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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.


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.