Radical Chemistry in Ribonucleotide Reduction

Ribonucleotide reductases (RNRs) catalyse the conversion of ribonucleotides into deoxyribonucleotides, a reaction essential for DNA synthesis and repair across all domains of life. This chemically demanding transformation is initiated by a carbon-centred free radical, generated and channelled through a finely tuned network of amino acid side chains or cofactors. In class I RNRs, a metal cofactor in the β subunit generates a tyrosyl radical that transfers over 30–35 Å via a series of proton-coupled electron transfer (PCET) steps to a cysteine residue in the α subunit, creating a thiyl radical that abstracts a hydrogen from the ribose sugar. Class II RNRs employ a vitamin B12-derived radical, while class III enzymes use a glycyl radical in an oxygen-sensitive mechanism. Activity and substrate specificity are tightly regulated by allosteric sites, notably the ATP-cone, which binds nucleotide effectors to modulate quaternary structure and radical access. Advances in structural biology and spectroscopy have begun to reveal how water molecules, protein dynamics and long-range electron-proton transfers are orchestrated to ensure fidelity and control in radical initiation, with implications for antibiotic and anticancer drug discovery.

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Technical terms

Ribonucleotide reductase (RNR): An enzyme family that converts ribonucleotides to deoxyribonucleotides via radical chemistry, essential for DNA synthesis.

Thiyl radical: A sulphur-centred radical on a cysteine residue that initiates ribose reduction by hydrogen abstraction.

Proton-coupled electron transfer (PCET): A mechanism in which electron transfer is directly linked to proton movement, enabling long-range radical propagation.

ATP-cone: A small, N-terminal domain found in many RNR catalytic subunits that binds ATP or dATP to regulate enzyme quaternary structure and activity.

Glycyl radical: A stable radical centred on a glycine residue used by class III RNRs under anaerobic conditions to initiate ribonucleotide reduction.

References

1. 2.6-Å resolution cryo-EM structure of a class Ia ribonucleotide reductase trapped with mechanism-based inhibitor N3CDP. Proceedings of the National Academy of Sciences of the United States of America (2024).
2. Nucleotide binding to the ATP-cone in anaerobic ribonucleotide reductases allosterically regulates activity by modulating substrate binding. eLife (2024).
3. The periodic table of ribonucleotide reductases. Journal of Biological Chemistry (2021).