A newly identified flavoprotein disulfide reductase Har protects Streptococcus pneumoniae against hypothiocyanous acid.

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dc.contributor.authorShearer, H.L.
dc.contributor.authorPace, P.E.
dc.contributor.authorPaton, J.C.
dc.contributor.authorHampton, M.B.
dc.contributor.authorDickerhof, N.
dc.date.issued2022
dc.description.abstractHypothiocyanous acid (HOSCN) is an antimicrobial oxidant produced from hydrogen peroxide and thiocyanate anions by heme peroxidases in secretory fluids such as in the human respiratory tract. Some respiratory tract pathogens display tolerance to this oxidant, which suggests that there might be therapeutic value in targeting HOSCN defense mechanisms. However, surprisingly little is known about how bacteria protect themselves from HOSCN. We hypothesized that tolerant pathogens have a flavoprotein disulfide reductase that uses NAD(P)H to directly reduce HOSCN, similar to thioredoxin reductase in mammalian cells. Here, we report the discovery of a previously uncharacterized flavoprotein disulfide reductase with HOSCN reductase activity, which we term Har (hypothiocyanous acid reductase), in Streptococcus pneumoniae, a bacterium previously found to be tolerant of HOSCN. S. pneumoniae generates large amounts of hydrogen peroxide that can be converted to HOSCN in the respiratory tract. Using deletion mutants, we demonstrate that the HOSCN reductase is dispensable for growth of S. pneumoniae in the presence of lactoperoxidase and thiocyanate. However, bacterial growth in the HOSCN-generating system was completely crippled when deletion of HOSCN reductase activity was combined with disruption of GSH import or recycling. Our findings identify a new bacterial HOSCN reductase and demonstrate a role for this protein in combination with GSH utilization to protect S. pneumoniae from HOSCN.
dc.description.statementofresponsibilityHeather L. Shearer, Paul E. Pace, James C. Paton, Mark B. Hampton, and Nina Dickerhof
dc.identifier.citationJournal of Biological Chemistry, 2022; 298(9):102359-1-102359-11
dc.identifier.doi10.1016/j.jbc.2022.102359
dc.identifier.issn0021-9258
dc.identifier.issn1083-351X
dc.identifier.orcidPaton, J.C. [0000-0001-9807-5278]
dc.identifier.urihttps://hdl.handle.net/2440/146529
dc.language.isoen
dc.publisherElsevier
dc.rights© 2022 The Authors. Published by Elsevier Inc on behalf of American Society for Biochemistry and Molecular Biology. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
dc.source.urihttps://doi.org/10.1016/j.jbc.2022.102359
dc.subjectmyeloperoxidase; lactoperoxidase; hypothiocyanous acid; pneumonia; SPD_1415; flavoprotein disulfide reductase; pyridine nucleotide-disulfide reductase; thioredoxin reductase
dc.subject.meshAnimals
dc.subject.meshMammals
dc.subject.meshHumans
dc.subject.meshStreptococcus pneumoniae
dc.subject.meshHydrogen Peroxide
dc.subject.meshDisulfides
dc.subject.meshThiocyanates
dc.subject.meshHeme
dc.subject.meshNAD
dc.subject.meshLactoperoxidase
dc.subject.meshAnti-Infective Agents
dc.subject.meshOxidants
dc.subject.meshThioredoxin-Disulfide Reductase
dc.titleA newly identified flavoprotein disulfide reductase Har protects Streptococcus pneumoniae against hypothiocyanous acid.
dc.typeJournal article
pubs.publication-statusPublished

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