ArticleThe Journal of biological chemistry2013
Selective metabolism of hypothiocyanous acid by mammalian thioredoxin reductase promotes lung innate immunity and antioxidant defense.
Article in The Journal of biological chemistry, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 44 papers.
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Who cites it
44 citing papers in PubMed, 77 citations in OpenAlex.
- Factors governing the response ofFrontiers in cellular and infection microbiology · 2026Review
- An Optimized Protocol for Enzymatic Hypothiocyanous Acid Synthesis.Methods and protocols · 2025Article
- A Defined Artificial Saliva Medium Allows Characterization of the Hypothiocyanite Response of Streptococcus sanguinis and Streptococcus mutans.Molecular oral microbiology · 2025Article
- Genome-wide characterization of hypothiocyanite stress response inJournal of bacteriology · 2025Article
- The role of metals in hypothiocyanite resistance inJournal of bacteriology · 2024Article
- The therapeutic potential of thiocyanate and hypothiocyanous acid against pulmonary infections.Free radical biology & medicine · 2024Review
- Article
- The role of metals in hypothiocyanite resistance inbioRxiv : the preprint server for biology · 2024Article
- Expression of RcrB confers resistance to hypochlorous acid in uropathogenicJournal of bacteriology · 2023Article
- Substrate-dependent metabolomic signatures of myeloperoxidase activity in airway epithelial cells: Implications for early cystic fibrosis lung disease.Free radical biology & medicine · 2023Article
- Expression of RcrB confers resistance to hypochlorous acid in uropathogenicbioRxiv : the preprint server for biology · 2023Article
- A Year at the Forefront of Bacterial Defense Systems Against Neutrophilic Oxidants.Biology open · 2023Article
- Hypothiocyanite and host-microbe interactions.Molecular microbiology · 2023Article
- Antioxidant Strategies to Modulate NETosis and the Release of Neutrophil Extracellular Traps during Chronic Inflammation.Antioxidants (Basel, Switzerland) · 2023Article
- Safety Assessment of the Modified Lactoperoxidase System-In Vitro Studies on Human Gingival Fibroblasts.International journal of molecular sciences · 2023Article
- A newly identified flavoprotein disulfide reductase Har protects Streptococcus pneumoniae against hypothiocyanous acid.The Journal of biological chemistry · 2022Article
- Advances in the Study of the Mechanism by Which Selenium and Selenoproteins Boost Immunity to Prevent Food Allergies.Nutrients · 2022Review
- Article
- The Use of Thiocyanate Formulations to Create Manganese Porphyrin Antioxidants That Supplement Innate Immunity.Antioxidants (Basel, Switzerland) · 2022Article
- Halogenation Activity of Mammalian Heme Peroxidases.Antioxidants (Basel, Switzerland) · 2022Review
Corrections and comments
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Authors and funding
5 authors at 3 institutions in 1 country.
Funding
Abstract
The endogenously produced oxidant hypothiocyanous acid (HOSCN) inhibits and kills pathogens but paradoxically is well tolerated by mammalian host tissue. Mammalian high molecular weight thioredoxin reductase (H-TrxR) is evolutionarily divergent from bacterial low molecular weight thioredoxin reductase (L-TrxR). Notably, mammalian H-TrxR contains a selenocysteine (Sec) and has wider substrate reactivity than L-TrxR. Recombinant rat cytosolic H-TrxR1, mouse mitochondrial H-TrxR2, and a purified mixture of both from rat selectively turned over HOSCN (kcat = 357 ± 16 min(-1); Km = 31.9 ± 10.3 μM) but were inactive against the related oxidant hypochlorous acid. Replacing Sec with Cys or deleting the final eight C-terminal peptides decreased affinity and turnover of HOSCN by H-TrxR. Similarly, glutathione reductase (an H-TrxR homologue lacking Sec) was less effective at HOSCN turnover. In contrast to H-TrxR and glutathione reductase, recombinant Escherichia coli L-TrxR was potently inhibited by HOSCN (IC50 = 2.75 μM). Similarly, human bronchial epithelial cell (16HBE) lysates metabolized HOSCN, but E. coli and Pseudomonas aeruginosa lysates had little or no activity. HOSCN selectively produced toxicity in bacteria, whereas hypochlorous acid was nonselectively toxic to both bacteria and 16HBE. Treatment with the H-TrxR inhibitor auranofin inhibited HOSCN metabolism in 16HBE lysates and significantly increased HOSCN-mediated cytotoxicity. These findings demonstrate both the metabolism of HOSCN by mammalian H-TrxR resulting in resistance to HOSCN in mammalian cells and the potent inhibition of bacterial L-TrxR resulting in cytotoxicity in bacteria. These data support a novel selective mechanism of host defense in mammals wherein HOSCN formation simultaneously inhibits pathogens while sparing host tissue.
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