Reactome | RNR (M1M2B) reduces nucleotide diphosphates to deoxynucleotide diphosphates (glutaredoxin)

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

Stable Identifier

R-HSA-8866405

Type

Reaction

Species

Homo sapiens

Compartment

cytosol

Synonyms

NDP + reduced glutaredoxin => dNDP + oxidized glutaredoxin + H2O

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

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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 glutaredoxin (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