Diphtheria toxin

Diphtheria toxin is an exotoxin secreted by "Corynebacterium", 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.
Structure.
Diphtheria toxin is a single polypeptide chain of 535 amino acids consisting of two subunits linked by disulfide bridges, known as an A-B toxin. Binding to the cell surface of the B subunit (the less stable of the two subunits) allows the A subunit (the more stable part of the protein) to penetrate the host cell.
The crystal structure of the diphtheria toxin homodimer has been determined to 2.5 Ångstrom resolution. The structure reveals a Y-shaped molecule consisting of three domains. Fragment A contains the catalytic C domain, and fragment B consists of the T and R domains:
Mechanism.
The diphtheria toxin has the same mechanism of action as the enzyme NAD(+)—diphthamide ADP-ribosyltransferase (). It catalyzes the transfer of NAD+ to a diphthamide residue in eEF-2, inactivating this protein. It does so by ADP-ribosylating the unusual amino acid diphthamide. In this way, it acts as an RNA translational inhibitor. The catalysed reaction is as follows:
The exotoxin A of "Pseudomonas aeruginosa" uses a similar mechanism of action.
Lethal dose and effects.
Diphtheria toxin is extraordinarily potent. 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. 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 Émile Roux and Alexandre Yersin. In 1890, Emil Adolf von Behring developed an anti-toxin based on the blood of horses immunized with attenuated bacteria. In 1951, Freeman found that the toxin gene was not encoded on the bacterial chromosome, but by a lysogenic phage (corynephage β) infecting all toxigenic strains.
Clinical use.
The drug denileukin diftitox uses diphtheria toxin as an antineoplastic agent.
Resimmune is an immunotoxin that is in clinical trials in cutaneous T cell lymphoma patients. It uses diphtheria toxin (truncated by the cell binding domain) coupled to an antibody to CD3ε (UCHT1).
Research.
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.
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.