RNR (M1M2B) reduces nucleotide diphosphates to deoxynucleotide diphosphates (thioredoxin)

Stable Identifier
Reaction [transition]
Homo sapiens
NDP + reduced thioredoxin => dNDP + oxidized thioredoxin + H2O
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Ribonucleotide reductase (RNR (M1M2B)) catalyzes the reduction of adenine, guanine, cytidine, and uridine ribonucleoside 5'-diphosphates (NDPs) to form the corresponding deoxyribonucleoside 5'-diphosphates, coupled to the oxidation of thioredoxin (Eklund et al. 2001). The enzyme complex is cytosolic (Pontarin et al. 2008). The form of ribonucleotide reductase annotated here is a tetramer of two large (M1) and two small (M2B) subunits (Shao et al. 2004; Zhou et al. 2005). M2B protein is stable throughout the cell cycle, unlike M2, and is induced by TP53 (Guittet et al. 2001; Tanaka et al. 2000). The RNR (M1M2B) complex can thus provide dNDPs for DNA repair in interphase and quiescent cells. Studies of mitochondrial instability in cells from patients deficient in M2 protein indicate that RNR (M1M2B) likewise provides dNDPs for mitochondrial DNA replication (Pontarin et al. 2012). The overall activity of the enzyme is regulated allosterically: ATP binding is stimulatory while dATP binding is inhibitory (Reichard et al. 2000).

The reducing equivalents needed for ribonucleotide reductase activity can be provided by either of two small proteins, glutaredoxin or thioredoxin (Holmgren 1989; Sun et al. 1998; Zahedi Avval & Holmgren 2009). Both are re-reduced with NADPH as the donor of reducing equivalents. The relative contributions of glutaredoxin and thioredoxin in vivo are unknown.

Literature References
PubMed ID Title Journal Year
10716435 A ribonucleotide reductase gene involved in a p53-dependent cell-cycle checkpoint for DNA damage

Arakawa, H, Nakamura, Y, Matsui, K, Takei, Y, Shiraishi, K, Fukuda, S, Tanaka, H, Yamaguchi, T

Nature 2000
9677297 The NMR solution structure of human glutaredoxin in the fully reduced form

Sun, C, Berardi, MJ, Bushweller, JH

J Mol Biol 1998
18997010 Ribonucleotide reduction is a cytosolic process in mammalian cells independently of DNA damage

Ferraro, P, Fijolek, A, Pontarin, G, Pizzo, P, Bianchi, V, Thelander, L, Reichard, PA, Rampazzo, C, Pozzan, T

Proc. Natl. Acad. Sci. U.S.A. 2008
19176520 Molecular mechanisms of thioredoxin and glutaredoxin as hydrogen donors for Mammalian s phase ribonucleotide reductase

Zahedi Avval, F, Holmgren, A

J. Biol. Chem. 2009
2668278 Thioredoxin and glutaredoxin systems

Holmgren, A

J Biol Chem 1989
22847445 Mammalian ribonucleotide reductase subunit p53R2 is required for mitochondrial DNA replication and DNA repair in quiescent cells

Ferraro, P, Pontarin, G, Bianchi, V, Bee, L, Reichard, PA

Proc. Natl. Acad. Sci. U.S.A. 2012
10884394 Cross-talk between the allosteric effector-binding sites in mouse ribonucleotide reductase

Thelander, L, Reichard, PA, Eliasson, R, Ingemarson, R

J Biol Chem 2000
14729598 In vitro characterization of enzymatic properties and inhibition of the p53R2 subunit of human ribonucleotide reductase

Yen, Y, Yuan, YC, Xi, B, Qiu, W, Zhu, L, Shao, J, Zhou, B

Cancer Res 2004
11517226 Mammalian p53R2 protein forms an active ribonucleotide reductase in vitro with the R1 protein, which is expressed both in resting cells in response to DNA damage and in proliferating cells

Arakawa, H, Guittet, O, Hakansson, P, Nakamura, Y, Thelander, L, Graslund, A, Voevodskaya, N, Fridd, S

J Biol Chem 2001
11796141 Structure and function of the radical enzyme ribonucleotide reductase

Farnegardh, M, Eklund, H, Nordlund, P, Logan, DT, Uhlin, U

Prog Biophys Mol Biol 2001
16373698 A dityrosyl-diiron radical cofactor center is essential for human ribonucleotide reductases

Yen, Y, Qi, C, Yuan, YC, Su, L, Chu, B, Xi, B, Shao, J, Zhou, B, Shih, J

Mol Cancer Ther 2005
Catalyst Activity

ribonucleoside-diphosphate reductase activity, thioredoxin disulfide as acceptor of RNR (M1M2B) [cytosol]

This event is regulated
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