Ribonucleoside-diphosphate reductase large subunit
EC=1.17.4.1
Alternative name(s):
Ribonucleoside-diphosphate reductase subunit M1
Ribonucleotide reductase large subunit
- Function
- Provides the precursors necessary for DNA synthesis. Catalyzes the biosynthesis of deoxyribonucleotides from the corresponding ribonucleotides.
- Catalytic activity
- 2'-deoxyribonucleoside diphosphate + thioredoxin disulfide + H2O = ribonucleoside diphosphate + thioredoxin.
- Enzyme regulation
- Under complex allosteric control mediated by deoxynucleoside triphosphates and ATP binding to separate specificity and activation sites on the M1 subunit. The type of nucleotide bound at the specificity site determines substrate preference. It seems probable that ATP makes the enzyme reduce CDP and UDP, dGTP favors ADP reduction and dTTP favors GDP reduction. Stimulated by ATP and inhibited by dATP binding to the activity site. Ref.6 Ref.8
- Pathway
- Genetic information processing; DNA replication.
- Subunit structure
- Heterodimer of a large and a small subunit. Heterodimer with small subunit RRM2 or RRM2B. The heterodimer with RRM2 has higher catalytic activity than the heterodimer with RRM2B.
- Miscellaneous
- Two distinct regulatory sites have been defined: the specificity site, which controls substrate specificity, and the activity site which regulates overall catalytic activity. A substrate-binding catalytic site, located on M1, is formed only in the presence of the second subunit M2. The level of the enzyme activity is closely correlated with the growth rate of a cell and appears to vary with the cell cycle.
Ribonucleoside-diphosphate reductase subunit M2
EC=1.17.4.1
- Alternative name(s)
- Ribonucleotide reductase small chain / Ribonucleotide reductase small subunit
- Function
- Provides the precursors necessary for DNA synthesis. Catalyzes the biosynthesis of deoxyribonucleotides from the corresponding ribonucleotides. Inhibits Wnt signaling.
- Post-translational modification
- Phosphorylation on Ser-20 relieves the inhibitory effect on Wnt signaling.
- Miscellaneous
- Two distinct regulatory sites have been defined: the specificity site, which controls substrate specificity, and the activity site which regulates overall catalytic activity. A substrate-binding catalytic site, located on M1, is formed only in the presence of the second subunit M2.
Ribonucleoside-diphosphate reductase subunit M2 B
EC=1.17.4.1
- Alternative name(s)
- TP53-inducible ribonucleotide reductase M2 B / p53-inducible ribonucleotide reductase small subunit 2-like protein (Short name=p53R2)
- Function
- Plays a pivotal role in cell survival by repairing damaged DNA in a p53/TP53-dependent manner. Supplies deoxyribonucleotides for DNA repair in cells arrested at G1 or G2. Contains an iron-tyrosyl free radical center required for catalysis. Forms an active ribonucleotide reductase (RNR) complex with RRM1 which is expressed both in resting and proliferating cells in response to DNA damage.
- Catalytic activity
- 2'-deoxyribonucleoside diphosphate + thioredoxin disulfide + H2O = ribonucleoside diphosphate + thioredoxin. Ref.13
- Cofactor
- Binds 2 iron ions per subunit.
- Subunit structure
- Heterotetramer with large (RRM1) subunit. Interacts with p53/TP53. Interacts with RRM1 in response to DNA damage.
- Subcellular location
- Cytoplasm. Nucleus. Note: Translocates from cytoplasm to nucleus in response to DNA damage.
- Tissue specificity
- Widely expressed at a high level in skeletal muscle and at a weak level in thymus. Expressed in epithelial dysplasias and squamous cell carcinoma.
- Induction
- In response to DNA damage in a wild-type p53/TP53-dependent manner.
Involvement in disease
- Mitochondrial DNA depletion syndrome 8A (MTDPS8A) [MIM:612075]: A disorder due to mitochondrial dysfunction characterized by various combinations of neonatal hypotonia, neurological deterioration, respiratory distress, lactic acidosis, and renal tubulopathy.
- Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.18 Ref.19
- Mitochondrial DNA depletion syndrome 8B (MTDPS8B) [MIM:612075]: A disease due to mitochondrial dysfunction and characterized by ophthalmoplegia, ptosis, gastrointestinal dysmotility, cachexia, peripheral neuropathy.
- Note: The disease is caused by mutations affecting the gene represented in this entry.
- Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant, 5 (PEOA5) [MIM:613077]: A disorder characterized by progressive weakness of ocular muscles and levator muscle of the upper eyelid. In a minority of cases, it is associated with skeletal myopathy, which predominantly involves axial or proximal muscles and which causes abnormal fatigability and even permanent muscle weakness. Ragged-red fibers and atrophy are found on muscle biopsy. A large proportion of chronic ophthalmoplegias are associated with other symptoms, leading to a multisystemic pattern of this disease. Additional symptoms are variable, and may include cataracts, hearing loss, sensory axonal neuropathy, ataxia, depression, hypogonadism, and parkinsonism.
Note: The disease is caused by mutations affecting the gene represented in this entry.
