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Ribonucleotide reductase (RNR) is an enzyme for the de novo conversion of ribonucleotides to deoxyribonucleotides. The two human RNR small subunits hRRM2 and hp53R2 share 83% sequence homology but show distinct expression patterns and function. Structural analyses of the oxidized form of hRRM2 and hp53R2 indicate that both proteins contain a conserved Gln127-hp53R2/Gln165-hRRM2 close to the dinuclear iron center and the essential tyrosine residue Tyr124-hp53R2/Tyr162-hRRM2 forms hydrogen bonds with the tyrosine and iron ligands, implying a critical role for the glutamine residue in assembling the dityrosyl-diiron radical cofactor. The present work also showed that Tyr221 in hRRM2, which is replaced by Phe183 in hp53R2, forms a hydrogen bond with Tyr162 to extend the hydrogen bond network from Gln165-hRRM2. Mutagenesis and spectroscopic experiments suggested that the tyrosine-to-phenylalanine switch at Phe183-hp53R2/Tyr221-hRRM2 could lead to differences in radical generation or enzymatic activity for hp53R2 and hRRM2. This study correlates the distinct catalytic mechanisms of the small subunits hp53R2 and hRRM2 with a hydrogen-bonding network and provides novel directions for designing and developing subunit-specific therapeutic agents for human RNR enzymes.

molecular cancer therapeutics

Structural Basis on the Dityrosyl-Diiron Radical Cluster and the Functional Differences of Human Ribonucleotide Reductase Small Subunits hp53R2 and hRRM2