The β2 subunit of a class Ia or Ib ribonucleotide reductase (RNR) is activated when its carboxylate-bridged Fe2II/II cluster reacts with O2 to oxidize a nearby tyrosine (Y) residue to a stable radical (Y). During turnover, the Y in β2 is thought to reversibly oxidize a cysteine (C) in the α2 subunit to a thiyl radical (C) by a long-distance (∼35 Å) proton-coupled electron-transfer (PCET) step. The C in α2 then initiates reduction of the 2′ position of the ribonucleoside 5′-diphosphate substrate by abstracting the hydrogen atom from C3′. The class I RNR from Chlamydia trachomatis (Ct) is the prototype of a newly recognized subclass (Ic), which is characterized by the presence of a phenylalanine (F) residue at the site of β2 where the essential radical-harboring Y is normally found. We recently demonstrated that Ct RNR employs a heterobinuclear Mn IV/FeIII cluster for radical initiation. In essence, the MnIV ion of the cluster functionally replaces the Y of the conventional class I RNR. The Ct β2 protein also autoactivates by reaction of its reduced (MnII/FeII) metal cluster with O2. In this reaction, an unprecedented MnIV/Fe IV intermediate accumulates almost stoichiometrically and decays by one-electron reduction of the FeIV site. This reduction is mediated by the near-surface residue, Y222, a residue with no functional counterpart in the well-studied conventional class I RNRs. In this review, we recount the discovery of the novel Mn/Fe redox cofactor in Ct RNR and summarize our current understanding of how it assembles and initiates nucleotide reduction.
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