page_title: Ribonucleotide reductase
section_title: Function
hierarchical_section_title: Ribonucleotide reductase / Function
caption_attribution_description: English: Mechanism to catalyze the conversion of ribonucleotides to deoxyribonucleotides (adapted from Nelson &amp; Cox, 2000).
context_page_description: Ribonucleotide reductase, also known as ribonucleotide diphosphate reductase, is an enzyme that catalyzes the formation of deoxyribonucleotides from ribonucleotides. It catalyzes this formation by removing the 2'-hydroxyl group of the ribose ring of nucleoside diphosphates. This reduction produces deoxyribonucleotides. Deoxyribonucleotides in turn are used in the synthesis of DNA. The reaction catalyzed by RNR is strictly conserved in all living organisms. Furthermore, RNR plays a critical role in regulating the total rate of DNA synthesis so that DNA to cell mass is maintained at a constant ratio during cell division and DNA repair. A somewhat unusual feature of the RNR enzyme is that it catalyzes a reaction that proceeds via a free radical mechanism of action. The substrates for RNR are ADP, GDP, CDP and UDP. dTDP is synthesized by another enzyme from dTMP.
context_section_description: The enzyme ribonucleotide reductase (RNR) catalyzes the de novo synthesis of dNDPs. Catalysis of ribonucleoside 5’-diphosphates (NDPs) involves a reduction at the 2’-carbon of ribose 5-phosphate to form the 2’-deoxy derivative-reduced 2’-deoxyribonucleoside 5’-diphosphates (dNDPs). This reduction is initiated with the generation of a free radical. Following a single reduction, RNR requires electrons donated from the dithiol groups of the protein thioredoxin. Regeneration of thioredoxin occurs when nicotinamide adenine dinucleotide phosphate (NADPH) provides two hydrogen atoms that are used to reduce the disulfide groups of thioredoxin.
  Three classes of RNR have similar mechanisms for the reduction of NDPs, but differ in the domain that generates the free radical, the specific metal in the metalloprotein structure, and the electron donors. All classes use free-radical chemistry. Class I reductases use an iron center with ferrous to ferric conversion to generate a tyrosyl free radical. Reduction of NDP substrates occurs under aerobic conditions. Class I reductases are divided into IA and IB due to differences in regulation. Class IA reductases are distributed in eukaryotes, eubacteria, bacteriophages, and viruses. Class IB reductases are found in eubacteria. Class IB reductases can also use a radical generated with the stabilization of a binuclear manganese center. Class II reductases generate the free radical 5’-deoxyadenosyl radical from cobalamin (coenzyme B12) and have a simpler structure than class I and class III reductases. Reduction of NDPs or ribonucleotide 5’-triphosphates (NTPs) occurs under either aerobic or anaerobic conditions. Class II reductases are distributed in archaebacteria, eubacteria, and bacteriophages. Class III reductases use a glycine radical generated with the help of an S-adenosyl methionine and an iron sulphur center. Reduction of NTPs is limited to anaerobic conditions. Class III reductases are distributed in archaebacteria, eubacteria, and bacteriophages. Organisms are not limited to having one class of enzymes. For example, E. coli have both class I and class III RNR.
caption: Mechanism to catalyze the conversion of ribonucleotides to deoxyribonucleotides. (adapted from Nelson & Cox, 2000). (1) an electron transfer on the RNR2 subunit activates a RNR1 cysteine residue in the active site with a free radical; (2) the free radical forms a stable radical on C-3, and cysteine radical removes a hydrogen atom; (3) cation is formed on C-2 by transferring a hydrogen from a dithiol group and is stabilized by the radical, resulting in the loss of H2O from C-2; (4) a hydrogen is transferred from the dithiol group to reduce the cation C-2; (5) the C-3 radical is reduced by the hydrogen removed in step 2, and the tyrosyl radical is generated; (6) redoxins transfer two hydrogen to the disulfide group that restores the original configuration.
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