ArticleThe Journal of biological chemistry2009
Molecular mechanisms of thioredoxin and glutaredoxin as hydrogen donors for Mammalian s phase ribonucleotide reductase.
Article in The Journal of biological chemistry, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 71 papers.
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71 citing papers in PubMed, 162 citations in OpenAlex.
- Paradoxical enhancement of oxidative stress-induced DNA damage and impaired redox homeostasis by Glutaredoxin 1 overexpression in human HeLa cells.Journal of radiation research · 2026Article
- Context‑dependent targeting of thioredoxin reductase 1 in cancer: a mechanistic review.Magyar onkologia · 2026Review
- CYB5R4 sustains endothelial proliferation and ischemia-induced angiogenesis by maintaining RRM2-dependent nucleotide balance.bioRxiv : the preprint server for biology · 2025Article
- Conformational landscapes of a class I ribonucleotide reductase complex during turnover reveal intrinsic dynamics and asymmetry.Nature communications · 2025Article
- Electron transfer in biological systems.Journal of biological inorganic chemistry : JBIC : a publication of the Society of Biological Inorganic Chemistry · 2024Review
- Human selenocysteine synthase, SEPSECS, has evolved to optimize binding of a tRNA-based substrate.Nucleic acids research · 2024Article
- The thioredoxin system determines CHK1 inhibitor sensitivity via redox-mediated regulation of ribonucleotide reductase activity.Nature communications · 2024Article
- Deciphering the mechanism of glutaredoxin-catalyzed roGFP2 redox sensing reveals a ternary complex with glutathione for protein disulfide reduction.Nature communications · 2024Article
- Glutaredoxin 2 Protein (Grx2) as an Independent Prognostic Factor Associated with the Survival of Colon Adenocarcinoma Patients.International journal of molecular sciences · 2024Article
- Benzophenanthridine Alkaloid Chelerythrine Elicits Necroptosis of Gastric Cancer Cells via Selective Conjugation at the Redox Hyperreactive C-Terminal SecMolecules (Basel, Switzerland) · 2023Article
- A new metabolic model ofLife science alliance · 2023Article
- Structural basis for the tRNA-dependent activation of the terminal complex of selenocysteine synthesis in humans.Nucleic acids research · 2023Article
- Glutathione-dependent thioredoxin reduction and lipoamide system support in-vitro mammalian ribonucleotide reductase catalysis: a possible antioxidant redundancy.Molecular biology reports · 2022Article
- The Thioredoxin System of Mammalian Cells and Its Modulators.Biomedicines · 2022Review
- Nucleotide biosynthesis links glutathione metabolism to ferroptosis sensitivity.Life science alliance · 2022Article
- Protective effect of Glutaredoxin 1 against oxidative stress in lens epithelial cells of age-related nuclear cataracts.Molecular vision · 2022Article
- Ribonucleotide reductase: In-vitro S-glutathionylation of R2 and p53R2 subunits of mammalian class I ribonucleotide reductase protein.Molecular biology reports · 2021Article
- Glutaredoxin: Discovery, redox defense and much more.Redox biology · 2021Review
- Autonomous Non Antioxidant Roles forFrontiers in cellular and infection microbiology · 2021Review
- Inhibition of selenoprotein synthesis by Zika virus may contribute to congenital Zika syndrome and microcephaly by mimicking SELENOP knockout and the genetic disease PCCA.BBA advances · 2021Article
11 more citing papers are in PubMed but not listed here.
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2 authors at 2 institutions in 1 country.
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No grant is acknowledged in the PubMed record.
Abstract
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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