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Title: Metal-free class Ie ribonucleotide reductase from pathogens initiates catalysis with a tyrosine-derived dihydroxyphenylalanine radical

Journal Article · · Proceedings of the National Academy of Sciences of the United States of America
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  1. Pennsylvania State Univ., University Park, PA (United States)
  2. Univ. of Pennsylvania, Philadelphia, PA (United States)
  3. Massachusetts Inst. of Technology (MIT), Cambridge, MA (United States)
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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. We conclude 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.

Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Organization:
Searle Scholars Program; National Institutes of Health (NIH); USDOE Office of Science (SC); National Cancer Institute (NCI); National Institute of General Medical Sciences (NIGMS); Michigan Economic Development Corporation and Michigan Technology Tri-Corridor
Grant/Contract Number:
GM119707; GM116353; AC02-06CH11357; ACB-12002; AGM-12006; 1S10OD012289-01A1; 085P1000817
OSTI ID:
1499708
Journal Information:
Proceedings of the National Academy of Sciences of the United States of America, Vol. 115, Issue 40; ISSN 0027-8424
Publisher:
National Academy of SciencesCopyright Statement
Country of Publication:
United States
Language:
ENGLISH
Citation Metrics:
Cited by: 28 works
Citation information provided by
Web of Science

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Cited By (10)

MaveDB: an open-source platform to distribute and interpret data from multiplexed assays of variant effect journal November 2019
Assembly of a heterodinuclear Mn/Fe cofactor is coupled to tyrosine–valine ether cross-link formation in the R2-like ligand-binding oxidase journal January 2019
Reannotation of the Ribonucleotide Reductase in a Cyanophage Reveals Life History Strategies Within the Virioplankton journal February 2019
Assembly of a heterodinuclear Mn/Fe cofactor is coupled to tyrosine–valine ether cross-link formation in the R2-like ligand-binding oxidase text January 2019
Redox-induced structural changes in the di-iron and di-manganese forms of Bacillus anthracis ribonucleotide reductase subunit NrdF suggest a mechanism for gating of radical access journal August 2019
Class Id ribonucleotide reductase utilizes a Mn2(IV,III) cofactor and undergoes large conformational changes on metal loading text January 2019
Chemical flexibility of heterobimetallic Mn/Fe cofactors: R2lox and R2c proteins journal October 2019
Metal sensing and regulation of adaptive responses to manganese limitation by MtsR is critical for group A streptococcus virulence journal June 2019
Metal sensing and regulation of adaptive responses to manganese limitation by MtsR is critical for group A streptococcus virulence journal July 2019
Class Id ribonucleotide reductase utilizes a Mn2(IV,III) cofactor and undergoes large conformational changes on metal loading journal August 2019

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Related Subjects

59 BASIC BIOLOGICAL SCIENCES
DNA biosynthesis
semiquinone
DOPA