6ebp

Publication Abstract from PubMed

All cells obtain 2'-deoxyribonucleotides for DNA synthesis through the activity of a ribonucleotide reductase (RNR). The class I RNRs found in humans and pathogenic bacteria differ in (i) use of Fe(II), Mn(II), or both for activation of the dinuclear-metallocofactor subunit, beta; (ii) reaction of the reduced dimetal center with dioxygen or superoxide for this activation; (iii) requirement (or lack thereof) for a flavoprotein activase, NrdI, to provide the superoxide from O2; and (iv) use of either a stable tyrosyl radical or a high-valent dimetal cluster to initiate each turnover by oxidizing a cysteine residue in the alpha subunit to a radical (Cys*). The use of manganese by bacterial class I, subclass b-d RNRs, which contrasts with the exclusive use of iron by the eukaryotic Ia enzymes, appears to be a countermeasure of certain pathogens against iron deprivation imposed by their hosts. Here, we report a metal-free type of class I RNR (subclass e) from two human pathogens. The Cys* in its alpha subunit is generated by a stable, tyrosine-derived dihydroxyphenylalanine radical (DOPA*) in beta. The three-electron oxidation producing DOPA* occurs in Escherichia coli only if the beta is coexpressed with the NrdI activase encoded adjacently in the pathogen genome. The independence of this new RNR from transition metals, or the requirement for a single metal ion only transiently for activation, may afford the pathogens an even more potent countermeasure against transition metal-directed innate immunity.

Metal-free class Ie ribonucleotide reductase from pathogens initiates catalysis with a tyrosine-derived dihydroxyphenylalanine radical.,Blaesi EJ, Palowitch GM, Hu K, Kim AJ, Rose HR, Alapati R, Lougee MG, Kim HJ, Taguchi AT, Tan KO, Laremore TN, Griffin RG, Krebs C, Matthews ML, Silakov A, Bollinger JM Jr, Allen BD, Boal AK Proc Natl Acad Sci U S A. 2018 Sep 17. pii: 1811993115. doi:, 10.1073/pnas.1811993115. PMID:30224458^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.