- Animals, Catalysis, Deoxyribonucleotides, DNA Replication, Escherichia coli, Hydrogen, Ribonucleotide Reductases, Thioredoxins, S Phase, Catalytic Domain, Escherichia coli Proteins, Mice, Glutaredoxins
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