The catalytic mechanism of a class I ribonucleotide reductase (RNR) is initiated by the generation of a hydrogen-abstracting thiyl radical via a conformationally gated, proton-coupled electron-transfer (PCET) from a cysteine residue in the α2 subunit over ∼35 Å to the cofactor in the β2 subunit. A chain of aromatic amino acids that spans the two subunits mediates this long-distance PCET by the formation of transient side-chain radicals. Details of the conformational gating, proton coupling, and 'radical-hopping' have, until very recently, been largely obscured by the failure of intermediate states to accumulate to high levels and the absence of sufficiently sensitive spectroscopic handles for intermediates that may accumulate to trace levels. In the most recently recognized subclass (c) of class I, founded by the enzyme from Chlamydia trachomatis (Ct), the stable tyrosyl radical that serves as the PCET acceptor in the conventional (subclass a or b) class I RNRs is functionally replaced by the MnIV ion of a MnIV/FeIII cofactor, which assembles in Ct β2 in place of the Fe2III/III cluster of the conventional β2s. The discovery of this novel radical-initiation cofactor and mechanism has raised intriguing questions concerning the evolution of class I RNRs and affords new opportunities for understanding the gated PCET step that initiates their catalytic mechanism.
All Science Journal Classification (ASJC) codes
- Structural Biology
- Molecular Biology