Ribonucleotide reductase small subunit (RRM2) (RRM2)

Ribonucleotide reductase (RNR) is the rate-limiting enzyme responsible for the de novo conversion of ribonucleoside diphosphates into deoxyribonucleoside diphosphates, which are the essential building blocks for DNA synthesis and repair [UniProt, PMID: 21572534]. The enzyme's catalytic activity is dependent on a stable tyrosyl radical located within the M2 subunit (RRM2), which is generated and stabilized by a non-heme binuclear iron center [PMID: 15153612]. This tyrosyl radical site is a critical therapeutic target; drugs like hydroxyurea act by quenching the radical, thereby inactivating the enzyme and depleting the cellular dNTP pools necessary for replication [DrugBank]. RRM2 expression is tightly regulated and typically peaks during the S-phase of the cell cycle, but it is frequently upregulated in various cancers to support rapid proliferation [PMID: 21572534]. High levels of RRM2 are often associated with poor prognosis and resistance to other chemotherapeutic agents like gemcitabine [PMID: 15153612]. Beyond oncology, the unique chemistry of the tyrosyl radical site makes it a target for developing specific antiviral and antimicrobial agents. Clinical use of RRM2 inhibitors is often limited by side effects such as myelosuppression, as the enzyme is also required for normal hematopoiesis [DrugBank].

Other names

Ribonucleoside-diphosphate reductase subunit M2Ribonucleotide reductase M2 subunitR2 subunitRNR2Ribonucleotide reductase M2 subunit tyrosyl radical site

Quenching of the essential tyrosyl radical and/or chelation of the binuclear iron cofactor required for radical stability, leading to the inhibition of dNTP production and subsequent arrest of DNA synthesis.