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Diphtheria toxin

Diphtheria Toxin is an exotoxin produced by the organism Corynebcterium diphtheria which has been infected by a bacteriophage that contains the Diphtheria toxin gene. The toxin is the causative agent of diphtheria. Symptoms for Diphtheria can range from a sore throat with low-grade fever and an adherent pseudomembrane of the tonsils, pharynx, or nose to infected skin lesions which lack a characteristic appearance.^[1] The toxin is distributed to distant organs by the circulatory system and may cause paralysis and congestive heart failure.^[2] The toxin attacks and kills eukaryotic cells by inactivating the Elongation factor (EF-2) in translation. EF-2 allows for translocation of the peptidyl-tRNA from the A-site to the P-site, which in turn frees the A site for another aminoacyl-tRNA to bind. By inactivating the elongation factor 2 during translation the protein being made cannot be completed and therefore becomes nonfunctional. The toxin is in a class of A-B which includes cholera toxin, Escherichia coli heat labile enterotoxin, Pseudomonas aeruginosa exotoxin A, tetanus, botulinum neurotoxins, and Shiga toxin. A-B class is characterized by two functionally distinct components such as component A is the catalytic components while component B does the receptor binding function.

History

Scientist have made efforts since at least the 1740's to find the caustion and cure for diphtheria toxin. It wasn't until Koch's devolpment of medical microbiology and Koch's postulates that it was even possible for progression towards understanding the molecular causes. It was later in Koch's laboratory that Friedrich Loeffler isolated a bacteria from a patient that died from Diphtheria toxin. Koch and Friedrich later inoculated 23 guinea pigs with the isolated bacteria and they all died in two to five days. Loeffler had another observation that only the isolated bacteria from the pigs were growing at the site of inoculation. Therefore, he came to the conclusion that the bacteria isolated was the causation of the Diphtheria toxin. In Pasture institute in Paris, both Emile Roux and Alexandre Yersin were able to isolate the toxin by growing a pure culture of Diphtheria bacilli and forcing them through a porcelain filter. This allowed to obtain no bacteria and only the toxin. The toxin was injected into laboratory animals and caused the same symptoms of Diphtheria bacilli. It wasn't until sixty-five years later that protein crystals were produced and the structure obtained. Emil von Behring published a paper with the discovery of diphtheria antitoxin one week after Koch found out the resistance gained by vaccination from Diphtheria bacilli. This lead to elimination of the disease diphtheria in developing countries.

Von Behring received a Nobel Prize for the antitoxin which later would be known as antibodies against Diphtheria toxin. The next vaccine made was one mixed of toxin and antitoxin. The antitoxin relieved the harmful effects of the toxin which was the real vaccine. This was later replaced in 1923 with a vaccine of a formaldehyde-treated Diphtheria toxin. Today in developing countries people get routine vaccinations so that diphtheria is unknown.

Structure

Diphtheria toxin is a protein made of 535 amino acids that makes up two fragments A & B. That contain C, T, and R domains that have different functions.

Mechanism

figure 3: Mechanism of inactivation of elongation factor 2 (EF2) by diphtheria toxin ^[3]

Image:Mech1.jpg

Medical Implications & Possible Application

Diphtheria toxin is the causative agent of the disease Diphtheria. The lethal dose for humans and other susceptible eukarya is .1μg of toxin per kg of body weight^[4] A vaccine has been made and is routinely used in first world countries as a basic immunization. The vaccine is made up of formaldehyde-treated Diphtheria toxin. However, Diphtheria toxin has been used is many other medical applications such as the drug Denileukin diftitox and cancer suppressors. Denileukin diftitox is a protein that combines Diphtheria toxin and Interleukin 2. In some Leukemias and Lymphomas cells express Interleukin receptors in which the drug can bind to and release the toxin within the cells.

Another application that Diphtheria toxin can be used for is a cancer suppressor. In terms of the R domain of the protein which as we know binds to pro-HB-EFG receptors of the surface of cells and is translocated into the cell by endocytosis. Some scientist have made a non-toxic mutant of diphtheria toxin CRM197 which is being used to block the signaling activity of the receptor. In some cancers such as ovarian cancer, pro-HB-EFG is overexpressed and blocking the signal has shown promise in suppressing the effects of pro-HB-EFG on cancer development.^[5] Another example, is called immunotoxins which change the R domain to recognize a specific cell surface and kill that cell. This is being tested against different cancer cell types and has been successful.

References

• Parker, M. (1996). Protein toxin structure. (1 ed., pp. 25-43). Georgetown: R.G. Landes Company.

• Stephen, J., & Pietrowski, R. (1981). Bacterial toxins. (1 ed., p. 11). Washington: Van Nostrand Reinhold Co. Ltd.

• Oram , D., & Holmes, R. (2006). Diphtheria toxin. (3 ed., pp. 245-252). Burlington, San Diego, London: Academic Press publications.

• Diphtheria toxin. (2011, November 25). Retrieved from <http://en.wikipedia.org/wiki/Diphtheria_toxin>

• Murphy JR (1996). "Corynebacterium Diphtheriae: Diphtheria Toxin Production". In Baron S et al.. Medical microbiology (4 ed.). Galveston, Texas: Univ. of Texas Medical Branch. ISBN 0-9631172-1-1.

Footnotes