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ribonucleotide reductase catalytic subunit M1

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Target id: 2630

Nomenclature: ribonucleotide reductase catalytic subunit M1

Abbreviated Name: ribonucleotide reductase M1

Family: 1.17.4.1 Ribonucleoside-diphosphate reductases, Nucleoside synthesis and metabolism

Contents:

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 792 11p15.4 RRM1 ribonucleotide reductase catalytic subunit M1
Mouse - 792 7 54.72 cM Rrm1 ribonucleotide reductase M1
Rat - 792 1q32 Rrm1 ribonucleotide reductase catalytic subunit M1
Previous and Unofficial Names Click here for help
ribonucleoside-diphosphate reductase large subunit | ribonucleotide reductase M1
Database Links Click here for help
Alphafold P23921 (Hs), P07742 (Mm)
BRENDA 1.17.14.1
ChEMBL Target CHEMBL1830 (Hs), CHEMBL3739 (Mm)
DrugBank Target P23921 (Hs)
Ensembl Gene ENSG00000167325 (Hs), ENSMUSG00000030978 (Mm), ENSRNOG00000045752 (Rn)
Entrez Gene 6240 (Hs), 20133 (Mm), 685579 (Rn)
Human Protein Atlas ENSG00000167325 (Hs)
KEGG Enzyme 1.17.14.1
KEGG Gene hsa:6240 (Hs), mmu:20133 (Mm), rno:685579 (Rn)
OMIM 180410 (Hs)
Pharos P23921 (Hs)
RefSeq Nucleotide NM_001033 (Hs), NM_009103 (Mm), NM_001013236 (Rn)
RefSeq Protein NP_001024 (Hs), NP_033129 (Mm), NP_001013254 (Rn)
UniProtKB P23921 (Hs), P07742 (Mm)
Wikipedia RRM1 (Hs)
Enzyme Reaction Click here for help
EC Number: 1.17.14.1

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Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
TAS1553 Small molecule or natural product Hs Binding 7.5 pKd 7
⤷ pKd 7.5 (Kd 3.5x10-8 M) [7]
Description: Binding affinity for human R1 subunit determined by SPR
clofarabine Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 8.3 pIC50 3
⤷ pIC50 8.3 (IC50 5x10-9 M) [3]
Description: Inhibition of K562 cell growth
fludarabine Small molecule or natural product Approved drug Primary target of this compound Click here for species-specific activity table Hs Inhibition 6.0 pIC50 6
⤷ pIC50 6.0 (IC50 1x10-6 M) [6]
Description: Inhibition of ADP reduction by ribonucleotide reductase from HeLa cells
hydroxyurea Small molecule or natural product Approved drug Primary target of this compound Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 3.8 pIC50 5
⤷ pIC50 3.8 (IC50 1.48x10-4 M) [5]
Description: Dissolved in 1% DMSO, in vitro assay using reconstituted RRM1/RRM2 holoenzyme
gemcitabine Small molecule or natural product Approved drug Primary target of this compound Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition - - 2
⤷ [2]
Inhibitor Comments
The ribonucleoside-diphosphate reductase (RNR) protein complex catalyses de novo synthesis deoxyribonucleotides (dNTPs) and is therefore essential for cell survival/proliferation. In humans the complex exists as a heterodimeric tetramer of protein products from three genes: RRM1 (large subunit, RR1) and RRM2 and RRM2B (which form the small subunit, RR2). RR1 contains an iron binding site, rendering the enzyme iron dependent. Gallium is able to inhibit the enzyme by substituting for Fe3+ in the active site [1]. Full enzymatic activity depends on the interaction between RR1 and RR2 to bring together the constituents of the active site (dithiol groups from RR1 and the iron center and a tyrosyl radical from RR2).

Gemcitabine has been identified as an inhibitor of ribonucleoside-diphosphate reductase (RNR) by its ability to reduce enzymic activity (by in excess of 90%) in in situ and in vitro assays [2], although this article does not address subunit specificity of the inhibitory action.
Clofarabine has similar action to gemcitabine, blocking both ribonucleotide reduction and DNA polymerisation [3].
Fludarabine also competitively inhibits DNA polymerase α with a Ki of 1200nM [6] and the hypothesis is that by inhibiting the formation of dATP, the drug potentiates its inhibition of DNA synthesis. Whilst clofarabine, fludarabine and gemcitabine act as antimetabolites in their inhibition or RNR, hydroxyurea scavenges the tyrosyl free radicals essential for the reduction of NDPs in the synthesis of dNTPs [4]. Note that we map the inhibitor drugs to RRM1 as the primary drug target for data retrieval purposes ONLY. This in no way infers lack of activity at other targets, especially in this case where the drug binding site is poorly defined within the context of a complex protein structure.

References

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1. Bernstein LR. (1998) Mechanisms of therapeutic activity for gallium. Pharmacol Rev, 50 (4): 665-82. [PMID:9860806]

2. Heinemann V, Xu YZ, Chubb S, Sen A, Hertel LW, Grindey GB, Plunkett W. (1990) Inhibition of ribonucleotide reduction in CCRF-CEM cells by 2',2'-difluorodeoxycytidine. Mol Pharmacol, 38 (4): 567-72. [PMID:2233693]

3. Parker WB, Shaddix SC, Chang CH, White EL, Rose LM, Brockman RW, Shortnacy AT, Montgomery JA, Secrist 3rd JA, Bennett Jr LL. (1991) Effects of 2-chloro-9-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)adenine on K562 cellular metabolism and the inhibition of human ribonucleotide reductase and DNA polymerases by its 5'-triphosphate. Cancer Res, 51 (9): 2386-94. [PMID:1707752]

4. Platt OS. (2008) Hydroxyurea for the treatment of sickle cell anemia. N Engl J Med, 358 (13): 1362-9. [PMID:18367739]

5. Shao J, Zhou B, Zhu L, Bilio AJ, Su L, Yuan YC, Ren S, Lien EJ, Shih J, Yen Y. (2005) Determination of the potency and subunit-selectivity of ribonucleotide reductase inhibitors with a recombinant-holoenzyme-based in vitro assay. Biochem Pharmacol, 69 (4): 627-34. [PMID:15670581]

6. Tseng WC, Derse D, Cheng YC, Brockman RW, Bennett Jr LL. (1982) In vitro biological activity of 9-beta-D-arabinofuranosyl-2-fluoroadenine and the biochemical actions of its triphosphate on DNA polymerases and ribonucleotide reductase from HeLa cells. Mol Pharmacol, 21 (2): 474-7. [PMID:7048062]

7. Ueno H, Hoshino T, Yano W, Tsukioka S, Suzuki T, Hara S, Ogino Y, Chong KT, Suzuki T, Tsuji S et al.. (2022) TAS1553, a small molecule subunit interaction inhibitor of ribonucleotide reductase, exhibits antitumor activity by causing DNA replication stress. Commun Biol, 5 (1): 571. [PMID:35681099]

How to cite this page

1.17.4.1 Ribonucleoside-diphosphate reductases: ribonucleotide reductase catalytic subunit M1. Last modified on 08/08/2022. Accessed on 18/04/2024. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetomalariapharmacology.org/GRAC/ObjectDisplayForward?objectId=2630.