Ribonucleotide reductase (RNR), also known as ribonucleoside diphosphate reductase (rNDP), 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 (deoxythymidine diphosphate) is synthesized by another enzyme (thymidylate kinase) from dTMP (deoxythymidine monophosphate). Structure Ribonucleotide reductases are divided into three classes. Class I RNR enzymes are constructed from large alpha subunit and small beta subunits which associate to form an active heterodimeric tetramer. By reducing NDPs to 2'-dNDPs, the enzyme catalyses the de novo synthesis of deoxyribonucleotides (dNTPs), which are precursors to DNA synthesis and essential for cell proliferation. Class II RNRs produce a 5'-deoxyadenosyl radical by homolytic cleavage of the C-Co bond in adenosylcobalamin. In addition, Class III RNRs contain a stable glycyl radical. Humans carry Class I RNRs. The alpha subunit is encoded by the RRM1 gene while there are two isoforms of the beta subunit, encoded by the RRM2 and RRM2B genes: Each Class I alpha monomer consists of three domains: one mainly helical domain comprising the 220 N-terminal residues, a second large ten-stranded α/β structure comprising 480 residues, and a third small five-stranded α/β structure comprising 70 residues. In Pfam, the second domain has been interpreted as two separate domains: a shorter all-alpha N-terminal domain, and a longer barrel C-terminal domain. The Class I beta subunit usually contains a di-metal center and a stable tyrosyl radical. In humans, the beta subunit relies on a di-iron cofactor. In E. coli, the tyrosyl radical is located at position 122 (Y122) providing the stable radical for the Class I RNR2 subunits. In A. aegypti, this tyrosyl radical is located at position 184 (Y184). The tyrosyl radical is deeply buried inside the protein in a hydrophobic environment, located close to the iron center that is used in the stabilization of a