Toxicity of botulinum toxin type A (botA)

Stable Identifier
R-HSA-5250968
Type
Pathway
Species
Homo sapiens
Related Species
Clostridium botulinum
ReviewStatus
5/5
Locations in the PathwayBrowser
Expand all
General
SVG | 
PNG
Low
Medium
High
 | PPTX  | SBGN
Toxicity of botulinum toxin type A (botA)
Click the image above or here to open this pathway in the Pathway Browser
Botulinum toxin type A (botA, also known as BoNT/A), a disulfide bonded heavy chain (HC) - light chain (LC) heterodimer ("dichain"), enters the gut typically as a result of consuming contaminated food (Hatheway 1995), as a complex with nontoxic nonhemagglutinin protein (NTNHA, encoded by the C. botulinum ntnha gene) and multiple copies of three hemagglutinin proteins (HA, encoded by the C. botulinum ha17, ha34, and ha70 genes) (Lee et al. 2013). The complex protects the toxin from degradation in the gut and mediates its association with the gut epithelium and transcytosis to enter the circulation. Recent studies in vitro raise the possibility that the toxin may also directly disrupt the basolateral membrane of the gut epithelium (Fujinaga et al. 2013). Circulating toxin molecules associate with gangliosides and synaptic vesicle protein 2 (SV2) exposed by exocytosis at a synapse of a target neuron in the neuromuscular junction (Yowler & Schengrund 2004; Dong et al. 2006). Vesicle recycling brings the toxin into the neuron where the vesicle is acidified (Sudhoff 2004). The lowered pH induces a conformational change in the toxin: its HC forms a passage in the vesicle membrane through which its LC is extruded into the neuronal cytosol and released by reduction of the HC - LC disulfide bond (Montal 2010). The cytosolic LC then catalyzes the cleavage of synaptosomal associated protein 25 (SNAP25) on the cytosolic face of the neuronal plasma membrane (Binz et al. 1994; Schiavo et al. 1993), thereby inhibiting synaptic vesicle fusion with the plasma membrane and exocytosis.
Literature References
PubMed ID Title Journal Year
23239348 Uptake of botulinum neurotoxin in the intestine

Fujinaga, Y, Sugawara, Y, Matsumura, T

Curr. Top. Microbiol. Immunol. 2013
16543415 SV2 is the protein receptor for botulinum neurotoxin A

Dong, M, Yeh, F, Tepp, WH, Dean, C, Johnson, EA, Janz, R, Chapman, ER

Science 2006
20233039 Botulinum neurotoxin: a marvel of protein design

Montal, M

Annu. Rev. Biochem. 2010
15514477 Glycosphingolipids-sweets for botulinum neurotoxin

Yowler, BC, Schengrund, CL

Glycoconj. J. 2004
8243676 Botulinum neurotoxins serotypes A and E cleave SNAP-25 at distinct COOH-terminal peptide bonds

Schiavo, G, Santucci, A, DasGupta, BR, Mehta, PP, Jontes, J, Benfenati, F, Wilson, MC, Montecucco, C

FEBS Lett 1993
15217342 The synaptic vesicle cycle

Südhof, TC

Annu Rev Neurosci 2004
8542759 Botulism: the present status of the disease

Hatheway, CL

Curr. Top. Microbiol. Immunol. 1995
24130488 Structure of a bimodular botulinum neurotoxin complex provides insights into its oral toxicity

Lee, K, Gu, S, Jin, L, Le, TT, Cheng, LW, Strotmeier, J, Kruel, AM, Yao, G, Perry, K, Rummel, A, Jin, R

PLoS Pathog. 2013
8294407 Proteolysis of SNAP-25 by types E and A botulinal neurotoxins

Binz, T, Blasi, J, Yamasaki, S, Baumeister, A, Link, E, Südhof, TC, Jahn, R, Niemann, H

J Biol Chem 1994
Participants
Events
Participates
as an event of
Disease
Name Identifier Synonyms
botulism DOID:11976 Botulism (disorder), Intoxication with Clostridium botulinum toxin, Botulism, Infection due to clostridium botulinum, Botulism, Foodborne botulism, botulism, Botulism, Botulism, Botulism, Food poisoning due to Clostridium botulinum, Botulism poisoning
Cross References
Mondo
Authored
Krupa, S  (2006-06-15)
Gopinathrao, G  (2006-06-15)
Reviewed
Ichtchenko, K  (2007-08-03)
Thirunavukkarasu, N  (2014-11-18)
Sharma, S  (2014-11-18)
Created
D'Eustachio, P  (2014-02-01)
Cite Us!