Metal-free class Ie ribonucleotide reductase from pathogens initiates catalysis with a tyrosine-derived dihydroxyphenylalanine radical
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10022.full.pdf
Description
Published version
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1.3 MB
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Author(s)
Blaesi, Elizabeth J.
Palowitch, Gavin M.
Hu, Kai
Kim, Amelia J.
Rose, Hannah R.
Alapati, Rahul
Lougee, Marshall G.
Kim, Hee Jong
Taguchi, Alexander T
Tan, Kong Ooi
Date Issued
September 2018
Journal
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Citation
Blaesi, Elizabeth J. et al. "Metal-free class Ie ribonucleotide reductase from pathogens initiates catalysis with a tyrosine-derived dihydroxyphenylalanine radical." Proceedings of the National Academy of Sciences 115, 40 (September 2018): 10022-10027 © 2018 National Academy of Sciences
Version
Final published version
Abstract
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, β; (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 α 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 α subunit is generated by a stable, tyrosine-derived dihydroxyphenylalanine radical (DOPA•) in β. The three-electron oxidation producing DOPA• occurs in Escherichia coli only if the β 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.
MIT Department
Massachusetts Institute of Technology. Department of Chemistry
Francis Bitter Magnet Laboratory (Massachusetts Institute of Technology)
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DOI of Published Version
https://doi.org/10.1073/pnas.1811993115
