Sandbox WWC1

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Looking great! You need to add something interactive with your structure. Perhaps feature the consensus sequence, or the heavy and light chains?

You need to format your references a little differently. I prefer that you use the PMID (Pubmed ID) whenever possible. This allows a user to have the paper one click away. Your citations should be placed outside the sentence, like this.[1] By naming the reference as I have, if you use it again, you only need to insert that name.[1]

I have additional comments that are easier to show on paper. I will scan the comments and send the to you, or give them to you during lab tomorrow.'

Leah, the problem with the references was that you were missing a ">" and instead had a period behind the name of one of your references.

Contents

Background

Botulinum Toxin (BTX) is produced by three species of obligate anaerobe bacterium, primarily Clostridium botulism, but Clostridium baratii and Clostridium butyricum also produce the protein. [2] [1] [3] Clostridium botulism is commonly found in soil, marine sediments, and the gut of grazing animals. [4] [5] [6] [7] [8] BTX is only produced by these bacteria under anaerobic conditions that induce spore germination. Once produced, the protein can have toxic effects on animals and humans by causing botulism, a potentially fatal illness.

Botulinum Toxin Neurotoxin Serotype A

Drag the structure with the mouse to rotate

Structure

There are seven forms of the BTX protein, named A through G, that are structurally similar but elicit different immune responses. [9] All seven polypeptides are produced as an inactive chain in the bacterium, but is activated when a protease cleaves the protein into a heavy and light chain connected by a single disulfide bond. The heavy chain is approximately 100 kDa and the light chain is 50 kDa (for reviews about structure see references). [10] [11] [12] [13] [8]

The light chain contains the that codes for the binding of zinc, which subsequently regulates the endopeptidase activity of the light chain.

BTX also has two auxiliary proteins that compromise a multimeric complex: hemagglutinins (HA) and nontoxic-nonhemagglutinin (NTNH). HA and NTNH do not directly play a role in the toxic effect of BTX, but have an indirect role during ingestion of the protein by making the BTX more resistant to low pH environments and proteolytic enzymes found in the gut. [14]

Function

The active form of BTX has three functional domains responsible for binding, translocation, and catalysis. [15] The C terminal of the heavy chain is responsible for binding a ganglioside and protein receptors on the nerve terminal while the N terminal half functions by translocating the protein across the membrane by signaling endocytosis. [16] Once in a vesicle in the cytosol of a nerve terminal, the light chain dissociates from the heavy chain and cleaves SNARE proteins involved in synaptic vesicle fusion. The cleavage of these SNARE proteins, VAMP, SNAP-25, and syntaxin, depends on the serotype of BTX where each serotype cuts at a different place. The cleaved SNAREs inhibit the binding of vesicles containing acetylcholine which effectively stops the signaling from nerves to muscle cells, resulting in paralysis. [13]

Disease

Of the seven serotypes of BTX, the forms that most often cause botulism in humans are A, B, and E. [3] Humans can be exposed to the neurotoxin through inhalation, ingestion, or surface wounds. The lethal doses for a human weighing 70 kg is 0.09-0.15 μg when administered intravenously or intramuscularly, 0.70 - 0.90 μg through inhalation, and 70 μg orally. [17] [18] Within 12 to 72 hours of exposure to BTX, the inhibition of acetylcholine signaling at nerve synapses creates symptoms of vomiting, nausea, diarrhea, blurred vision, ptosis, dysarthria and dysphagia, and finally weakness of muscles beginning with the head and moving down to the lower extremities. [19] If not treated, BTX can cause death due to respiratory failure or due to complications when on prolonged medical ventilation.

The treatment for human exposure to BTX is an antitoxin developed from horse plasma. Horses are exposed naturally to Clostridium botulism in their gut and therefore produce antibodies against Clostridium botulism to prevent the bacteria population from growing to an extreme. [20] Antitoxins have been developed by isolating this antibody from horses, and in some cases, removing the Fc from the immunoglobulin and leaving the F(ab')2 fragment. By removing the Fc fragment, the incidence of hypersensitivity and anaphylaxis are reduced. There are divalent, trivalent, and heptavalent antitoxins available that treat botulinum serotypes A and B (divalent), serotypes A, B, and C (trivalent), and all seven serotypes (heptavalent). An antitoxin, botulism immune globulin (BabyBIG) has also been developed that can be used in infantile cases of botulism. BabyBIG is produced by using the human antibodies produced when a person is injected with pentavalent botulinum toxoid vaccine. By using human antibodies, there is less of a risk of anaphylactic shock and hypersensitivity to equine antigens. [21]

The antitoxins cannot stop BTX from inhibiting acetylcholine signaling once it has started in parts of the body, but it can stop the progression of paralysis. Thus, treatment can decrease fatalities to 5-10% if administered within 24 hours of exposure. [22]

Relevance

Due to the powerful toxicity of BTX, the protein could be used as a biological weapon. The countries that have developed BTX to be used in warfare include Japan, Germany, United States, Russia, and Iraq. [23]

BTX has also been used medically and cosmetically as Botox. Various disorders characterized by involuntary muscle contraction can be treated with a small injection of BTX to weaken the spastic muscles for three to four months. [24] Some of these diseases include cervical dystonia, blepharospasm, strabismus, chronic migraines, primary axillary hyperhidrosis, oesophageal achalasia, vaginismus, and detrusor overactivity among others.

Botulinum toxin is also used in small quantities to prevent the formation of wrinkles. Small muscles in the face create wrinkles after years of repeated contraction. [25] By injecting botulinum toxin into specific muscles, contraction is inhibited and wrinkles are prevented. Continual injections are needed every few weeks because the SNAP-25 proteins regenerate allowing signaling for muscle contraction to begin again.

References

  1. ↑ 1.0 1.1 1.2 Aureli P, Fenicia L, Pasolini B, Gianfranceschi M, McCroskey LM, Hatheway CL. Two cases of type E infant botulism caused by neurotoxigenic Clostridium butyricum in Italy. J Infect Dis. 1986 Aug;154(2):207-11. PMID:3722863
  2. ↑ Hall JD, McCroskey LM, Pincomb BJ, Hatheway CL. Isolation of an organism resembling Clostridium barati which produces type F botulinal toxin from an infant with botulism. J Clin Microbiol. 1985 Apr;21(4):654-5. PMID:3988908
  3. ↑ 3.0 3.1 Arnon SS, Schechter R, Inglesby TV, Henderson DA, Bartlett JG, Ascher MS, Eitzen E, Fine AD, Hauer J, Layton M, Lillibridge S, Osterholm MT, O'Toole T, Parker G, Perl TM, Russell PK, Swerdlow DL, Tonat K. Botulinum toxin as a biological weapon: medical and public health management. JAMA. 2001 Feb 28;285(8):1059-70. PMID:11209178
  4. ↑ Ward BQ, Carroll BJ, Garrett ES, Reese GB. Survey of the U.S. Gulf Coast for the presence of Clostridium botulinum. Appl Microbiol. 1967 May;15(3):629-36. PMID:5340653
  5. ↑ Smith LD. The occurrence of Clostridium botulinum and Clostridium tetani in the soil of the United States. Health Lab Sci. 1978 Apr;15(2):74-80. PMID:355208
  6. ↑ Sugiyama H. Clostridium botulinum neurotoxin. Microbiol Rev. 1980;44:419–448. 28. Dodds KL. Clostridium botulinum in the environment. In: Hauschild AHW
  7. ↑ Dodds KL, eds. Clostridium botulinum—Ecology and Control in Foods. New York, NY: Marcel Dekker, Inc; 1992: 21–51. 29.
  8. ↑ 8.0 8.1 Popoff MR. Ecology of neurotoxigenic strains of clostridia. Curr Top Microbiol Immunol. 1995;195:1-29. PMID:8542750
  9. ↑ Hatheway cL. Clostridium botulinum and other clostridia that produce botulinum neurotoxins. in: Hauschild aHW, Dodds kL, eds. Clostridium botulinum—Ecology and Control in Foods. new york, ny: marcel Dekker, inc; 1992: 3–10
  10. ↑ Sakaguchi G. 1983. Clostridium botulinum toxins. Pharmacol. Ther. 19:165– 94.
  11. ↑ Minton NP. Molecular genetics of clostridial neurotoxins. Curr Top Microbiol Immunol. 1995;195:161-94. PMID:8542753
  12. ↑ Oguma K, Fujinaga Y, Inoue K. 1995.Structure and function of Clostridium botulinum toxins. Microbiol. Immunol. 39:161–68
  13. ↑ 13.0 13.1 Lacy DB, Stevens RC. Sequence homology and structural analysis of the clostridial neurotoxins. J Mol Biol. 1999 Sep 3;291(5):1091-104. PMID:10518945 doi:http://dx.doi.org/10.1006/jmbi.1999.2945
  14. ↑ Simpson LL. Identification of the major steps in botulinum toxin action. Annu Rev Pharmacol Toxicol. 2004;44:167-93. PMID:14744243 doi:http://dx.doi.org/10.1146/annurev.pharmtox.44.101802.121554
  15. ↑ Montecucco C, Schiavo G. Structure and function of tetanus and botulinum neurotoxins. Q Rev Biophys. 1995 Nov;28(4):423-72. PMID:8771234
  16. ↑ Dolly JO, Black J, Williams RS, Melling J. Acceptors for botulinum neurotoxin reside on motor nerve terminals and mediate its internalization. Nature. 1984 Feb 2-8;307(5950):457-60. PMID:6694738
  17. ↑  Franz DR, Pitt LM, Clayton MA, Hanes MA, Rose KJ. Efficacy of prophylactic and therapeutic administration of antitoxin for inhalation botulism. In: DasGupta BR, ed. Botulinum and Tetanus Neurotoxins: Neurotransmission and Biomedical Aspects. New York, NY: Plenum Press; 1993:473-476.
  18. ↑ Herrero BA, Ecklung AE, Streett CS, Ford DF, King JK. Experimental botulism in monkeys--a clinical pathological study. Exp Mol Pathol. 1967 Feb;6(1):84-95. PMID:4960839
  19. ↑ Dembek, Z. F.; Smith, L. A.; Rusnak, J. Botulinum Toxin. In Medical Aspects of Biological Warfare; 2007.
  20. ↑ Dembek, Z. F.; Smith, L. A.; Rusnak, J. Botulinum Toxin. In Medical Aspects of Biological Warfare; 2007.
  21. ↑ Dembek, Z. F.; Smith, L. A.; Rusnak, J. Botulinum Toxin. In Medical Aspects of Biological Warfare; 2007.
  22. ↑ Dembek, Z. F.; Smith, L. A.; Rusnak, J. Botulinum Toxin. In Medical Aspects of Biological Warfare; 2007.
  23. ↑ Dembek, Z. F.; Smith, L. A.; Rusnak, J. Botulinum Toxin. In Medical Aspects of Biological Warfare; 2007.
  24. ↑ Nayyar P, Kumar P, Nayyar PV, Singh A. BOTOX: Broadening the Horizon of Dentistry. J Clin Diagn Res. 2014 Dec;8(12):ZE25-9. doi: 10.7860/JCDR/2014/11624.5341. Epub , 2014 Dec 5. PMID:25654058 doi:http://dx.doi.org/10.7860/JCDR/2014/11624.5341
  25. ↑ Botulinum Toxin Injection for Facial Wrinkles - American Family Physician http://www.aafp.org/afp/2014/0801/p168.html#sec-1 (accessed Apr 28, 2016).
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