Pseudomonas exotoxin

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Exotoxin A
1aer.jpg
Exotoxin A dimer, Pseudomonas aeruginosa
Identifiers
Organism Pseudomonas aeruginosa
Symboleta
UniProt P11439
Other data
EC number 2.4.2.36
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Structures Swiss-model
Domains InterPro

The Pseudomonas exotoxin (or exotoxin A) is an exotoxin produced by Pseudomonas aeruginosa . [1] Vibrio cholerae produces a similar protein called the Cholix toxin ( Q5EK40 ). [2]

It inhibits elongation factor-2. It does so by ADP-ribosylation of EF2 using NAD+. This then causes the elongation of polypeptides to cease. This mechanism is similar to that of diphtheria toxin. [3]

It has been investigated as a treatment for hepatitis B [4] and cancer. [5]

Related Research Articles

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Adenylate cyclase is an enzyme with systematic name ATP diphosphate-lyase . It catalyzes the following reaction:

<i>Vibrio cholerae</i> Species of bacterium

Vibrio cholerae is a species of Gram-negative, facultative anaerobe and comma-shaped bacteria. The bacteria naturally live in brackish or saltwater where they attach themselves easily to the chitin-containing shells of crabs, shrimp, and other shellfish. Some strains of V. cholerae are pathogenic to humans and cause a deadly disease called cholera, which can be derived from the consumption of undercooked or raw marine life species.

<span class="mw-page-title-main">Exotoxin</span> Toxin from bacteria that destroys or disrupts cells

An exotoxin is a toxin secreted by bacteria. An exotoxin can cause damage to the host by destroying cells or disrupting normal cellular metabolism. They are highly potent and can cause major damage to the host. Exotoxins may be secreted, or, similar to endotoxins, may be released during lysis of the cell. Gram negative pathogens may secrete outer membrane vesicles containing lipopolysaccharide endotoxin and some virulence proteins in the bounding membrane along with some other toxins as intra-vesicular contents, thus adding a previously unforeseen dimension to the well-known eukaryote process of membrane vesicle trafficking, which is quite active at the host–pathogen interface.

<span class="mw-page-title-main">Secretion</span> Controlled release of substances by cells or tissues

Secretion is the movement of material from one point to another, such as a secreted chemical substance from a cell or gland. In contrast, excretion is the removal of certain substances or waste products from a cell or organism. The classical mechanism of cell secretion is via secretory portals at the plasma membrane called porosomes. Porosomes are permanent cup-shaped lipoprotein structures embedded in the cell membrane, where secretory vesicles transiently dock and fuse to release intra-vesicular contents from the cell.

<i>Pseudomonas aeruginosa</i> Species of bacterium

Pseudomonas aeruginosa is a common encapsulated, Gram-negative, aerobic–facultatively anaerobic, rod-shaped bacterium that can cause disease in plants and animals, including humans. A species of considerable medical importance, P. aeruginosa is a multidrug resistant pathogen recognized for its ubiquity, its intrinsically advanced antibiotic resistance mechanisms, and its association with serious illnesses – hospital-acquired infections such as ventilator-associated pneumonia and various sepsis syndromes.

Virulence factors are cellular structures, molecules and regulatory systems that enable microbial pathogens to achieve the following:

<span class="mw-page-title-main">Cholera toxin</span> Protein complex secreted by the bacterium Vibrio cholerae

Cholera toxin is an AB5 multimeric protein complex secreted by the bacterium Vibrio cholerae. CTX is responsible for the massive, watery diarrhea characteristic of cholera infection. It is a member of the heat-labile enterotoxin family.

<span class="mw-page-title-main">Diphtheria toxin</span> Exotoxin

Diphtheria toxin is an exotoxin secreted mainly by Corynebacterium diphtheriae but also by Corynebacterium ulcerans and Corynebacterium pseudotuberculosis. the pathogenic bacterium that causes diphtheria. The toxin gene is encoded by a prophage called corynephage β. The toxin causes the disease in humans by gaining entry into the cell cytoplasm and inhibiting protein synthesis.

<span class="mw-page-title-main">Elongation factor</span> Proteins functioning in translation

Elongation factors are a set of proteins that function at the ribosome, during protein synthesis, to facilitate translational elongation from the formation of the first to the last peptide bond of a growing polypeptide. Most common elongation factors in prokaryotes are EF-Tu, EF-Ts, EF-G. Bacteria and eukaryotes use elongation factors that are largely homologous to each other, but with distinct structures and different research nomenclatures.

<span class="mw-page-title-main">Diphthamide</span> Chemical compound

Diphthamide is a post-translationally modified histidine amino acid found in archaeal and eukaryotic elongation factor 2 (eEF-2).

<span class="mw-page-title-main">ADP-ribosylation</span> Addition of one or more ADP-ribose moieties to a protein.

ADP-ribosylation is the addition of one or more ADP-ribose moieties to a protein. It is a reversible post-translational modification that is involved in many cellular processes, including cell signaling, DNA repair, gene regulation and apoptosis. Improper ADP-ribosylation has been implicated in some forms of cancer. It is also the basis for the toxicity of bacterial compounds such as cholera toxin, diphtheria toxin, and others.

In enzymology, a NAD+-diphthamide ADP-ribosyltransferase (EC 2.4.2.36) is an enzyme that catalyzes the chemical reaction

<span class="mw-page-title-main">EEF2</span> Protein-coding gene in the species Homo sapiens

Eukaryotic elongation factor 2 is a protein that in humans is encoded by the EEF2 gene. It is the archaeal and eukaryotic counterpart of bacterial EF-G.

<span class="mw-page-title-main">DPH5</span> Protein-coding gene in the species Homo sapiens

Diphthine synthase is an enzyme that in humans is encoded by the DPH5 gene.

<span class="mw-page-title-main">AB toxin</span>

The AB toxins are two-component protein complexes secreted by a number of pathogenic bacteria, though there is a pore-forming AB toxin found the eggs of a snail. They can be classified as Type III toxins because they interfere with internal cell function. They are named AB toxins due to their components: the "A" component is usually the "active" portion, and the "B" component is usually the "binding" portion. The "A" subunit possesses enzyme activity, and is transferred to the host cell following a conformational change in the membrane-bound transport "B" subunit. These proteins consist of two independent polypeptides, which correspond to the A/B subunit moieties. The enzyme component (A) enters the cell through endosomes produced by the oligomeric binding/translocation protein (B), and prevents actin polymerisation through ADP-ribosylation of monomeric G-actin.

Microbial toxins are toxins produced by micro-organisms, including bacteria, fungi, protozoa, dinoflagellates, and viruses. Many microbial toxins promote infection and disease by directly damaging host tissues and by disabling the immune system. Endotoxins most commonly refer to the lipopolysaccharide (LPS) or lipooligosaccharide (LOS) that are in the outer plasma membrane of Gram-negative bacteria. The botulinum toxin, which is primarily produced by Clostridium botulinum and less frequently by other Clostridium species, is the most toxic substance known in the world. However, microbial toxins also have important uses in medical science and research. Currently, new methods of detecting bacterial toxins are being developed to better isolate and understand these toxin. Potential applications of toxin research include combating microbial virulence, the development of novel anticancer drugs and other medicines, and the use of toxins as tools in neurobiology and cellular biology.

The type VI secretion system (T6SS) is molecular machine used by a wide range of Gram-negative bacterial species to transport effectors from the interior of a bacterial cell across the cellular envelope into an adjacent target cell. While often reported that the T6SS was discovered in 2006 by researchers studying the causative agent of cholera, Vibrio cholerae, the first study demonstrating that T6SS genes encode a protein export apparatus was actually published in 2004, in a study of protein secretion by the fish pathogen Edwardsiella tarda.

<span class="mw-page-title-main">Bacterial secretion system</span> Protein complexes present on the cell membranes of bacteria for secretion of substances

Bacterial secretion systems are protein complexes present on the cell membranes of bacteria for secretion of substances. Specifically, they are the cellular devices used by pathogenic bacteria to secrete their virulence factors to invade the host cells. They can be classified into different types based on their specific structure, composition and activity. Generally, proteins can be secreted through two different processes. One process is a one-step mechanism in which proteins from the cytoplasm of bacteria are transported and delivered directly through the cell membrane into the host cell. Another involves a two-step activity in which the proteins are first transported out of the inner cell membrane, then deposited in the periplasm, and finally through the outer cell membrane into the host cell.

<span class="mw-page-title-main">Pho regulon</span>

The Phosphate (Pho) regulon is a regulatory mechanism used for the conservation and management of inorganic phosphate within the cell. It was first discovered in Escherichia coli as an operating system for the bacterial strain, and was later identified in other species. The Pho system is composed of various components including extracellular enzymes and transporters that are capable of phosphate assimilation in addition to extracting inorganic phosphate from organic sources. This is an essential process since phosphate plays an important role in cellular membranes, genetic expression, and metabolism within the cell. Under low nutrient availability, the Pho regulon helps the cell survive and thrive despite a depletion of phosphate within the environment. When this occurs, phosphate starvation-inducible (psi) genes activate other proteins that aid in the transport of inorganic phosphate.

References

  1. Yates SP, Taylor PL, Jørgensen R, Ferraris D, Zhang J, Andersen GR, Merrill AR (February 2005). "Structure-function analysis of water-soluble inhibitors of the catalytic domain of exotoxin A from Pseudomonas aeruginosa". The Biochemical Journal. 385 (Pt 3): 667–75. doi:10.1042/BJ20041480. PMC   1134741 . PMID   15458385.
  2. Jørgensen R, Purdy AE, Fieldhouse RJ, Kimber MS, Bartlett DH, Merrill AR (April 2008). "Cholix toxin, a novel ADP-ribosylating factor from Vibrio cholerae". The Journal of Biological Chemistry. 283 (16): 10671–8. doi: 10.1074/jbc.M710008200 . PMID   18276581.
  3. Yates SP, Merrill AR (May 2004). "Elucidation of eukaryotic elongation factor-2 contact sites within the catalytic domain of Pseudomonas aeruginosa exotoxin A". The Biochemical Journal. 379 (Pt 3): 563–72. doi:10.1042/BJ20031731. PMC   1224111 . PMID   14733615.
  4. Hafkemeyer P, Brinkmann U, Brinkmann E, Pastan I, Blum HE, Baumert TF (May 2008). "Pseudomonas exotoxin antisense RNA selectively kills hepatitis B virus infected cells". World Journal of Gastroenterology. 14 (18): 2810–7. doi: 10.3748/wjg.14.2810 . PMC   2710720 . PMID   18473403.
  5. Stuckey DW, Hingtgen SD, Karakas N, Rich BE, Shah K (February 2015). "Engineering toxin-resistant therapeutic stem cells to treat brain tumors". Stem Cells. 33 (2): 589–600. doi:10.1002/stem.1874. PMC   4305025 . PMID   25346520.