Editing Botulinum toxin (section)

==Mechanism of action==
[[File:Presynaptic CNTs targets.svg|thumb|right|425px|Target molecules of botulinum neurotoxin (abbreviated ''BoNT'') and [[Tetanospasmin|tetanus neurotoxin]] (''TeNT''), toxins acting inside the axon terminal<ref name=Barr2005>{{cite journal |vauthors = Barr JR, Moura H, Boyer AE, Woolfitt AR, Kalb SR, Pavlopoulos A, McWilliams LG, Schmidt JG, Martinez RA, Ashley DL |title = Botulinum neurotoxin detection and differentiation by mass spectrometry |journal = Emerging Infectious Diseases |volume = 11 |issue = 10 |pages = 1578–1583 |date = October 2005 |pmid = 16318699 |pmc = 3366733 |doi = 10.3201/eid1110.041279 }}</ref>]]

Botulinum toxin exerts its effect by cleaving key proteins required for nerve activation. First, the toxin binds specifically to presynaptic surface of [[cholinergic neuron|neurons]] that use the neurotransmitter [[acetylcholine]]. Once bound to the nerve terminal, the neuron [[endocytosis|takes up]] the toxin into a [[vesicle (biology and chemistry)|vesicle]] by receptor-mediated [[endocytosis]].<ref name=Dressler05>{{cite journal |vauthors = Dressler D, Saberi FA, Barbosa ER |title = Botulinum toxin: mechanisms of action |journal = Arquivos de Neuro-Psiquiatria |volume = 63 |issue = 1 |pages = 180–185 |date = March 2005 |pmid = 15830090 |doi = 10.1159/000083259 |s2cid = 16307223 |title-link = doi |doi-access = free }}</ref> As the vesicle moves farther into the cell, it acidifies, activating a portion of the toxin that triggers it to push across the vesicle membrane and into the cell [[cytoplasm]].<ref name=Montecucco2005/> Botulinum neurotoxins recognize distinct classes of receptors simultaneously ([[ganglioside]]s, [[synaptotagmin]] and [[Atypical SLCs|SV2]]).<ref name="pmid30388027">{{cite journal |vauthors = Dong M, Masuyer G, Stenmark P |title = Botulinum and Tetanus Neurotoxins |journal = Annual Review of Biochemistry |volume = 88 |issue = 1 |pages = 811–837 |date = June 2019 |pmid = 30388027 |pmc = 7539302 |doi = 10.1146/annurev-biochem-013118-111654 }}</ref> Once inside the cytoplasm, the toxin cleaves [[SNARE (protein)|SNARE proteins]] (proteins that mediate vesicle fusion, with their target membrane bound compartments) meaning that the acetylcholine vesicles cannot bind to the intracellular cell membrane,<ref name=Dressler05/> preventing the cell from releasing vesicles of neurotransmitter. This stops nerve signaling, leading to [[flaccid paralysis]].<ref name=Montecucco2005/><ref name="pmid30388027" />

The toxin itself is released from the bacterium as a single chain, then becomes activated when cleaved by its own proteases.<ref name="Primary"/> The active form consists of a two-chain [[protein]] composed of a 100-[[dalton (unit)|kDa]] heavy chain [[polypeptide]] joined via [[disulfide bond]] to a 50-kDa light chain polypeptide.<ref name=Bowlin11/> The heavy chain contains domains with several functions; it has the domain responsible for binding specifically to [[synapse|presynaptic]] nerve terminals, as well as the domain responsible for mediating translocation of the light chain into the cell cytoplasm as the vacuole acidifies.<ref name=Montecucco2005/><ref name=Bowlin11/> The light chain is a M27-family zinc [[metalloprotease]] and is the active part of the toxin. It is translocated into the host cell cytoplasm where it cleaves the host protein [[SNAP-25]], a member of the SNARE protein family, which is responsible for [[vesicle fusion|fusion]]. The cleaved SNAP-25 cannot mediate fusion of vesicles with the host cell membrane, thus preventing the release of the [[neurotransmitter]] acetylcholine from axon endings.<ref name=Montecucco2005/> This blockage is slowly reversed as the toxin loses activity and the SNARE proteins are slowly regenerated by the affected cell.<ref name=Montecucco2005/>

The seven toxin serotypes (A–G) are traditionally separated by their antigenicity. They have different tertiary structures and sequence differences.<ref name=Bowlin11/><ref name="Genetic Diversity">{{cite book |vauthors = Hill KK, Smith TJ |title = Botulinum Neurotoxins |chapter = Genetic diversity within Clostridium botulinum serotypes, botulinum neurotoxin gene clusters and toxin subtypes |series = Current Topics in Microbiology and Immunology |volume = 364 |pages = 1–20 |date = 2013 |pmid = 23239346 |doi = 10.1007/978-3-642-33570-9_1 |publisher = Springer |isbn = 978-3-642-33569-3 |veditors = Rummel A, Binz T }}</ref> While the different toxin types all target members of the SNARE family, different toxin types target different SNARE family members.<ref name=Barr2005/> The A, B, and E serotypes cause human botulism, with the activities of types A and B enduring longest ''in vivo'' (from several weeks to months).<ref name=Bowlin11/> Existing toxin types can recombine to create "hybrid" (mosaic, chimeric) types. Examples include BoNT/CD, BoNT/DC, and BoNT/FA, with the first letter indicating the light chain type and the latter indicating the heavy chain type.<ref name="pmid30347838">{{cite journal |vauthors = Davies JR, Liu SM, Acharya KR |title = Variations in the Botulinum Neurotoxin Binding Domain and the Potential for Novel Therapeutics |journal = Toxins |volume = 10 |issue = 10 |pages = 421 |date = October 2018 |pmid = 30347838 |pmc = 6215321 |doi = 10.3390/toxins10100421 |doi-access = free |title-link = doi }}</ref> BoNT/FA received considerable attention under the name "BoNT/H", as it was mistakenly thought it could not be neutralized by any existing antitoxin.<ref name=BotH/>

Botulinum toxins are closely related to [[tetanus toxin]]. The two are collectively known as [[Clostridium neurotoxins|''Clostridium'' neurotoxins]] and the light chain is classified by [[MEROPS]] as family M27.<ref>{{cite web |url = https://www.ebi.ac.uk/merops/cgi-bin/famsum?family=M27 |title = Family M27 |work = MEROPS Peptidase Database }}</ref> ''Clostridium'' neurotoxins belong in the wider family of [[AB toxin]]s, which also includes  [[Anthrax toxin]] and [[Diphtheria toxin]]. Nonclassical types include BoNT/X ({{UniProt|P0DPK1}}), which is toxic in mice and possibly in humans;<ref name=BotX/> a BoNT/J ({{UniProt|A0A242DI27}}) found in cow ''[[Enterococcus]]'';<ref>{{cite journal |vauthors = Brunt J, Carter AT, Stringer SC, Peck MW |title = Identification of a novel botulinum neurotoxin gene cluster in Enterococcus |journal = FEBS Letters |volume = 592 |issue = 3 |pages = 310–317 |date = February 2018 |pmid = 29323697 |pmc = 5838542 |doi = 10.1002/1873-3468.12969 |doi-access = free |title-link = doi }}</ref> and a BoNT/Wo ({{UniProt|A0A069CUU9}}) found in the rice-colonizing ''[[Weissella oryzae]]''.<ref name="pmid30347838"/>