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

Proceedings of the National Academy of Sciences of the United States of America
Elizabeth J BlaesiAmie K Boal

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 ...Continue Reading

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Citations

Oct 9, 2019·The Journal of Biological Chemistry·Yury KutinJulia J Griese
Jun 23, 2020·Annual Review of Biochemistry·Brandon L GreeneJoAnne Stubbe
Aug 16, 2019·Journal of Biological Inorganic Chemistry : JBIC : a Publication of the Society of Biological Inorganic Chemistry·Inna Rozman GrinbergGustav Berggren
May 10, 2020·Nature Communications·Christopher ZappFrauke Gräter
Aug 15, 2019·Journal of Biological Inorganic Chemistry : JBIC : a Publication of the Society of Biological Inorganic Chemistry·Kristīne GrāveMartin Högbom
Jan 29, 2019·Journal of Biological Inorganic Chemistry : JBIC : a Publication of the Society of Biological Inorganic Chemistry·Julia J GrieseMartin Högbom
Apr 17, 2020·Journal of Biological Inorganic Chemistry : JBIC : a Publication of the Society of Biological Inorganic Chemistry·Kristīne GrāveMartin Högbom
Nov 17, 2020·Current Protocols in Chemical Biology·Suzanne E DettlingMegan L Matthews
Mar 19, 2020·Biochemistry·Kanchana R RavichandranJoAnne Stubbe
Aug 24, 2021·Journal of the American Chemical Society·JoAnne Stubbe, Daniel G Nocera
Aug 31, 2021·The Journal of Biological Chemistry·Terry B Ruskoski, Amie K Boal
Nov 1, 2021·Metallomics : Integrated Biometal Science·Megha JayachandranOlga Makhlynets

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Methods Mentioned

BETA
X-ray
ENDOR

Software Mentioned

DOPA

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