dies. The diphtheria toxin has the same mechanism of action as the enzyme NAD(+)—diphthamide ADP-ribosyltransferase (). It catalyzes the ADP ribosylation of the unusual amino acid diphthamide in eEF-2 by transferring the ADP-ribosyl group from NAD+. The ADP ribosylation of diphthamide inactivates the eEF-2 protein, thus, inhibiting the translation of mRNA. The catalysed reaction is as follows: NAD+ + peptide diphthamide nicotinamide + peptide N-(ADP-D-ribosyl)diphthamide. 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. Annotations References External links Hepatotoxins Protein domains Peripheral membrane proteins Bacterial toxins Toxin Protein synthesis inhibitors