L-Arginine Metabolism in the Lung: Reciprocal Regulation of the NOS and Arginase Pathways

North, Michelle L.; Scott, Jeremy A.

doi:10.2174/1875042701103010048

Cited by 8 publications

(19 citation statements)

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“…Previous work characterized this operon as being vital for the utilization of peptide substrates between 5 and 10 amino acids long (16).We hypothesized that the presence of peptide substrates would increase the transcription of this operon under nutrient-limiting conditions with only peptide substrates as the source of arginine, which is an essential amino acid for M. catarrhalis and a limiting nutrient in the respiratory tract (16,(35)(36)(37)(38). Total RNA was isolated from WT bacteria grown from an OD 600 of 0.07 to an OD 600 of 0.8 at 37°C and 26°C in chemically defined medium containing free arginine (R) and defined medium with no free arginine supplemented with the peptide VANRP.…”

Section: Resultsmentioning

confidence: 99%

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Expression of the Oligopeptide Permease Operon of Moraxella catarrhalis Is Regulated by Temperature and Nutrient Availability

Jones

Murphy

2015

Infect Immun

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Moraxella catarrhalis causes otitis media in children and exacerbations of chronic obstructive pulmonary disease in adults. Together, these two conditions contribute to enormous morbidity and mortality worldwide. The oligopeptide permease (opp) ABC transport system is a nutritional virulence factor important for the utilization of peptides. The substrate binding protein OppA, which binds peptides for uptake, is a potential vaccine antigen, but little was known about the regulation of gene expression. The five opp genes oppB, oppC, oppD, oppF, and oppA are in the same open reading frame. Sequence analysis predicted two promoters, one located upstream of oppB and one within the intergenic region between oppF and oppA. We have characterized the gene cluster as an operon with two functional promoters and show that cold shock at 26°C for <0.5 h and the presence of a peptide substrate increase gene transcript levels. Additionally, the putative promoter upstream of oppA contributes to the transcription of oppA but is not influenced by the same environmental cues as the promoter upstream of oppB. We conclude that temperature and nutrient availability contribute to the regulation of the Opp system, which is an important nutritional virulence factor in M. catarrhalis. Moraxella catarrhalis is an increasingly important human-specific pathogen contributing to worldwide morbidity and mortality that has transitioned from an emerging to an established pathogen (1-3). Otitis media in children is the primary cause of new antibiotic prescriptions and pediatric office visits, with M. catarrhalis accounting for 10% to 20% of acute otitis media episodes (2, 4-6). Chronic obstructive pulmonary disease (COPD) is the third leading cause of death in the United States, with M. catarrhalis contributing to at least 10% of exacerbations (7-11). The socioeconomic burden of otitis media and COPD is significant, with an estimated $50 billion dollars annually in health care expenses globally (5, 9, 12). In view of the morbidity and health care cost associated with M. catarrhalis, it is important to understand the mechanisms of pathogenesis in order to guide development of novel approaches to treatment and prevention (2,13,14). In previous work, we identified OppA as a promising vaccine antigen and a nutritional virulence factor for M. catarrhalis (15,16).We previously characterized the oligopeptide permease (opp) gene cluster as an ABC transport system vital for the utilization of peptide substrates. The gene cluster encodes two permeases, OppB and OppC; two ATPases, OppD and OppF; and a substrate binding protein, OppA (16). We hypothesized that this gene cluster was transcribed as an operon and that environmental factors, temperature and essential nutrients available as peptides, would alter the rate of transcription.The lower respiratory tract has a normal body temperature of 37°C, while the upper airways, specifically the nasopharynx, where M. catarrhalis first colonizes, ranges from 34°C at room temperature (25°C) down to 26°C after a short...

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Section: Resultsmentioning

confidence: 99%

“…For example, much of the free arginine in the human respiratory tract is methylated or sequestered inside cells, particularly under conditions that promote lung inflammation, such as that of a COPD exacerbation (36,38,(57)(58)(59)(60). Thus, the ability of M. catarrhalis to utilize peptide substrates is essential for survival in vivo (16).…”

Section: Figmentioning

confidence: 99%

Expression of the Oligopeptide Permease Operon of Moraxella catarrhalis Is Regulated by Temperature and Nutrient Availability

Jones

Murphy

2015

Infect Immun

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“…In particular, the constitutive neuronal and endothelial isoforms (nNOS and eNOS) support lung smooth muscle tone and relaxation. Noteworthy, NO scarcity may be compensated by the presence of inducible NOS (iNOS), which is upregulated in airway inflammation, e.g., in asthma (North et al, 2010 ; North and Scott, 2011 ). A negative role for PA in lung diseases was suggested by studies showing that an increase in the arginase/PA pathway at the expense of the NOS/NO output exacerbates COPD and asthma (Bergeron et al, 2007 ).…”

Section: Role Of Polyamines In Lung Cell Physiologymentioning

confidence: 99%

Soft TCPTP Agonism—Novel Target to Rescue Airway Epithelial Integrity by Exogenous Spermidine

et al. 2016

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A reparative approach of disrupted epithelium in obstructive airway diseases, namely asthma and chronic obstructive pulmonary disease (COPD), may afford protection and long-lasting results compared to conventional therapies, e.g., corticosteroids or immunosuppressant drugs. Here, we propose the polyamine spermidine as a novel therapeutic agent in airways diseases, based on a recently identified mode of action: T-cell protein tyrosine phosphatase (TCPTP) agonism. It may include and surpass single-inhibitors of stress and secondary growth factor pathway signaling, i.e., the new medicinal chemistry in lung diseases. Enhanced polyamine biosynthesis has been charged with aggravating prognosis by competing for L-arginine at detriment of nitric oxide (NO) synthesis with bronchoconstrictive effects. Although excess spermine, a higher polyamine, is harmful to airways physiology, spermidine can pivot the cell homeostasis during stress conditions by the activation of TCPTP. In fact, the dephosphorylating activity of TCPTP inhibits the signaling cascade that leads to the expression of genes involved in detachment and epithelial-to-mesenchymal transition (EMT), and increases the expression of adhesion and tight junction proteins, thereby enhancing the barrier functionality in inflammation-prone tissues. Moreover, a further beneficial effect of spermidine may derive from its ability to promote autophagy, possibly in a TCPTP-dependent way. Since doses of spermidine in the micromolar range are sufficient to activate TCPTP, low amounts of spermidine administered in sustained release modality may provide an optimal pharmacologic profile for the treatment of obstructive airway diseases.

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“…There is a need to understand bacterial physiology and metabolism during infection as these pathways and traits could be exploited for development of new treatments (30). For example, M. catarrhalis is an arginine auxotroph, yet it is not known whether the bacterium can utilize methylated arginine, the predominant form of arginine available in the airways (31)(32)(33)(34)(35)(36). The annotated oligopeptide permease (opp) gene cluster in the M. catarrhalis genome has homology with the peptide import ATPbinding cassette (ABC) transport systems composed of permease, ATPase, and substrate binding proteins (37,38).…”

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confidence: 99%

Role of the Oligopeptide Permease ABC Transporter of Moraxella catarrhalis in Nutrient Acquisition and Persistence in the Respiratory Tract

et al. 2014

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Moraxella catarrhalis is a strict human pathogen that causes otitis media in children and exacerbations of chronic obstructive pulmonary disease in adults, resulting in significant worldwide morbidity and mortality. M. catarrhalis has a growth requirement for arginine; thus, acquiring arginine is important for fitness and survival. M. catarrhalis has a putative oligopeptide permease ABC transport operon (opp) consisting of five genes (oppB, oppC, oppD, oppF, and oppA), encoding two permeases, two ATPases, and a substrate binding protein. Thermal shift assays showed that the purified recombinant substrate binding protein OppA binds to peptides 3 to 16 amino acid residues in length regardless of the amino acid composition. A mutant in which the oppBCDFA gene cluster is knocked out showed impaired growth in minimal medium where the only source of arginine came from a peptide 5 to 10 amino acid residues in length. Whether methylated arginine supports growth of M. catarrhalis is important in understanding fitness in the respiratory tract because methylated arginine is abundant in host tissues. No growth of wildtype M. catarrhalis was observed in minimal medium in which arginine was present only in methylated form, indicating that the bacterium requires L-arginine. An oppA knockout mutant showed marked impairment in its capacity to persist in the respiratory tract compared to the wild type in a mouse pulmonary clearance model. We conclude that the Opp system mediates both uptake of peptides and fitness in the respiratory tract. Moraxella catarrhalis, a Gram-negative diplococcus, is a commensal of the upper respiratory tract, as well as a humanspecific pathogen responsible for 10 to 20% of otitis media in children and approximately 10% of exacerbations of chronic obstructive pulmonary disease (COPD) in adults in the United States (1-6). Otitis media is the most common reason for pediatric office visits and the prescribing of antibiotics to children, typically by the age of 3 years (7-12). COPD is the third leading cause of death in the United States, affecting at least 24 million people, and costs $50 billion in health care expenses each year (13-16). COPD is considered a major unmet medical need that is increasing in prevalence throughout the world (17, 18). Antibiotic resistance is an additional concern, with nearly 100% of clinical isolates of M. catarrhalis displaying resistance to ␤-lactam drugs with the ability to protect other ␤-lactam-sensitive bacteria in the surrounding environment (3, 9, 19-23).In the last 2 decades, M. catarrhalis has transitioned from being considered an emerging to an established pathogen. Since this bacterium was previously considered to be a commensal, the literature on mechanisms that allow M. catarrhalis to thrive in the harsh environment of the human respiratory tract is sparse, and the associated virulence mechanisms are not well studied (1, 2, 24-29). There is a need to understand bacterial physiology and metabolism during infection as these pathways and traits could be exploited f...

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L-Arginine Metabolism in the Lung: Reciprocal Regulation of the NOS and Arginase Pathways

Cited by 8 publications

References 84 publications

Expression of the Oligopeptide Permease Operon of Moraxella catarrhalis Is Regulated by Temperature and Nutrient Availability

Expression of the Oligopeptide Permease Operon of Moraxella catarrhalis Is Regulated by Temperature and Nutrient Availability

Soft TCPTP Agonism—Novel Target to Rescue Airway Epithelial Integrity by Exogenous Spermidine

Role of the Oligopeptide Permease ABC Transporter of Moraxella catarrhalis in Nutrient Acquisition and Persistence in the Respiratory Tract

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