Diphtheria toxin consists of a single polypeptide. Proteolysis yields two fragments (A and B) which are held together by a disulfide bond. The toxin binds to EGF-like domain of Heparin-binding EGF-like growth factor (HB-EGF) through fragment B and is internalized with HB-EGF by receptor-mediated endocytosis.
The low pH in the late endosomes induce pore formation by fragment B as well as catalyses the release of catalytic fragment A into the cytosol. Diphtheria toxin catalyzes the ADP-ribosylation of, and inactivates, the elongation factor eEF-2. In this way, it acts to inhibit translation during eukaryotic protein synthesis. The toxin enters the host cell and is hydrolysed by a trypsin-like protease to give a fragment with enzymatic activity.
The toxin then transfers an ADP-ribose from NAD+ to a diphthamide residue, a modified histidine (amino acid), which is found within the EF-2 protein. EF-2 is needed for translocation of tRNA from the A-site to the P-site of the ribosome during translation. The ADP-ribosylation is reversible by administering high concentrations of nicotinamide, one of the reaction products.
Diphtheria toxin is only produced by C. diphtheriae when it is infected with a bacteriophage. The bacteriophage integrates a gene into the bacteria that causes the toxin to be produced.
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