Diphtheria toxin

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^{[annotation 1]} called corynephage β.^[1][2] The toxin causes the disease in humans by gaining entry into the cell cytoplasm and inhibiting protein synthesis.^[3]

Structure

Diphtheria toxin is a single

• The
  ADP-ribose from NAD to a diphthamide residue of eukaryotic elongation factor 2 (eEF-2).^[7][3]
• A central translocation domain, known as the T domain or TM domain, has a multi-helical
  endosomal membrane and facilitates the transfer of the C domain into the cytoplasm.^[7][3]
• A
  cell surface receptor, permitting the toxin to enter the cell by receptor-mediated endocytosis.^[7][3]

The diphtheria toxin has the same mechanism of action as the enzyme

NAD⁺ + peptide diphthamide ${\displaystyle \rightleftharpoons }$ nicotinamide + peptide N-(ADP-D-ribosyl)diphthamide.

The exotoxin A of Pseudomonas aeruginosa uses a similar mechanism of action.

The steps involved in generating toxicity are as follows:^{[citation needed]}

1. Processing
   1. The leader region is cleaved during secretion.
   2. Proteolytic nicking separates A and B subunits, which remain joined by disulfide bonds until they reach the cytosol.
2. The toxin binds to heparin-binding epidermal growth factor precursor (
   HB-EGF).^[9]
   ^: 116
3. The complex undergoes endocytosis by the host cell.
4. Acidification inside the endosome induces translocation of the A subunit into the cytosol.
   1. Disulfide bonds are broken.
   2. The B subunit remains in the endosome as a pore.
5. The A subunit ADP-ribosylates host eEF-2, which is required for protein synthesis; when it is inactivated, the host cannot make protein and thus dies.

Lethal dose and effects

Diphtheria toxin is extraordinarily potent.^[4] The lethal dose for humans is about 0.1 μg of toxin per kg of body weight. Death occurs through necrosis of the heart and liver.^[10] Diphtheria toxin has also been associated with the development of myocarditis. Myocarditis secondary to diphtheria toxin is considered one of the biggest risks to unimmunized children.

History

Diphtheria toxin was discovered in 1888 by

Similar to other A-B toxins, diphtheria toxin is adept at transporting exogenous proteins across mammalian cell membranes, which are usually impermeable to large proteins. This unique ability can be repurposed to deliver therapeutic proteins, instead of the catalytic domain of the toxin.[16]^[17]

This toxin has also been used in neuroscientific and cancer research to ablate specific populations of cells which express the diphtheria toxin receptor (heparin-binding EGF-like growth factor). Administration of the toxin into the organism which does not naturally express this receptor (e.g. mice) will result in the selective ablation of the cell population which do express it.^[18][19]

Annotations

References