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Pseudomonas Exotoxin A: optimized by evolution for effective killing.

Michalska M, Wolf P - Front Microbiol (2015)

Bottom Line: Pseudomonas Exotoxin A (PE) is the most toxic virulence factor of the pathogenic bacterium Pseudomonas aeruginosa.This review describes current knowledge about the intoxication pathways of PE.Moreover, PE represents a remarkable example for pathoadaptive evolution, how bacterial molecules have been structurally and functionally optimized under evolutionary pressure to effectively impair and kill their host cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Urology, Medical Center, University of Freiburg Freiburg, Germany.

ABSTRACT
Pseudomonas Exotoxin A (PE) is the most toxic virulence factor of the pathogenic bacterium Pseudomonas aeruginosa. This review describes current knowledge about the intoxication pathways of PE. Moreover, PE represents a remarkable example for pathoadaptive evolution, how bacterial molecules have been structurally and functionally optimized under evolutionary pressure to effectively impair and kill their host cells.

No MeSH data available.


Related in: MedlinePlus

ADP-ribosylation of eEF-2. Dipth, diphthamide.
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Figure 2: ADP-ribosylation of eEF-2. Dipth, diphthamide.

Mentions: The ADP-ribosylation mechanism of PE was studied in detail and it turned out that it follows an SN1 nucleophilic substitution mechanism (Beattie et al., 1996; Armstrong et al., 2002; Jorgensen et al., 2005; Figure 2). Initially, the PE-fragment binds to NAD+ and interacts via the so-called “active-site loop L4” (aa 483–490 of domain III) with eEF-2 (Yates and Merrill, 2004). Afterward it facilicates the cleavage of the glycosidic bond (C-N) between the nicotinamide and N-ribose of NAD+. This results in a reactive oxacarbenium intermediate, which in turn is stabilized by residue E-553 of the PE-fragment (Li et al., 1996; Jorgensen et al., 2005). This step is followed by a nucleophilic attack of eEF-2, based on its nucleophilic residue diphthamide, a post-translationally modified histidine residue (2-(3-carboxyamido-3-[trimethylammonio]propyl) histidine) (Ortiz and Kinzy, 2005). The ADP-ribose group is subsequently transferred to the N3 atom of the diphthamide imidazole ring, which results in the ADP-ribosylated eEF-2 protein (Armstrong et al., 2002; Jorgensen et al., 2005).


Pseudomonas Exotoxin A: optimized by evolution for effective killing.

Michalska M, Wolf P - Front Microbiol (2015)

ADP-ribosylation of eEF-2. Dipth, diphthamide.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4584936&req=5

Figure 2: ADP-ribosylation of eEF-2. Dipth, diphthamide.
Mentions: The ADP-ribosylation mechanism of PE was studied in detail and it turned out that it follows an SN1 nucleophilic substitution mechanism (Beattie et al., 1996; Armstrong et al., 2002; Jorgensen et al., 2005; Figure 2). Initially, the PE-fragment binds to NAD+ and interacts via the so-called “active-site loop L4” (aa 483–490 of domain III) with eEF-2 (Yates and Merrill, 2004). Afterward it facilicates the cleavage of the glycosidic bond (C-N) between the nicotinamide and N-ribose of NAD+. This results in a reactive oxacarbenium intermediate, which in turn is stabilized by residue E-553 of the PE-fragment (Li et al., 1996; Jorgensen et al., 2005). This step is followed by a nucleophilic attack of eEF-2, based on its nucleophilic residue diphthamide, a post-translationally modified histidine residue (2-(3-carboxyamido-3-[trimethylammonio]propyl) histidine) (Ortiz and Kinzy, 2005). The ADP-ribose group is subsequently transferred to the N3 atom of the diphthamide imidazole ring, which results in the ADP-ribosylated eEF-2 protein (Armstrong et al., 2002; Jorgensen et al., 2005).

Bottom Line: Pseudomonas Exotoxin A (PE) is the most toxic virulence factor of the pathogenic bacterium Pseudomonas aeruginosa.This review describes current knowledge about the intoxication pathways of PE.Moreover, PE represents a remarkable example for pathoadaptive evolution, how bacterial molecules have been structurally and functionally optimized under evolutionary pressure to effectively impair and kill their host cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Urology, Medical Center, University of Freiburg Freiburg, Germany.

ABSTRACT
Pseudomonas Exotoxin A (PE) is the most toxic virulence factor of the pathogenic bacterium Pseudomonas aeruginosa. This review describes current knowledge about the intoxication pathways of PE. Moreover, PE represents a remarkable example for pathoadaptive evolution, how bacterial molecules have been structurally and functionally optimized under evolutionary pressure to effectively impair and kill their host cells.

No MeSH data available.


Related in: MedlinePlus