SifR is an Rrf2-family quinone sensor associated with catechol iron uptake in Streptococcus pneumoniae D39

Yifan Zhang; Julia E Martin; Katherine A Edmonds; Malcolm E Winkler; David P Giedroc

doi:10.1016/j.jbc.2022.102046

SifR is an Rrf2-family quinone sensor associated with catechol iron uptake in Streptococcus pneumoniae D39

J Biol Chem. 2022 Jul;298(7):102046. doi: 10.1016/j.jbc.2022.102046. Epub 2022 May 18.

Authors

Yifan Zhang¹, Julia E Martin², Katherine A Edmonds³, Malcolm E Winkler⁴, David P Giedroc⁵

Affiliations

¹ Department of Chemistry, Indiana University, Bloomington, Indiana, USA; Department of Molecular and Cellular Biochemistry, Indiana University, Bloomington, Indiana, USA.
² Department of Chemistry, Indiana University, Bloomington, Indiana, USA; Department of Biological Sciences, Idaho State University, Pocatello, Idaho, USA.
³ Department of Chemistry, Indiana University, Bloomington, Indiana, USA.
⁴ Department of Molecular and Cellular Biochemistry, Indiana University, Bloomington, Indiana, USA; Department of Biology, Indiana University, Bloomington, Indiana, USA.
⁵ Department of Chemistry, Indiana University, Bloomington, Indiana, USA; Department of Molecular and Cellular Biochemistry, Indiana University, Bloomington, Indiana, USA. Electronic address: giedroc@indiana.edu.

Abstract

Streptococcus pneumoniae (pneumococcus) is a Gram-positive commensal and human respiratory pathogen. How this bacterium satisfies its nutritional iron (Fe) requirement in the context of endogenously produced hydrogen peroxide is not well understood. Here, we characterize a novel virulence-associated Rrf2-family transcriptional repressor that we term SifR (streptococcal IscR-like family transcriptional repressor) encoded by spd_1448 and conserved in Streptococci. Global transcriptomic analysis of a ΔsifR strain defines the SifR regulon as genes encoding a candidate catechol dioxygenase CatE, an uncharacterized oxidoreductase YwnB, a candidate flavin-dependent ferric reductase YhdA, a candidate heme-based ferric reductase domain-containing protein and the Piu (pneumococcus iron uptake) Fe transporter (piuBCDA). Previous work established that membrane-anchored PiuA binds Fe^III-bis-catechol or monocatechol complexes with high affinity, including the human catecholamine stress hormone, norepinephrine. We demonstrate that SifR senses quinone via a single conserved cysteine that represses its regulon when in the reduced form. Upon reaction with catechol-derived quinones, we show that SifR dissociates from the DNA leading to regulon derepression, allowing the pneumococcus to access a catechol-derived source of Fe while minimizing reactive electrophile stress induced by quinones. Consistent with this model, we show that CatE is an Fe^II-dependent 2,3-catechol dioxygenase with broad substrate specificity, YwnB is an NAD(P)H-dependent quinone reductase capable of reducing the oxidized and cyclized norepinephrine, adrenochrome, and YhdA is capable of reducing a number of Fe^III complexes, including PiuA-binding transport substrates. These findings are consistent with a model where Fe^III-catechol complexes serve as significant nutritional Fe sources in the host.

Keywords: bacterial iron metabolism; catechol; catecholamine; iron homeostasis; quinone sensor; transcriptional repressor.

MeSH terms

Bacterial Proteins* / genetics
Bacterial Proteins* / metabolism
Catechols* / chemistry
Catechols* / metabolism
Dioxygenases / metabolism
Iron* / metabolism
Norepinephrine / metabolism
Quinones* / metabolism
Regulon
Streptococcus pneumoniae* / genetics
Streptococcus pneumoniae* / metabolism

Substances

Bacterial Proteins
Catechols
Quinones
Iron
Dioxygenases
Norepinephrine

Abstract

MeSH terms

Substances

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