Oxygen, Cyanide and Energy Generation in the Cystic Fibrosis Pathogen Pseudomonas aeruginosa
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Introduction to Pseudomonas aeruginosa
Pseudomonas aeruginosa is a Gram-negative, rod-shaped bacterium that belongs to the γ-proteobacteria (Holt and Kreig, 1984). This clinically challenging, opportunistic pathogen occupies a wide range of niches from an almost ubiquitous environmental presence to causing infections in a wide range of animals and plants (Van Delden and Iglewski, 1998; Tummler and Kiewitz, 1999; Stover et al., 2000). P. aeruginosa has a large genome of around 6.3 million base pairs encoding some 5270 predicted open
Oxygen and P. aeruginosa Infection of the Cystic Fibrosis Lung – the Scope of this Review
CF is caused by mutation of the gene encoding the CF transmembrane regulator (CFTR), which functions as a chloride channel in epithelial membranes (Collins, 1992). Several hypotheses link mutations in CFTR to development of chronic P. aeruginosa infections (Ratjen and Doring, 2003). A hypothesis for which there is increasing support is the isotonic fluid depletion/hypoxic mucus hypothesis (Fig. 1). This proposes that isotonic salt concentrations resulting from abnormal sodium absorption from
Means of Energy Generation in P. aeruginosa
It is in their methods of energy generation that bacteria demonstrate their exceptional metabolic versatility and diversity. Pseudomonads use a remarkably eclectic range of carbon and energy sources (Stanier et al., 1966). Irrespective of the energy source used, energy-generating reactions must accomplish the same metabolic functions, that is, to produce precursor metabolites, reducing power and the energy required by the cell in the form of ATP and Δp (proton and/or sodium electrochemical
Aerobic respiration in P. aeruginosa
Bacterial respiratory chains are complex organisations of electron-transfer components, which together can oxidise a broad array of substrates via substrate-specific dehydrogenases. These initial oxidations of redox couples with low negative redox potentials are linked to the four-electron reduction of oxygen to water by a sequence of electron transfer components that are common to all organisms. These include quinones, cytochromes and terminal oxidases and contain as redox centres haems, Fe-S
Anaerobic Respiration
P. aeruginosa is a denitrifying bacterium. It is able to carry out anaerobic respiration with N-oxides as terminal electron acceptors for anaerobic respiration. Denitrification is the sequential reduction of nitrate to N2 via nitrite, nitric oxide and nitrous oxide, a process that is catalysed by four enzymes: nitrate reductase (NAR), nitrite reductase (NIR), nitric oxide reductase (NOR) and nitrous oxide reductase (N2OR) (Figure 3, Figure 6; Zumft, 1997). The denitrifying enzymes provide
Fermentation
P. aeruginosa has often been described as a non-fermentative bacterium. This is not the case, but it has only limited fermentative capacity. It has been long recognised that in the absence of oxygen and nitrate P. aeruginosa can use arginine as source of energy for growth using the arginine deiminase (ADI) pathway (Shoesmith and Sherris, 1960; Van der Wauven et al., 1984). This pathway catalyses the breakdown of l-arginine to l-ornithine, with the formation of an ATP (Fig. 7). However,
Anaerobic Metabolism in the Cystic Fibrosis Lung
Recent research has implicated the formation of anaerobic biofilms and consequently the operation of anaerobic respiratory pathways in the colonisation of and survival in the CF lung by P. aeruginosa.
In an elegant study, referred to earlier, Worlitzsch et al. (2002) showed that steep oxygen gradients exist in the mucus lining of the CF lung, whereas no equivalent gradients exist in the mucus of the healthy non-CF lung. There is evidence of raised oxygen consumption by CF epithelial cells (
Synthesis of the Respiratory Inhibitor Hydrogen Cyanide in P. aeruginosa
An intriguing aspect of the biology of P. aeruginosa is its ability to synthesise the respiratory inhibitor hydrogen cyanide, which can reach concentrations of 300 μM in laboratory cultures (Blumer and Haas, 2000; Zlosnik and Williams, 2004). The fact that cyanide is synthesised aerobically raises the interesting issue of how can the bacteria respire aerobically while producing cyanide. The fact that cyanide is made only under low oxygen conditions raises the issue of whether it is made in the
Mucoid Conversion of P. aeruginosa in the Cystic Fibrosis Lung: the Role of Oxygen and Energy Metabolism
The production of the exopolysaccharide alginate confers the well-described mucoid phenotype on P. aeruginosa. Alginate is a linear copolymer composed of β-d-mannuronic acid and α-l-guluronic acids and its production in bacteria was first described in P. aeruginosa in 1964 (Linker and Jones, 1964). Alginate is also known to be produced as an extracellular polysaccharide by A. vinelandi and other Pseudomonads (Gacesa, 1998).
In CF a typical pattern of P. aeruginosa infection has long been
Conclusion
P. aeruginosa has broad-ranging energy-generating pathways which will be important in the adaptation of P. aeruginosa to the niche of the CF lung. The recent demonstration of oxygen gradients across and anaerobic conditions in the depths of the mucus layer of the CF lung suggest that a full range of energy generating pathways will function in P. aeruginosa during colonisation and chronic infection of the CF lung. This information, coupled with the HCN production in the mucus layer and the
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