IntEnz

EC 1.17.4.1 - Ribonucleoside-diphosphate reductase

IntEnz Enzyme Nomenclature
EC 1.17.4.1

Names

Reaction

• 2'-deoxyribonucleoside diphosphate + thioredoxin disulfide + H2O = ribonucleoside diphosphate + thioredoxin

Cofactor

• Fe³⁺ adenosylcob(III)alamin Mn²⁺

Comments:

This enzyme is responsible for the de novo conversion of ribonucleoside diphosphates into deoxyribonucleoside diphosphates, which are essential for DNA synthesis and repair. There are three types of this enzyme differing in their cofactors. Class Ia enzymes contain a diiron(III)-tyrosyl radical, class Ib enzymes contain a dimanganese-tyrosyl radical, and class II enzymes contain adenosylcobalamin. In all cases the cofactors are involved in generation of a transient thiyl (sulfanyl) radical on a cysteine residue, which attacks the substrate, forming a ribonucleotide 3'-radical, followed by water loss to form a ketyl (α-oxoalkyl) radical. The ketyl radical is reduced to 3'-keto-deoxynucleotide concomitant with formation of a disulfide anion radical between two cysteine residues. A proton-coupled electron-transfer from the disulfide radical to the substrate generates a 3'-deoxynucleotide radical, and the the final product is formed when the hydrogen atom that was initially removed from the 3'-position of the nucleotide by the thiyl radical is returned to the same position. The disulfide bridge is reduced by the action of thioredoxin. cf. EC 1.1.98.6, ribonucleoside-triphosphate reductase (formate) and EC 1.17.4.2, ribonucleoside-triphosphate reductase (thioredoxin).

Links to other databases

References

1. Larsson, A. and Reichard, P.
   Enzymatic synthesis of deoxyribonucleotides. IX. Allosteric effects in the reduction of pyrimidine ribonucleotides by the ribonucleoside diphosphate reductase system of Escherichia coli.
   J. Biol. Chem. 241 : 2533-2539 (1966). [PMID: 5330119]
2. Larsson, A. and Reichard, P.
   Enzymatic synthesis of deoxyribonucleotides. X. Reduction of purine ribonucleotides; allosteric behavior and substrate specificity of the enzyme system from Escherichia coli B.
   J. Biol. Chem. 241 : 2540-2549 (1966). [PMID: 5330120]
3. Moore, E.C. and Hurlbert, R.B.
   Regulation of mammalian deoxyribonucleotide biosynthesis by nucleotides as activators and inhibitors.
   J. Biol. Chem. 241 : 4802-4809 (1966). [PMID: 5926184]
4. Larsson, A.
   Ribonucleotide reductase from regenerating rat liver. II. Substrate phosphorylation level and effect of deoxyadenosine triphosphate.
   Biochim. Biophys. Acta 324 : 447-451 (1973). [PMID: 4543472]
5. Lammers, M. and Follmann, H.
   The ribonucleotide reductases - a unique group of metalloenzymes essential for cell-proliferation.
   Struct. Bonding 54 : 27-91 (1983).
6. Lawrence, C. C., Bennati, M., Obias, H. V., Bar, G., Griffin, R. G., Stubbe, J.
   High-field EPR detection of a disulfide radical anion in the reduction of cytidine 5'-diphosphate by the E441Q R1 mutant of Escherichia coli ribonucleotide reductase.
   Proc. Natl. Acad. Sci. U.S.A. 96 : 8979-8984 (1999). [PMID: 10430881]
7. Qiu, W., Zhou, B., Darwish, D., Shao, J., Yen, Y.
   Characterization of enzymatic properties of human ribonucleotide reductase holoenzyme reconstituted in vitro from hRRM1, hRRM2, and p53R2 subunits.
   Biochem. Biophys. Res. Commun. 340 : 428-434 (2006). [PMID: 16376858]

[EC 1.17.4.1 created 1972, modified 2017]