Ribonucleotide reductase metallocofactor: assembly, maintenance and inhibition

Abstract

Ribonucleotide reductase (RNR) supplies cellular deoxyribonucleotide triphosphates (dNTP) pools by converting ribonucleotides to the corresponding deoxy forms using radical-based chemistry. Eukaryotic RNR comprises α and β subunits: α contains the catalytic and allosteric sites; β houses a diferric-tyrosyl radical cofactor (Fe^III₂-Y•) that is required to initiates nucleotide reduction in α. Cells have evolved multi-layered mechanisms to regulate RNR level and activity in order to maintain the adequate sizes and ratios of their dNTP pools to ensure high-fidelity DNA replication and repair. The central role of RNR in nucleotide metabolism also makes it a proven target of chemotherapeutics. In this review, we discuss recent progress in understanding the function and regulation of eukaryotic RNRs, with a focus on studies revealing the cellular machineries involved in RNR metallocofactor biosynthesis and its implication in RNR-targeting therapeutics.

Key words： ribonucleotide reductase (RNR); diferric-tyrosyl radical (Fe^III₂-Y•); iron homeostasis

Acknowledgements

This work was supported by National Institutes of Health (CA125574 and GM81393).

Compliance with ethics guidelines

The authors declare no conflict of interest.

This article does not contain any studies with human or animal as subjects performed by any of the authors.

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