Neurotoxicity of clostridium toxins (Homo sapiens)

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6, 105, 9, 11, 146, 12, 175, 9, 11, 144, 13, 16, 181, 7, 204, 13, 16, 182, 8, 15, 19935, 9, 11, 14204, 13, 16, 18Activated BoNT bound to invaginated membrane BoNT Light chain Type E GangliosidesSynaptotagmin Synaptotagmins BoNT Heavy Chain BoNT Light chain Type G BoNT Light Chain BoNT Heavy Chain BoNT Light chain Type C1 BoNT Heavy Chain with inserted N-terminal BoNT Light chain Type D BoNT Light chain Type F GangliosidesSynaptogamin BoNT with conformational change in Heavy chain N-terminal BoNT Light chain Type A BoNT Light Chain BoNT Light chain Type F BoNT Light chain Type E BoNT Light chain Type A Synaptotagmins BoNT Light chain Type A BoNT Light chain Type B BoNT Light chain Type E BoNT Light Chain GangliosidesSynaptogamin Activated BoNT bound to membrane receptor BoNT Light chain Type C BoNT Light chain Type D BoNT Light chain Type B Synaptotagmins BoNT with Heavy chain N-terminal inserted into endosomal membrane BoNT Light chain Type C BoNT Light chain Type D BoNT Light chain Type A BoNT Light chain Type B BoNT Light chain Type F BoNT Light chain Type F GangliosidesSynaptogamin BoNT Light chain Type E Activated BoNT BoNT Light Chain GangliosidesSynaptotagmin BoNT Light chain Type D BoNT Light chain Type G BoNT Light chain Type C BoNT Light chain Type B endocytic vesicleBoNT Light chain Type F BoNT Light chain Type G cytosolBoNT bound to membrane receptor BoNT Light chain Type B BoNT Light chain Type E BoNT Light chain Type C BoNT Light chain Type D BoNT Heavy Chain BoNT Light chain Type D BoNT Light chain Type A internalized BoNT BoNT Light chain Type C BoNT Light chain Type A BoNT Light Chain Synaptotagmins Synaptotagmins BoNT Heavy Chain BoNT Light chain Type E BoNT Light chain Type B BoNT Light chain Type G BoNT Light chain Type G BoNT Light chain Type F internalized BoNTSyntaxin fragmentBoNT Light chain Type D polypeptide BoNT Light chain Type F polypeptide BoNT Light chain Type A polypeptide VAMP2BoNT Heavy chain Type E BoNT Heavy chain Type D BoNT Light chain Types A,C and ESYT2 Gangliosides VAMP2BoNT Light chain Type EBoNT Heavy chain Type C BoNT Light chain Type E polypeptide BoNT Heavy chain Type E BoNT Light chain Type F polypeptide SNAP25SYT2 BoNT Light chain Type G polypeptide BoNT Heavy chain Type D Zn2+ BoNT Light chain Type C1 polypeptide BoNT Heavy chain Type A BoNT Light chain Type C polypeptide BoNT Heavy chain Type B SYT1 BoNT Light chain Type C1BoNT Light chain Types B,D,F,GBoNT Light chain Type F polypeptide BoNT Heavy chain Type E BoNT Heavy chain Type C Zn2+ BoNT Light chain Type BBoNT Light chain Type B polypeptide BoNT Light chain Type D polypeptide SNAP25BoNT Heavy chain Type B BoNT F cleaved VAMP/SynaptobrevinBoNT Light chain Type E polypeptide BoNT Light chain Type G polypeptide BoNT D cleaved VAMP/SynaptobrevinSYT1 BoNT Light chain Type A polypeptide SYT1 BoNT Light chain Type FBoNT Light chain Type B polypeptide GangliosidesSynaptogaminBoNT Heavy chain Type G Gangliosides Activated BoNTBoNT Light chain Type B polypeptide BoNT Light chain Type D polypeptide SYT2 BoNT Heavy chain Type A BoNT Heavy chain Type F BoNT Heavy chain Type F Zn2+ Gangliosides BoNT Heavy chain Type F BoNT Heavy chain Type F Zn2+ BoNT Heavy chain Type F SNAP25BoNT Light chain Type E polypeptide Zn2+ BoNT Heavy chain Type B Gangliosides BoNT Heavy chain Type A BoNT Light chain Type DBoNT Heavy chain Type B VAMP/SynaptobrevinZn2+ BoNT Heavy chain Type G Zn2+ BoNT Light chain Type B polypeptide Zn2+ BoNT Light chain Type C polypeptide BoNT Heavy chain Type D BoNT Light chain Type C polypeptide BoNT Light chain Type C polypeptide BoNT Heavy chain Type G BoNT Heavy chain Type G SYT1 BoNT Light chain Type D polypeptide BoNT Light chain Type F polypeptide BoNT Light chain Type B polypeptide BoNT Light chain Type B polypeptide BoNT with Heavy chain N-terminal inserted into endosomal membraneZn2+ Gangliosides BoNT Light chain Type E polypeptide BoNT Light chain Type A polypeptide BoNT Heavy chain Type C BoNT Light chain Type E polypeptide BoNT Heavy chain Type C BoNT Heavy chain Type C SYT1 BoNT Heavy chain Type E BoNT Light chain Type ABoNT Heavy chain Type A BoNT Light chain Type G polypeptide BoNT Light chain Type C polypeptide SYT2 Zn2+ BoNT Heavy chain Type B BoNT Heavy chain Type E BoNT Light chain Type A polypeptide BoNT Light chain Type F polypeptide SyntaxinsZn2+ SYT2 BoNT Light chain Type C1 polypeptideBoNT Light chain Type F polypeptide BoNT Light chain Type D polypeptide BoNT Heavy chain Type D BoNT Light chain Type D polypeptide GangliosidesSynaptotagminBoNT Light chain Type G polypeptide SNAP25BoNT Light chain Type A polypeptide BoNT Heavy chain Type G BoNT Heavy chain Type D BoNT Light chain Type A polypeptide BoNT Light chain Type G polypeptide BoNT Heavy chain Type A BoNT bound to membrane receptorBoNT with conformational change in Heavy chain N-terminalBoNT Light chain Type E polypeptide


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Botulism, caused by botulinum neurotoxin (BoNT), is characterized by descending flaccid paralysis as a result of inhibition of neurotransmitter release at the neuromuscular junction - NMJ (Turton et al., 2002). According to their antigenic properties, BoNTs are classified into seven different toxin types (A, B, C1, D, E, F and G) although more than 50 sequences encoding 18 subtypes are known (Smith et al., 2005). The toxin is released as a 900 kDa complex containing some accessory proteins of unknown functions (Chen et al., 1998). The toxin types A, B and E are mainly involved in human botulism whereas C and D predominantly cause animal botulism (Poulain et al, 2006). The toxin is absorbed from the gut or other epithelium and reaches neuromuscular junctions by transcytosis (Park and Simpson, 2003). The binding sites for the toxins are distributed across the apical surface of the epithelium (Ahsan et al., 2005). It has been observed that the neurotoxin alone is capable of transcytosis across epithelial cells (Maksymowych and Simpson, 2004). Once internalized, the neurotoxin is dissociated from the non-toxic components of the progenitor toxin in endosome (Uotsu et al., 2006).
The neurological inhibition is caused by the specific cleavage of a group of proteins integral to NMJ exocytosis, SNARE proteins (soluble NSF-attachment protein receptors). One or more SNARE proteins are cleaved by BoNT, blocking the release of synaptic vesicular contents like acetylcholine as in the case of motor neurons.
BoNTs are synthesized as polypeptides of 150 kDa that are cleaved into heavy and light chains linked by a single disulfide bond. Cleavage takes place within a surface-exposed loop at the N-terminal of the Heavy chain subunit. Both bacterial and host endopeptidases can catalyze BoNT cleavage into heavy and light chains, but bacterial enzymes are thought to carry out this function in vivo.The Heavy Chain (HC) has two 50 kDa functional domains: the N-terminal translocation domain is capable of forming channels in lipid bilayers; the C-terminal ganglioside-binding domain is important for membrane binding and subsequent internalization of toxins by host neurons. The 50 kDa Light chain (LC) is a zinc-dependent endopeptidase specific for core components of neurotransmitter release complexes.
BoNT action proceeds in the following steps: binding of cleaved toxin to the target cell membrane; transcytosis from epithelial membrane to target neuromuscular junction cells; release of BoNT Light chain into the target cell cytosol; and proteolytic cleavage of target cell proteins catalyzed by the BoNT Light chain.

Original Pathway at Reactome: http://www.reactome.org/PathwayBrowser/#DB=gk_current&FOCUS_SPECIES_ID=48887&FOCUS_PATHWAY_ID=168799

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Bibliography

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101270view11:16, 1 November 2018ReactomeTeamreactome version 66
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93784view13:36, 16 August 2017ReactomeTeamreactome version 61
93317view11:20, 9 August 2017ReactomeTeamreactome version 61
87757view09:56, 25 July 2016RyanmillerOntology Term : 'disease pathway' added !
87755view09:56, 25 July 2016RyanmillerOntology Term : 'infectious disease pathway' added !
87752view09:53, 25 July 2016RyanmillerOntology Term : 'bacterial infectious disease' added !
86402view09:17, 11 July 2016ReactomeTeamreactome version 56
83321view10:46, 18 November 2015ReactomeTeamVersion54
81748view09:47, 26 August 2015ReactomeTeamVersion53
76848view08:07, 17 July 2014ReactomeTeamFixed remaining interactions
76552view11:53, 16 July 2014ReactomeTeamFixed remaining interactions
75885view09:54, 11 June 2014ReactomeTeamRe-fixing comment source
75585view10:42, 10 June 2014ReactomeTeamReactome 48 Update
74940view13:46, 8 May 2014AnweshaFixing comment source for displaying WikiPathways description
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External references

DataNodes

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NameTypeDatabase referenceComment
Activated BoNTComplexREACT_11835 (Reactome)
BoNT D cleaved VAMP/SynaptobrevinProteinREACT_11414 (Reactome)
BoNT F cleaved VAMP/SynaptobrevinProteinREACT_11808 (Reactome)
BoNT Heavy chain Type A ProteinP10845 (Uniprot-TrEMBL)
BoNT Heavy chain Type B ProteinP10844 (Uniprot-TrEMBL)
BoNT Heavy chain Type C ProteinP18640 (Uniprot-TrEMBL)
BoNT Heavy chain Type D ProteinP19321 (Uniprot-TrEMBL)
BoNT Heavy chain Type E ProteinQ00496 (Uniprot-TrEMBL)
BoNT Heavy chain Type F ProteinP30996 (Uniprot-TrEMBL)
BoNT Heavy chain Type G ProteinQ60393 (Uniprot-TrEMBL)
BoNT Light chain Type A polypeptide ProteinP10845 (Uniprot-TrEMBL)
BoNT Light chain Type AComplexREACT_11247 (Reactome)
BoNT Light chain Type B polypeptide ProteinP10844 (Uniprot-TrEMBL)
BoNT Light chain Type BComplexREACT_11746 (Reactome)
BoNT Light chain Type C polypeptide ProteinP18640 (Uniprot-TrEMBL)
BoNT Light chain Type C1 polypeptide ProteinP18640 (Uniprot-TrEMBL)
BoNT Light chain Type C1 polypeptideProteinP18640 (Uniprot-TrEMBL)
BoNT Light chain Type C1ComplexREACT_11290 (Reactome)
BoNT Light chain Type D polypeptide ProteinP19321 (Uniprot-TrEMBL)
BoNT Light chain Type DComplexREACT_11845 (Reactome)
BoNT Light chain Type E polypeptide ProteinQ00496 (Uniprot-TrEMBL)
BoNT Light chain Type EComplexREACT_11278 (Reactome)
BoNT Light chain Type F polypeptide ProteinP30996 (Uniprot-TrEMBL)
BoNT Light chain Type FComplexREACT_11984 (Reactome)
BoNT Light chain Type G polypeptide ProteinQ60393 (Uniprot-TrEMBL)
BoNT Light chain Types A,C and EComplexREACT_11662 (Reactome)
BoNT Light chain Types B,D,F,GComplexREACT_11940 (Reactome)
BoNT bound to membrane receptorComplexREACT_11594 (Reactome)
BoNT with Heavy chain N-terminal inserted into endosomal membraneComplexREACT_11623 (Reactome)
BoNT with conformational change in Heavy chain N-terminalComplexREACT_11938 (Reactome)
Gangliosides SynaptogaminComplexREACT_11246 (Reactome)
Gangliosides SynaptotagminComplexREACT_11647 (Reactome)
Gangliosides MetaboliteCHEBI:28892 (ChEBI)
SNAP25ProteinP60880 (Uniprot-TrEMBL)
SYT1 ProteinP21579 (Uniprot-TrEMBL)
SYT2 ProteinQ8N9I0 (Uniprot-TrEMBL)
Syntaxin fragmentProteinREACT_11762 (Reactome)
SyntaxinsProteinREACT_11590 (Reactome)
VAMP/SynaptobrevinProteinREACT_11688 (Reactome)
VAMP2ProteinP63027 (Uniprot-TrEMBL)
Zn2+ MetaboliteCHEBI:29105 (ChEBI)
internalized BoNTComplexREACT_11848 (Reactome)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
Activated BoNTREACT_11084 (Reactome)
BoNT Light chain Type Amim-catalysisREACT_11146 (Reactome)
BoNT Light chain Type Bmim-catalysisREACT_11165 (Reactome)
BoNT Light chain Type C1 polypeptideArrowREACT_11226 (Reactome)
BoNT Light chain Type C1mim-catalysisREACT_11130 (Reactome)
BoNT Light chain Type C1mim-catalysisREACT_11195 (Reactome)
BoNT Light chain Type Dmim-catalysisREACT_11179 (Reactome)
BoNT Light chain Type Emim-catalysisREACT_11089 (Reactome)
BoNT Light chain Type Fmim-catalysisREACT_11158 (Reactome)
BoNT Light chain Types A,C and EArrowREACT_11226 (Reactome)
BoNT Light chain Types B,D,F,GArrowREACT_11226 (Reactome)
BoNT with Heavy chain N-terminal inserted into endosomal membraneArrowREACT_11217 (Reactome)
BoNT with Heavy chain N-terminal inserted into endosomal membraneArrowREACT_11226 (Reactome)
Gangliosides SynaptogaminArrowREACT_11217 (Reactome)
Gangliosides SynaptotagminREACT_11084 (Reactome)
REACT_11084 (Reactome) Botulinum neurotoxins (BoNTs) bind to polysialogangliosides, including GT1b, GD1b and GQ1b and synaptotagmin polypeptides on the neuronal plasma membrane (Verderio et al., 2006). In the body, this dual binding may have the effect of targeting BoNTs to specific regions of the neuromuscular junction for endocytosis. Different serotypes are known to bind to different receptors: Bont/A to SV2, Bont/B and G to Syt1 and Syt2 with different affinities.
REACT_11086 (Reactome) Once BoNT molecules are bound to the host cell surface via their HC domains, they undergo transcytosis which include sorting and endocytosis into an acidic vesicular compartment within the cytosol. As a result of endocytosis, the toxin becomes resistant to neutralization by antisera. Endocytosis is temperature and energy-dependent. In the body, endocytosed BoNT molecules remain associated with the neuromuscular junction which they finally reach by transcytosis.
REACT_11089 (Reactome) BoNT Light Chain type E protein cleaves SNAP-25 protein of human SNARE complex.
REACT_11130 (Reactome) BoNT Light Chain type C1 protein cleaves SNAP-25 protein of human SNARE complex.
REACT_11131 (Reactome) The N-terminal half of the BoNT Heavy Chain undergoes conformational changes effected by endosomal pH resulting in ion channel formation (Blaustein et al., 1987). This process has been demonstrated experimentally for BoNT serotypes A and B, but all serotypes are thought to have this property (Pellizzari et al. 1999).
REACT_11146 (Reactome) BoNT Light Chain type A protein cleaves SNAP-25 protein of human SNARE complex.
REACT_11158 (Reactome) BoNT Light Chain type F protein cleaves VAMP proteins of human SNARE complex.
REACT_11165 (Reactome) BoNT Light Chain type B protein cleaves Vamp-2 protein, a member of SNARE complex.
REACT_11179 (Reactome) BoNT Light Chain type D protein cleaves VAMP proteins of human SNARE complex.
REACT_11195 (Reactome) Syntaxins are involved in the localization (docking) of both synaptic vesicles and calcium channels to the presynaptic active zone. Syntaxin 1A interacts with SNAP-25 in forming t-SNARE part of SNARE complex. BoNT Type C specifically cleaves Syntaxin 1A although a broader target spectrum is suspected.
REACT_11217 (Reactome) Acidic pH triggers a conformation change in the Heavy chain N-terminal domain leading to its insertion into the lipid bilayer and formation of a trans-membrane channel large enough to accommodate the unfolded Light chain. It has been observed that in the closely related Diptheria toxin, a 10-aa motif is critical for pore formation. Ratts et al. identified this motif in some of the virulent BoNTs (Ratts et al., 2005).
REACT_11226 (Reactome) The BoNT L chain traverses the H chain channel into the cytosol, refolds, and is released into the cytosol. The complete molecular details of cleavage of the L- H disulfide bond and L chain refolding are not yet known (Pellizzari et al.,1999). The cleavage of host proteins may require the toxins binding to specific recogntion sites as well as cleavage sites (Rossetto et al., 1994).
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