Selective Metabolism of Hypothiocyanous Acid by Mammalian Thioredoxin Reductase Promotes Lung Innate Immunity and Antioxidant Defense

Chandler, Joshua D.; Nichols, David P.; Nick, Jerry A.; Hondal, Robert J.; Day, Brian J.

doi:10.1074/jbc.m113.468090

Cited by 67 publications

(95 citation statements)

References 48 publications

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“…Altered redox signaling of HOSCN may be reflected in altered cellular responses to this oxidant instead of others, e.g., removal of H 2 O 2 and HOCl by SCN − protects against mammalian cell death and decreases inflammation [179, 205]. Furthermore, mammalian innate immunity exploits specificity of HOSCN reactivity to place selective oxidative pressure on microbes [206]. The biochemical and physiological effects of SCN − and HOSCN have been recently reviewed [207].…”

Section: Protein Cys Redox Regulationmentioning

confidence: 99%

The cysteine proteome

Chandler

Jones

2015

Free Radical Biology and Medicine

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305

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The cysteine (Cys) proteome is a major component of the adaptive interface between the genome and the exposome. The thiol moiety of Cys undergoes a range of biologic modifications enabling biological switching of structure and reactivity. These biological modifications include sulfenylation and disulfide formation, formation of higher oxidation states, S-nitrosylation, persulfidation, metallation, and other modifications. Extensive knowledge about these systems and their compartmentalization now provides a foundation to develop advanced integrative models of Cys proteome regulation. In particular, detailed understanding of redox signaling pathways and sensing networks is becoming available to discriminate network structures. This research focuses attention on the need for atlases of Cys modifications to develop systems biology models. Such atlases will be especially useful for integrative studies linking the Cys proteome to imaging and other omics platforms, providing a basis for improved redox-based therapeutics. Thus, a framework is emerging to place the Cys proteome as a complement to the quantitative proteome in the omics continuum connecting the genome to the exposome.

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Section: Protein Cys Redox Regulationmentioning

confidence: 99%

The cysteine proteome

Chandler

Jones

2015

Free Radical Biology and Medicine

Self Cite

305

243

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“…However, the physiologic range of SCN − in many compartments is limiting (≤100 μM) so that HOSCN comprises <50% of oxidants produced during inflammation [58]. Concentrations of SCN − ≥400 μM drive the totality of oxidant output by MPO to generate HOSCN in vitro [74,75]. …”

Section: Redox Biochemistry Of Scn− and Hoscnmentioning

confidence: 99%

“…However, metazoan TrxR also acts on targets beside Trx [94]. E.g., HOSCN is catalytically reduced by direct reaction with mammalian TrxR, which is a cytoprotective mechanism, while bacterial TrxR is potently inhibited by HOSCN [75]. Expression of Sec by mammalian TrxR significantly enhances the removal of HOSCN [75] and improves its resistance to oxidative inactivation [94], suggesting Sec expression may have been selected to confer host-specific resistance to oxidative stress during infection [75].…”

Section: Redox Biochemistry Of Scn− and Hoscnmentioning

confidence: 99%

“…Mammalian TrxR evolved as a selenoprotein mutation of GR and significantly diverged from the ancestral TrxR protein family found in the overwhelming majority of human pathogens [92]. Furthermore, mammalian TrxR catalytically reduces HOSCN at biologically relevant rates, GR is capable of the same but much less efficient and bacterial TrxR is metabolically incompetent in this reaction [75]. Pharmacologic inhibition of mammalian TrxR with auranofin sensitized bronchial epithelia to HOSCN-mediated cell death [75].…”

Section: Redox Biochemistry Of Scn− and Hoscnmentioning

confidence: 99%

“…Furthermore, mammalian TrxR catalytically reduces HOSCN at biologically relevant rates, GR is capable of the same but much less efficient and bacterial TrxR is metabolically incompetent in this reaction [75]. Pharmacologic inhibition of mammalian TrxR with auranofin sensitized bronchial epithelia to HOSCN-mediated cell death [75]. The GSH-GR pathway has been posited as a regulator of HOSCN metabolism as well [35], which is supported by the great abundance of intracellular GSH compared to other HOSCN targets.…”

Section: Redox Biochemistry Of Scn− and Hoscnmentioning

confidence: 99%

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Biochemical mechanisms and therapeutic potential of pseudohalide thiocyanate in human health

Chandler

Day

2015

Free Radical Research

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Thiocyanate (SCN−) is an ubiquitous molecule in mammalian biology, reaching up to mM concentrations in extracellular fluids. Two-electron oxidation of SCN− by H2O2 produces hypothiocyanous acid (HOSCN), a potent antimicrobial species. This reaction is catalyzed by chordate peroxidases (e.g., myeloperoxidase and lactoperoxidase), occurring in human secretory mucosa, including the oral cavity, airway and alimentary tract, and regulates resident and transient flora as part of innate immunity. Increasing SCN− levels limits the concentrations of a family of 2-electron oxidants (H2O2, hypohalous acids and haloamines) in favor of HOSCN formation, altering the oxidative impact on host tissue by substitution of repairable thiol and selenol oxidations instead of biomolecule degradation. This fine-tuning of inflammatory oxidation paradoxically associates with maintained host defense and decreased host injury during infections, due in part to phylogenetic differences in the thioredoxin reductase system between mammals and their pathogens. These differences could be exploited by pharmacologic use of SCN−. Recent preclinical studies have identified antimicrobial and anti-inflammatory effects of SCN− in pulmonary and cardiovascular animal models, with implications for treatment of infectious lung disease and atherogenesis. Further research is merited to expand on these findings and identify other diseases where SCN− may be of use. High oral bioavailability and an increased knowledge of the biochemical effects of SCN− on a subset of pro-inflammatory reactions suggest clinical utility.

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Inflammation and its genesis in cystic fibrosis

Nichols

Chmiel

2015

Pediatric Pulmonology

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162

150

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Summary. The host inflammatory response in cystic fibrosis (CF) lung disease has long been recognized as a central pathological feature and an important therapeutic target. Indeed, many believe that bronchiectasis results largely from the oxidative and proteolytic damage comprised within an exuberant airway inflammatory response that is dominated by neutrophils. In this review, we address the longstanding argument of whether or not the inflammatory response is directly attributable to impairment of the cystic fibrosis transmembrane conductance regulator or only secondary to airway obstruction and chronic bacterial infection and challenge the importance of this distinction in the context of therapy. We also review the centrality of neutrophils in CF lung pathophysiology and highlight more recent data that suggest the importance of other cell types and signaling beyond NF-kB activation. We discuss how protease and redox imbalance are critical factors in CF airway inflammation and end by reviewing some of the more promising therapeutic approaches now under development. Pediatr Pulmonol. 2015;50:S39-S56.

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Selective Metabolism of Hypothiocyanous Acid by Mammalian Thioredoxin Reductase Promotes Lung Innate Immunity and Antioxidant Defense

Cited by 67 publications

References 48 publications

The cysteine proteome

The cysteine proteome

Biochemical mechanisms and therapeutic potential of pseudohalide thiocyanate in human health

Inflammation and its genesis in cystic fibrosis

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