Isocitrate Lyase Supplies Precursors for Hydrogen Cyanide Production in a Cystic Fibrosis Isolate of
            <i>Pseudomonas aeruginosa</i>

Hagins, Jessica M.; Locy, Robert D.; Silo-Suh, Laura

doi:10.1128/jb.00692-09

Cited by 20 publications

(15 citation statements)

References 37 publications

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“…Additional evidence has demonstrated a role in the production of hydrogen cyanide, which can be derived from the intermediates of the glyoxylate shunt, by P. aeruginosa and impairment in lung function in CF patients [129,130]. Here we observed small-to-moderate fluxes through this shunt in all strains, and a significant correlation between this flux and intrinsic growth rate across strains.…”

Section: Metabolism and Pathogenicitymentioning

confidence: 50%

Metabolic flux analyses of Pseudomonas aeruginosa cystic fibrosis isolates

Opperman

Shachar‐Hill

2016

Metabolic Engineering

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Section: Metabolism and Pathogenicitymentioning

confidence: 50%

Metabolic flux analyses of Pseudomonas aeruginosa cystic fibrosis isolates

Opperman

Shachar‐Hill

2016

Metabolic Engineering

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“…Taken together, ICL activity may not be required solely for catabolism of carbon sources in the CF lung, but may benefit the bacterium in other ways. Consistent with this possibility, both alginate and hydrogen cyanide production are reduced in an FRD1 aceA mutant (Hagins et al, 2009;Lindsey et al, 2008). Alginate protects P. aeruginosa during chronic infections by limiting the diffusion of oxidative radicals, antibiotics, opsonizing antibodies and phagocytes (Hatch & Schiller, 1998;Oliver & Weir, 1985;Pedersen et al, 1990;Simpson et al, 1989).…”

Section: Discussionmentioning

confidence: 94%

Influence of RpoN on isocitrate lyase activity in Pseudomonas aeruginosa

et al. 2010

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Pseudomonas aeruginosa is the major aetiological agent of chronic pulmonary infections in patients with cystic fibrosis (CF). The metabolic pathways utilized by P. aeruginosa during these infections, which can persist for decades, are poorly understood. Several lines of evidence suggest that the glyoxylate pathway, which utilizes acetate or fatty acids to replenish intermediates of the tricarboxylic acid cycle, is an important metabolic pathway for P. aeruginosa adapted to the CF lung. Isocitrate lyase (ICL) is one of two major enzymes of the glyoxylate pathway. In a previous study, we determined that P. aeruginosa is dependent upon aceA, which encodes ICL, to cause disease on alfalfa seedlings and in rat lungs. Expression of aceA in PAO1, a P. aeruginosa isolate associated with acute infection, is regulated by carbon sources that utilize the glyoxyate pathway. In contrast, expression of aceA in FRD1, a CF isolate, is constitutively upregulated. Moreover, this deregulation of aceA occurs in other P. aeruginosa isolates associated with chronic infection, suggesting that high ICL activity facilitates adaptation of P. aeruginosa to the CF lung. Complementation of FRD1 with a PAO1 clone bank identified that rpoN negatively regulates aceA. However, the deregulation of aceA in FRD1 was not due to a knockout mutation of rpoN. Regulation of the glyoxylate pathway by RpoN is likely to be indirect, and represents a unique regulatory role for this sigma factor in bacterial metabolism. INTRODUCTIONBronchopulmonary infections caused by Pseudomonas aeruginosa are the leading cause of mortality for cystic fibrosis (CF) patients. These infections resist eradication by antibiotic therapy and the host immune system, and indicate a need for novel therapeutic strategies. The ability of P. aeruginosa to maintain decade-long infections within the CF lung is attributed in part to virulence mechanisms that evolve as the bacterium adapts to this environment (Lindsey et al., 2008;Nguyen & Singh, 2006). Although P. aeruginosa is nutritionally versatile, within human niches it must adapt to the availability of host-derived nutrients. Within the lungs of CF patients, these nutrients are probably contained in sputum.The composition of CF sputum is complex. It contains host and bacterial cells, as well as various host-and bacterialderived compounds (Hoiby, 1998). Transcriptome studies have indicated that PAO1, a wound isolate of P. aeruginosa, primarily uses amino acids as a carbon source when grown in CF sputum (Palmer et al., 2005;Son et al., 2007). In contrast, a CF isolate of P. aeruginosa uses amino acids and lipids (Palmer et al., 2005;Son et al., 2007). The different carbon utilization patterns by these isolates suggest that P. aeruginosa alters its metabolic pathways during chronic infection of the CF lung. This is supported by the observation that regulatory control of several central metabolic enzymes is altered in FRD1, a CF isolate, compared with PAO1 (Lindsey et al., 2008;Silo-Suh et al., 2005).In a previous study, we exploited t...

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“…ICL expression is stimulated during growth in oxygen-limiting conditions, and, consistent with the anaerobic nature of the CF lung, the enzyme was found to be highly expressed in P. aeruginosa isolates from chronically infected CF individuals [24,25,29,37]. Although its primary function in P. aeruginosa is carbon catabolism, recent evidence suggests that ICL can also have an impact on pathogenesis [36–38]. For example, in the mucoid P. aeruginosa CF isolate, FRD1, increased ICL activity was directly linked to the production of a precursor metabolite (glycine) of hydrogen cyanide (HCN), a poison and potent inhibitor of cytochrome c oxidase and other metalloenzymes, including nitrite reductase and superoxide dismutase [38,39].…”

Section: Discussionmentioning

confidence: 99%

Type III secretion system expression in oxygen-limited Pseudomonas aeruginosa cultures is stimulated by isocitrate lyase activity

et al. 2013

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Pseudomonas aeruginosa is an opportunistic human pathogen and a common cause of chronic infections in individuals with cystic fibrosis (CF). Oxygen limitation was recently reported to regulate the expression of a major virulence determinant in P. aeruginosa, the type III secretion system (T3SS). Here, we show that expression of the T3SS in oxygen-limited growth conditions is strongly dependent on the glyoxylate shunt enzyme, isocitrate lyase (ICL; encoded by aceA), which was previously shown to be highly expressed in CF isolates. ICL-dependent regulation of the T3SS did not alter the expression level of the master transcriptional regulator, ExsA, but did affect expression of the T3 structural proteins, effectors and regulators (ExsC, ExsD and ExsE). An aceA mutant displayed enhanced biofilm formation during anaerobic growth, which suggested that AceA-dependent modulation of type III secretion might impinge upon the RetS/LadS signalling pathways. Indeed, our data suggest that RetS is able to mediate some of its effects through AceA, as expression of aceA in trans partially restored T3SS expression in a retS mutant. Our findings indicate that AceA is a key player in the metabolic regulation of T3SS expression during oxygen-limited growth of P. aeruginosa. To the best of our knowledge, this is the first demonstration that the T3SS can be regulated by factors that do not affect ExsA expression levels.

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Isocitrate Lyase Supplies Precursors for Hydrogen Cyanide Production in a Cystic Fibrosis Isolate of Pseudomonas aeruginosa

Cited by 20 publications

References 37 publications

Metabolic flux analyses of Pseudomonas aeruginosa cystic fibrosis isolates

Metabolic flux analyses of Pseudomonas aeruginosa cystic fibrosis isolates

Influence of RpoN on isocitrate lyase activity in Pseudomonas aeruginosa

Type III secretion system expression in oxygen-limited Pseudomonas aeruginosa cultures is stimulated by isocitrate lyase activity

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