Ribonucleoside-diphosphate reductase subunit alpha (RNR1, RRM1 (in humans), α subunit)

The ribonucleoside-diphosphate reductase subunit alpha (RNR1 or RRM1) is the large catalytic subunit of class Ia ribonucleotide reductase, an essential enzyme responsible for converting ribonucleotides to deoxyribonucleotides, which are critical precursors for DNA synthesis and repair[1][2]. This enzyme is found in eukaryotes, including humans, as well as in certain bacteria and viruses[2]. The alpha subunit exists as a homodimer (α2) and contains the active site where nucleoside diphosphate (NDP) reduction occurs[1][2]. Each alpha monomer consists of three distinct structural domains: a helical N-terminal domain (approximately 220 residues), a large ten-stranded α/β barrel structure (approximately 480 residues) that houses the active site, and a smaller five-stranded α/β structure (approximately 70 residues)[2]. The active site features a 10-stranded β-barrel architecture with three essential cysteine residues that provide reducing equivalents for the reduction reaction[1]. The alpha subunit contains two types of allosteric regulatory sites that control enzyme function. The specificity sites regulate substrate preference, determining which of the four ribonucleotides will be reduced, while the activity sites control overall enzyme activity[5]. ATP binding to the activity site activates the enzyme, whereas dATP binding deactivates it, ensuring balanced production of all four deoxyribonucleotides needed for DNA synthesis[2]. For catalytic activity, the α2 homodimer must associate with the beta subunit homodimer (β2), which contains a stable tyrosyl radical and a diiron cofactor, to form an active α2β2 heterotetramer[1][5]. The enzyme operates through a remarkable mechanism involving long-range radical transfer over approximately 32-35 Ångströms from the tyrosyl radical (Y122) in the beta subunit to cysteine-439 in the alpha subunit active site[1][5]. This radical transfer occurs through a pathway of transient tyrosyl radicals including Y356 on the beta subunit and Y730 and Y731 on the alpha subunit, proceeding via proton-coupled electron transfer (PCET)[1][5]. In humans, the alpha subunit is encoded by the RRM1 gene[2]. Because ribonucleotide reductase is essential for DNA replication and cell proliferation, it represents an important therapeutic target for cancer treatment. Several FDA-approved anticancer drugs, including nucleoside analogs such as clofarabine, cladribine, and fludarabine, target this enzyme[1][5]. These inhibitors work by various mechanisms, including formation of inactive oligomeric states (such as α6 hexamers in human cells or α4β4 rings in E. coli) that prevent the formation of active α2β2 complexes and shut down radical transfer[1][5]. The enzyme's dependence on radical transfer represents both a remarkable catalytic feature and a therapeutic vulnerability, as inhibitors can intercept radical species during the transfer process[5].

Other names

RNR alpha subunitRNR1RRM1 (human gene)Ribonucleotide reductase large subunitRibonucleotide reductase α2Class Ia RNR alpha subunitR1 subunit

Mechanism-based inhibition (intercepts radical transfer pathway); Allosteric inhibition (dATP binding to activity site); Formation of inactive oligomeric states (α6 or α4β4 complexes); Disruption of α2β2 active complex formation; Inhibition of radical transfer between subunits