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Information on EC 3.4.24.68 - tentoxilysin
for references in articles please use BRENDA:EC3.4.24.68
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EC Tree 3 Hydrolases
3.4 Acting on peptide bonds (peptidases)
3.4.24 Metalloendopeptidases
3.4.24.68 tentoxilysin
IUBMB Comments
Zinc enzyme produced by Clostridium tetani. Proenzyme of 150 kDa is processed to disulfide-linked subunits of 100 and 50 kDa, the latter being responsible for the endopeptidase activity. Weakly inhibited by captopril, and phosphoramidon. The clostridial neurotoxins disable the neuroexocytosis apparatus, and have been described as the most toxic substances known. Tentoxilysin acts at the spinal inhibitory interneurons, blocking the release of various neurotransmitters to produce spastic paralysis. Type example of peptidase family M27 (tentoxilysin family)
The expected taxonomic range for this enzyme is: Clostridium tetani
- 3.4.24.68
- synaptic
- botulinum
- toxoid
- nerve
- epitope
-
neurotransmitter
-
exocytosis
- spinal
- ganglioside
- tetany
- cord
-
clostridial
-
retrograde
-
presynaptic
- synaptobrevin
- snare
- antitoxin
- epilepsy
- neuromuscular
-
transmitter
- synapses
- diphtheria
-
excitatory
-
bonts
-
vesicle-associated
- snap-25
- syntaxin
-
postsynaptic
- paralysis
- vamp
- motoneuron
-
synaptosomes
- gt1b
-
booster
-
n-ethylmaleimide-sensitive
-
toxin-induced
-
v-snares
-
intrahippocampal
-
transsynaptic
-
phrenic
-
neuroparalytic
-
holotoxin
-
k+-evoked
-
neurospecific
-
electrograph
-
monosynaptic
-
circumsporozoite
-
synaptosome-associated
- medicine
-
interictal
-
3hnoradrenaline
Reaction Schemes
showHydrolysis of -Gln76-/-Phe- bond in synaptobrevin (also known as neuronal vesicle-associated membrane protein, VAMP)
Synonyms
tetanus toxin, tetanus neurotoxin, tetanospasmin, tent-hc, more
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SYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
FRC
Hc-TeTx
TeNT
Tentoxylysin
-
-
-
-
Tetanus neurotoxin
tetanus toxin
tetanus toxin fragment C
TetX
TTc
TeNT
-
-
Tetanus neurotoxin
-
-
-
-
Tetanus neurotoxin
-
-
tetanus toxin
-
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REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
Hydrolysis of -Gln76-/-Phe- bond in synaptobrevin (also known as neuronal vesicle-associated membrane protein, VAMP)
Hydrolysis of -Gln76-/-Phe- bond in synaptobrevin (also known as neuronal vesicle-associated membrane protein, VAMP)
structure and mechanism
-
Hydrolysis of -Gln76-/-Phe- bond in synaptobrevin (also known as neuronal vesicle-associated membrane protein, VAMP)
structure and mechanism
-
-
Hydrolysis of -Gln76-/-Phe- bond in synaptobrevin (also known as neuronal vesicle-associated membrane protein, VAMP)
-
-
-
-
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REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
hydrolysis of peptide bond
-
-
-
-
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CAS REGISTRY NUMBER
COMMENTARY
107231-12-9
-
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SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
LITERATURE
COMMENTARY
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
rat synaptobrevin 2 + H2O
?
-
Substrates: catalytic activity of all mutants
Products: -
Products: -
?
vesicle associated membrane protein 1 + H2O
?
-
Substrates: -
Products: -
Products: -
?
vesicle associated membrane protein-1 + H2O
?
-
Substrates: -
Products: -
Products: -
?
vesicle associated membrane protein-2 + H2O
?
-
Substrates: -
Products: -
Products: -
?
vesicle-associated membrane protein-2 + H2O
?
-
Substrates: neuronal SNARE protein, i.e. VAMP2
Products: -
Products: -
?
Abz-GASQ?FETSA-Q-EDDnp + H2O
Abz-GASQ + FETSA-Q-EDDnp
Substrates: the FRET substrate is composed by ortho-aminobenzoic acid (Abz) as fluorescent group and N-(2,4-dinitrophenyl)ethylenediamine (EDDnp) as quencher group. Abz is bound to the N-amino terminal of synaptobrevin (aminoacids residues 73-81) and EDDnp to the C-terminal carboxyl group: Abz-GASQFETSA-Q-EDDnp
Products: -
Products: -
?
Abz-GASQ?FETSA-Q-EDDnp + H2O
Abz-GASQ + FETSA-Q-EDDnp
Substrates: the FRET substrate is composed by ortho-aminobenzoic acid (Abz) as fluorescent group and N-(2,4-dinitrophenyl)ethylenediamine (EDDnp) as quencher group. Abz is bound to the N-amino terminal of synaptobrevin (aminoacids residues 73-81) and EDDnp to the C-terminal carboxyl group: Abz-GASQFETSA-Q-EDDnp
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?
Abz-GASQ?FETSA-Q-EDDnp + H2O
Abz-GASQ + FETSA-Q-EDDnp
Substrates: the FRET substrate is composed by ortho-aminobenzoic acid (Abz) as fluorescent group and N-(2,4-dinitrophenyl)ethylenediamine (EDDnp) as quencher group. Abz is bound to the N-amino terminal of synaptobrevin (aminoacids residues 73-81) and EDDnp to the C-terminal carboxyl group: Abz-GASQFETSA-Q-EDDnp
Products: -
Products: -
?
synaptobrevin + H2O
?
-
Substrates: tetanus neurotoxin receptors are located on the motor neuron plasmalemma at neuromuscular junction, after binding the toxin is internalized inside vesicles of unknown nature and then translocated across the vesicle membrane
Products: -
Products: -
?
synaptobrevin + H2O
?
-
Substrates: i.e. VAMP, neuronal vesicle-associated membrane protein, predominantly exposed to cytosol
Products: -
Products: -
?
synaptobrevin + H2O
?
-
Substrates: enzyme disables neuroexocytosis apparatus, acts at spinal inhibitory interneurons, blocking release of various neurotransmitters to produce spastic paralysis, clostridial neurotoxins are described as the most toxic substances known
Products: -
Products: -
?
synaptobrevin + H2O
?
-
Substrates: neurotoxin blocks neurotransmitter release in Aplysia neurons
Products: -
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?
synaptobrevin + H2O
?
-
Substrates: TeNT is a zinc metalloprotease, that is produced by anaerobically grown Clostridium tetani in infected tissue, where it binds to ganglioside receptors of peripheral nerves. TeNT is then endocytosed. The A subunit exits from the endosome and undergoes retrograde transport via the nerve axon to the spinal cord of the host, where it specifically cleaves one of the nerve cell SNARE proteins, synaptobrevin
Products: -
Products: -
?
synaptobrevin + H2O
?
-
Substrates: a host nerve cell SNARE protein, purified recombinant His-tagged synaptobrevin expressed in Escherichia coli
Products: -
Products: -
?
synaptobrevin + H2O
?
-
Substrates: enzyme disables neuroexocytosis apparatus, acts at spinal inhibitory interneurons, blocking release of various neurotransmitters to produce spastic paralysis, clostridial neurotoxins are described as the most toxic substances known
Products: -
Products: -
?
Synaptobrevin + H2O
Hydrolyzed synaptobrevin
-
Substrates: -
Products: -
Products: -
?
Synaptobrevin + H2O
Hydrolyzed synaptobrevin
-
Substrates: i.e. VAMP, neuronal vesicle-associated membrane protein, MW 19000, with 2 isoforms in human, chicken, in rat brain: synaptobrevin/VAMP-1 and synaptobrevin/VAMP-2, cleaves at Gln76-Phe77, the same site as botulin neurotoxin B
Products: -
Products: -
?
Synaptobrevin + H2O
Hydrolyzed synaptobrevin
-
Substrates: i.e. VAMP, neuronal vesicle-associated membrane protein, MW 19000, with 2 isoforms in human, chicken, in rat brain: synaptobrevin/VAMP-1 and synaptobrevin/VAMP-2, cleaves at Gln76-Phe77, the same site as botulin neurotoxin B
Products: -
Products: -
?
synaptobrevin-2 + H2O
?
-
Substrates: i.e. vesicle associated membrane protein-2, VAMP-2
Products: -
Products: -
?
synaptobrevin-2 + H2O
?
-
Substrates: i.e. vesicle associated membrane protein-2, VAMP-2, or Syb2, specific proteolytic cleavage, development of a sensitive in vitro assay method using immobilized recombinant substrate and a highly specific polyclonal antibody against the newly generated C-terminus of the product, overview
Products: -
Products: -
?
vesicle associated membrane protein + H2O
?
Substrates: -
Products: -
Products: -
?
vesicle associated membrane protein + H2O
?
-
Substrates: -
Products: -
Products: -
?
vesicle associated membrane protein + H2O
?
Clostridium tetani ATCC 10779
-
Substrates: -
Products: -
Products: -
?
vesicle associated membrane protein + H2O
?
Substrates: -
Products: -
Products: -
?
vesicle associated membrane protein 2 + H2O
?
-
Substrates: preferred substrate
Products: -
Products: -
?
vesicle associated membrane protein 2 + H2O
?
-
Substrates: -
Products: -
Products: -
?
vesicle-associated membrane protein VAMP + H2O
?
-
Substrates: L-chain highly specific for the substrate
Products: -
Products: -
?
vesicle-associated membrane protein VAMP + H2O
?
Substrates: -
Products: -
Products: -
?
vesicle-associated membrane protein VAMP + H2O
?
-
Substrates: L-chain highly specific for the substrate
Products: -
Products: -
?
additional information
?
-
-
Substrates: synaptobrevin-1 (with Val76 instead of Gln76) or short peptides containing the cleavage site of the target protein
Products: -
Products: -
?
additional information
?
-
-
Substrates: synaptobrevin-1 (with Val76 instead of Gln76) or short peptides containing the cleavage site of the target protein
Products: -
Products: -
?
additional information
?
-
-
Substrates: catalytic activity requires reduction of the single interchain disulfide bond of the neurotoxin
Products: -
Products: -
?
additional information
?
-
-
Substrates: no substrates are rat or chicken
Products: -
Products: -
?
additional information
?
-
-
Substrates: no substrates are rat or chicken
Products: -
Products: -
?
additional information
?
-
-
Substrates: most powerful known natural toxin
Products: -
Products: -
?
additional information
?
-
-
Substrates: most powerful known natural toxin
Products: -
Products: -
?
additional information
?
-
-
Substrates: most powerful known natural toxin
Products: -
Products: -
?
additional information
?
-
-
Substrates: most powerful known natural toxin, 2 carbohdrate binding sites in the Hcc-domain of tetanus neurotoxin are required for toxicity
Products: -
Products: -
?
additional information
?
-
-
Substrates: most powerful known natural toxin, acts by blocking the release of glycine from inhibitory neurons within the spinal cords
Products: -
Products: -
?
additional information
?
-
-
Substrates: tetanus neurotoxin is a potent inhibitor of neuroexocytosis. Organization and regulation of the neurotoxin gene. The gene located immediately upstream of the tetanus toxin gene, encodes a positive regulatory protein, TetR
Products: -
Products: -
?
additional information
?
-
-
Substrates: TeNT high affinity binding to neurons is mediated solely by its gangliosides, both of the W and R pockets are necessary for high affinity binding to neuronal and non-neuronal cells. Gangliosides are functional dual receptors for TeNT, overview
Products: -
Products: -
?
additional information
?
-
-
Substrates: the conformational changes of the C fragment of tetanus neurotoxin (TeNTHc) resulting from disulfide bond formation reduce the ganglioside-binding activity but do not destroy its immunogenicity as a potent vaccine candidate
Products: -
Products: -
?
additional information
?
-
Substrates: anti-THc antibodies to neutralise TeNT and inhibit the binding of the Hc domain of the tetanus toxin (THc) to ganglioside GT1b
Products: -
Products: -
-
additional information
?
-
Substrates: anti-THc antibodies to neutralise TeNT and inhibit the binding of the Hc domain of the tetanus toxin (THc) to ganglioside GT1b
Products: -
Products: -
-
additional information
?
-
-
Substrates: synaptobrevin-1 (with Val76 instead of Gln76) or short peptides containing the cleavage site of the target protein
Products: -
Products: -
?
additional information
?
-
Substrates: anti-THc antibodies to neutralise TeNT and inhibit the binding of the Hc domain of the tetanus toxin (THc) to ganglioside GT1b
Products: -
Products: -
-
additional information
?
-
-
Substrates: most powerful known natural toxin
Products: -
Products: -
?
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NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
LITERATURE
COMMENTARY
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
synaptobrevin-2 + H2O
?
-
Substrates: i.e. vesicle associated membrane protein-2, VAMP-2
Products: -
Products: -
?
vesicle associated membrane protein 1 + H2O
?
-
Substrates: -
Products: -
Products: -
?
vesicle associated membrane protein-1 + H2O
?
-
Substrates: -
Products: -
Products: -
?
vesicle associated membrane protein-2 + H2O
?
-
Substrates: -
Products: -
Products: -
?
vesicle-associated membrane protein-2 + H2O
?
-
Substrates: neuronal SNARE protein, i.e. VAMP2
Products: -
Products: -
?
synaptobrevin + H2O
?
-
Substrates: tetanus neurotoxin receptors are located on the motor neuron plasmalemma at neuromuscular junction, after binding the toxin is internalized inside vesicles of unknown nature and then translocated across the vesicle membrane
Products: -
Products: -
?
synaptobrevin + H2O
?
-
Substrates: i.e. VAMP, neuronal vesicle-associated membrane protein, predominantly exposed to cytosol
Products: -
Products: -
?
synaptobrevin + H2O
?
-
Substrates: enzyme disables neuroexocytosis apparatus, acts at spinal inhibitory interneurons, blocking release of various neurotransmitters to produce spastic paralysis, clostridial neurotoxins are described as the most toxic substances known
Products: -
Products: -
?
synaptobrevin + H2O
?
-
Substrates: neurotoxin blocks neurotransmitter release in Aplysia neurons
Products: -
Products: -
?
synaptobrevin + H2O
?
-
Substrates: TeNT is a zinc metalloprotease, that is produced by anaerobically grown Clostridium tetani in infected tissue, where it binds to ganglioside receptors of peripheral nerves. TeNT is then endocytosed. The A subunit exits from the endosome and undergoes retrograde transport via the nerve axon to the spinal cord of the host, where it specifically cleaves one of the nerve cell SNARE proteins, synaptobrevin
Products: -
Products: -
?
synaptobrevin + H2O
?
-
Substrates: enzyme disables neuroexocytosis apparatus, acts at spinal inhibitory interneurons, blocking release of various neurotransmitters to produce spastic paralysis, clostridial neurotoxins are described as the most toxic substances known
Products: -
Products: -
?
vesicle associated membrane protein + H2O
?
Substrates: -
Products: -
Products: -
?
vesicle associated membrane protein + H2O
?
-
Substrates: -
Products: -
Products: -
?
vesicle associated membrane protein + H2O
?
Clostridium tetani ATCC 10779
-
Substrates: -
Products: -
Products: -
?
vesicle associated membrane protein + H2O
?
Substrates: -
Products: -
Products: -
?
vesicle associated membrane protein 2 + H2O
?
-
Substrates: preferred substrate
Products: -
Products: -
?
vesicle associated membrane protein 2 + H2O
?
-
Substrates: -
Products: -
Products: -
?
additional information
?
-
-
Substrates: most powerful known natural toxin
Products: -
Products: -
?
additional information
?
-
-
Substrates: most powerful known natural toxin
Products: -
Products: -
?
additional information
?
-
-
Substrates: most powerful known natural toxin
Products: -
Products: -
?
additional information
?
-
-
Substrates: most powerful known natural toxin, 2 carbohdrate binding sites in the Hcc-domain of tetanus neurotoxin are required for toxicity
Products: -
Products: -
?
additional information
?
-
-
Substrates: most powerful known natural toxin, acts by blocking the release of glycine from inhibitory neurons within the spinal cords
Products: -
Products: -
?
additional information
?
-
-
Substrates: tetanus neurotoxin is a potent inhibitor of neuroexocytosis. Organization and regulation of the neurotoxin gene. The gene located immediately upstream of the tetanus toxin gene, encodes a positive regulatory protein, TetR
Products: -
Products: -
?
additional information
?
-
-
Substrates: TeNT high affinity binding to neurons is mediated solely by its gangliosides, both of the W and R pockets are necessary for high affinity binding to neuronal and non-neuronal cells. Gangliosides are functional dual receptors for TeNT, overview
Products: -
Products: -
?
additional information
?
-
-
Substrates: most powerful known natural toxin
Products: -
Products: -
?
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METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
Zinc
Zn2+
Zinc
-
1 atom zinc per molecule toxin, zinc-binding motif: His-Glu-X-X-His, nickel or cobalt can replace zinc
Zinc
-
L-chain: form of zinc-endopeptidase, 0.8-1 gatom zinc/mol toxin, bound to light or L-chain
Zn2+
crystal structure provides insight into the role of the zinc ion
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INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
Ala-Ser-Gln-Phe-Glu-Thr-Ser
-
synthetic peptide containing cleavage site of synaptobrevin, inhibits toxin action on buccal ganglion of Aplysia californica
Gln-Phe-Glu-Thr
-
synthetic peptide containing cleavage site of synaptobrevin, inhibits toxin action on buccal ganglion of Aplysia californica
additional information
-
enzyme inhibition by a cleavage site-specific antibody, overview
-
additional information
-
design, random selection, and recombinant production from phagemid in Escherichia coli of human single chain antibody fragments that inhibit tetanus toxin binding to retinoic acid pulsed human neuroblastoma cells and TeNT protease activity completely, overview
-
additional information
-
geldanamycin efficiently blocks the neurotoxic activity of the enzyme. The interchain disulfide of the enzyme can be specifically reduced by incubating the enzyme with NADPH, thioredoxin and thioredoxin reductase. Reduced enzyme is not toxic
-
additional information
-
not inhibited by botulinum antitoxin types A, C, D, E and F
-
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ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
Proteases
-
activation by rapid cleavage within an exposed loop of the single inactive MW 150000 polypeptide chain and generation of active di-chain neurotoxin
-
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SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
additional information
-
in neurotoxin-injected Aplysia neurons 4-10 molecules of L-chains are sufficient to cause blockade of neurotransmitter release with a t1/2 of 20-40 min at 20°C
additional information
-
quantitative immunoaffinity assay method development and evaluation, overview
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pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
37
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ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
-
Uniprot
brenda
-
Uniprot
brenda
-
-
-
brenda
all toxigenic strains synthesize only one type of neurotoxin
-
-
brenda
tetanus toxin is encoded on a 74082 kb plasmid containing 61 genes
SwissProt
brenda
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SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
additional information
additional information
-
effect of medium composition on the production of tetanus toxin. The highest final average yield of tetanus toxin is obtained at 9.7 mg/ml starting level of glucose and 43.5 g/l N-T Case TT as carbon and nitrogen source
brenda
additional information
upon addition of recombinant purified labeled Hc-TeTx to the culture, the protein is localized around the human NSC-34 cells, binding to the cell membranes occurs in the first 15 min after addition to the culture media
brenda
additional information
-
upon addition of recombinant purified labeled Hc-TeTx to the culture, the protein is localized around the human NSC-34 cells, binding to the cell membranes occurs in the first 15 min after addition to the culture media
-
brenda
additional information
-
upon addition of recombinant purified labeled Hc-TeTx to the culture, the protein is localized around the human NSC-34 cells, binding to the cell membranes occurs in the first 15 min after addition to the culture media
-
brenda
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LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
Highest Expressing Human Cell Lines
Cell Line LinksPlease wait a moment until the data is sorted. This message will disappear when the data is sorted.
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
evolution
malfunction
-
TeNT cleaves vesicle-associated membrane protein-2, thereby inhibiting neurotransmitter release in the central nervous system to elicit spastic paralysis
metabolism
-
the enzyme cleaves a neuronal soluble N-ethylmaleimide-sensitive attachment receptor protein, leading to the blockade of inhibitory neurotransmitter release and subsequent generalized muscular spasm
physiological function
additional information
evolution
equivalent K768, involved in light chain translocation, is conserved among the clostridial neurotoxin family of proteins as a conserved structural motif
evolution
-
equivalent K768, involved in light chain translocation, is conserved among the clostridial neurotoxin family of proteins as a conserved structural motif
-
evolution
-
equivalent K768, involved in light chain translocation, is conserved among the clostridial neurotoxin family of proteins as a conserved structural motif
-
physiological function
-
cleavage of synaptobrevin results in inhibition of release of neurotransmitters glycine and gamma-amino butyric acid from inhibitory interneurons causing spastic paralysis
physiological function
-
the enzyme undergoes binding to specific components of the basal membrane at the neuromuscular junction, is endocytosed into motor neurons and sorted to axonal signaling endosomes. Following this, the enzyme is transported to the soma of motor neurons located in the spinal cord or brainstem, and then transcytosed to inhibitory interneurons, where it blocks synaptic transmission. Enzyme-induced impairment of inhibitory input leads to hyperactivity of motor neurons, causing spastic paralysis
physiological function
-
the enzyme is the most important virulence factor that plays a key role in the pathogenicity of tetanus
physiological function
in male Wistar rats, striatal dopaminergic damage induced by 6-hydoxydopamine (6-OHDA) can be blocked by C-terminal domain of tetanus toxin (Hc-TeTx), suggesting possible therapeutic potential of Hc-TeTx in Parkinson's disease (PD). Pramipexole (PPX), a D2/D3 dopaminergic agonist, is currently used in PD treatment. Both Hc-TeTx and PPX ameliorate the motor and neurochemical deficits induced by 6-OHDA lesion, but the combination of the two drugs is not superior to each alone in treated rats, no significant advantage in combining Hc-TeTx with PPX is noted, overview
physiological function
tetanus toxin blocks the release of the inhibitory neurotransmitters in the central nervous system and causes tetanus
physiological function
the Hc domain of TeNT plays a key role in binding to neuronal gangliosides, it can recognise gangliosides, and bind to them in a dose-dependent manner
physiological function
the C-terminal domain of the heavy chain of tetanus toxin has neurotrophic properties on human motor neuron disease. The C-terminal domain of the heavy chain of tetanus toxin (Hc-TeTx) is a non-toxic fragment that binds to the cell membrane, e.g. of SMI-32 or NSC-34 cells. Hc-TeTx preserves human motoneurons from chronic excitotoxicity in an in vitro model of amyotrophic lateral sclerosis, a PI3-K/Akt signaling cascade is induced by Hc-TeTx under chronic excitotoxicity. Hc-TeTx can rescue cerebellar granule neurons from apoptotic cell death caused by potassium deprivation and MPP+ toxicity, molecular mechanisms and modelling of chronic excitotoxicity, overview
physiological function
-
in male Wistar rats, striatal dopaminergic damage induced by 6-hydoxydopamine (6-OHDA) can be blocked by C-terminal domain of tetanus toxin (Hc-TeTx), suggesting possible therapeutic potential of Hc-TeTx in Parkinson's disease (PD). Pramipexole (PPX), a D2/D3 dopaminergic agonist, is currently used in PD treatment. Both Hc-TeTx and PPX ameliorate the motor and neurochemical deficits induced by 6-OHDA lesion, but the combination of the two drugs is not superior to each alone in treated rats, no significant advantage in combining Hc-TeTx with PPX is noted, overview
-
physiological function
-
tetanus toxin blocks the release of the inhibitory neurotransmitters in the central nervous system and causes tetanus
-
physiological function
-
the Hc domain of TeNT plays a key role in binding to neuronal gangliosides, it can recognise gangliosides, and bind to them in a dose-dependent manner
-
physiological function
-
the C-terminal domain of the heavy chain of tetanus toxin has neurotrophic properties on human motor neuron disease. The C-terminal domain of the heavy chain of tetanus toxin (Hc-TeTx) is a non-toxic fragment that binds to the cell membrane, e.g. of SMI-32 or NSC-34 cells. Hc-TeTx preserves human motoneurons from chronic excitotoxicity in an in vitro model of amyotrophic lateral sclerosis, a PI3-K/Akt signaling cascade is induced by Hc-TeTx under chronic excitotoxicity. Hc-TeTx can rescue cerebellar granule neurons from apoptotic cell death caused by potassium deprivation and MPP+ toxicity, molecular mechanisms and modelling of chronic excitotoxicity, overview
-
physiological function
-
in male Wistar rats, striatal dopaminergic damage induced by 6-hydoxydopamine (6-OHDA) can be blocked by C-terminal domain of tetanus toxin (Hc-TeTx), suggesting possible therapeutic potential of Hc-TeTx in Parkinson's disease (PD). Pramipexole (PPX), a D2/D3 dopaminergic agonist, is currently used in PD treatment. Both Hc-TeTx and PPX ameliorate the motor and neurochemical deficits induced by 6-OHDA lesion, but the combination of the two drugs is not superior to each alone in treated rats, no significant advantage in combining Hc-TeTx with PPX is noted, overview
-
physiological function
-
tetanus toxin blocks the release of the inhibitory neurotransmitters in the central nervous system and causes tetanus
-
physiological function
-
the Hc domain of TeNT plays a key role in binding to neuronal gangliosides, it can recognise gangliosides, and bind to them in a dose-dependent manner
-
physiological function
-
the C-terminal domain of the heavy chain of tetanus toxin has neurotrophic properties on human motor neuron disease. The C-terminal domain of the heavy chain of tetanus toxin (Hc-TeTx) is a non-toxic fragment that binds to the cell membrane, e.g. of SMI-32 or NSC-34 cells. Hc-TeTx preserves human motoneurons from chronic excitotoxicity in an in vitro model of amyotrophic lateral sclerosis, a PI3-K/Akt signaling cascade is induced by Hc-TeTx under chronic excitotoxicity. Hc-TeTx can rescue cerebellar granule neurons from apoptotic cell death caused by potassium deprivation and MPP+ toxicity, molecular mechanisms and modelling of chronic excitotoxicity, overview
-
additional information
the ability of anti-THc antibodies to block the binding of the Hc domain of the tetanus toxin (THc) to gangliosides is assessed using a solid phase assay
additional information
tetanus toxin (TT) is produced as a single protein and cleaved to a light chain (LC) and a heavy chain (HC) connected by an interchain disulfide bond. LC is a zinc metalloprotease (cleaving soluble N-ethylmaleimide-sensitive factor attachment protein receptors [SNAREs]), while HC contains an N-terminal translocation domain (HCN) and a C-terminal receptor binding domain (HCC). HCN mediates LC translocation, role for residue K768 in LC translocation via its cis-loop. K768 is located between alpha15 and alpha16 (termed the cis-loop). K768 does not interfere with other toxin functions, including cell binding, intracellular trafficking, and pore formation. betaslac-TT and cis-loop variants traffic to similar vesicles within Neuro-2a cells, a polarity in HCN cis-loop orientation with the cell membrane is observed
additional information
-
the ability of anti-THc antibodies to block the binding of the Hc domain of the tetanus toxin (THc) to gangliosides is assessed using a solid phase assay
-
additional information
-
tetanus toxin (TT) is produced as a single protein and cleaved to a light chain (LC) and a heavy chain (HC) connected by an interchain disulfide bond. LC is a zinc metalloprotease (cleaving soluble N-ethylmaleimide-sensitive factor attachment protein receptors [SNAREs]), while HC contains an N-terminal translocation domain (HCN) and a C-terminal receptor binding domain (HCC). HCN mediates LC translocation, role for residue K768 in LC translocation via its cis-loop. K768 is located between alpha15 and alpha16 (termed the cis-loop). K768 does not interfere with other toxin functions, including cell binding, intracellular trafficking, and pore formation. betaslac-TT and cis-loop variants traffic to similar vesicles within Neuro-2a cells, a polarity in HCN cis-loop orientation with the cell membrane is observed
-
additional information
-
the ability of anti-THc antibodies to block the binding of the Hc domain of the tetanus toxin (THc) to gangliosides is assessed using a solid phase assay
-
additional information
-
tetanus toxin (TT) is produced as a single protein and cleaved to a light chain (LC) and a heavy chain (HC) connected by an interchain disulfide bond. LC is a zinc metalloprotease (cleaving soluble N-ethylmaleimide-sensitive factor attachment protein receptors [SNAREs]), while HC contains an N-terminal translocation domain (HCN) and a C-terminal receptor binding domain (HCC). HCN mediates LC translocation, role for residue K768 in LC translocation via its cis-loop. K768 is located between alpha15 and alpha16 (termed the cis-loop). K768 does not interfere with other toxin functions, including cell binding, intracellular trafficking, and pore formation. betaslac-TT and cis-loop variants traffic to similar vesicles within Neuro-2a cells, a polarity in HCN cis-loop orientation with the cell membrane is observed
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UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable).
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable). TETX_CLOTE
Clostridium tetani (strain Massachusetts / E88)
1315
0
150682
Swiss-Prot
-
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PDB
SCOP
CATH
UNIPROT
ORGANISM
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MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
100000
-
1 * 100000, C-terminal heavy chain, + 1 * 50000, N-terminal light chain
150000
50000
-
1 * 100000, C-terminal heavy chain, + 1 * 50000, N-terminal light chain
additional information
-
amino acid sequence homologies between tetanus toxin TeNT and botulinum toxins BoNT/A, B and E
150000
-
activated by proteolytic cleavage with formation of a 50 kDa L-chain and a 100 kDa H-chain
150000
-
single-chain protein, cleaved by proteases into a 100 kDa heavy chain HC and a 50 kDa light chain LC, SELDI-TOF MS
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SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
dimer
-
1 * 100000, C-terminal heavy chain, + 1 * 50000, N-terminal light chain
additional information
additional information
-
the enzyme consists of a heavy (H) chain and a light (L) chain
additional information
-
the enzyme consists of a heavy (H) chain and a light (L) chain
additional information
-
held together by a single disulfide bond and non-covalent forces
additional information
-
MW 52288 (L-chain) and MW 98300 (H-chain), calculated from amino acid sequence
additional information
-
TeNT is an A-B toxin. It consits of a heavy chain containing cellular receptor binding domain and a light chain with zinc metalloprotease activity
additional information
-
the TeNT heavy chain contains two functional domains: a translocation domain and a C-terminal receptor binding domain. C-terminal heavy and N-terminal light chains are linked through a single disulfide bond, overview
additional information
secondary beta-sheet structure of tetanus toxin fragment C by circular dichroism, overview
additional information
trypsin enzymatic digestion and peptide mapping, of tetanus toxin, overview. MALDI-TOF mass spectrometry and proteomic analysis of nTeNT and iTeNT peptides
additional information
tetanus toxin (TT) is a clostridial neurotoxin (CNT), Clostridia produce CNTs as 150-kDa single-chain proteins, which are cleaved into di-chain proteins that remain linked by an interchain disulfide bond. Di-chain CNT is composed of light chain (LC), which is a Zn2x03 metalloprotease, and heavy chain (HC), which contains a translocation domain (heavy-chain N-terminal translocation domain [HCN]/HCT) and receptor-binding domain (heavy-chain C-terminal receptor binding domain [HCC]/HCR). LC is a zinc metalloprotease (cleaving soluble N-ethylmaleimide-sensitive factor attachment protein receptors [SNAREs]). Enzyme structure, detailed overview
additional information
-
secondary beta-sheet structure of tetanus toxin fragment C by circular dichroism, overview
-
additional information
-
trypsin enzymatic digestion and peptide mapping, of tetanus toxin, overview. MALDI-TOF mass spectrometry and proteomic analysis of nTeNT and iTeNT peptides
-
additional information
-
tetanus toxin (TT) is a clostridial neurotoxin (CNT), Clostridia produce CNTs as 150-kDa single-chain proteins, which are cleaved into di-chain proteins that remain linked by an interchain disulfide bond. Di-chain CNT is composed of light chain (LC), which is a Zn2x03 metalloprotease, and heavy chain (HC), which contains a translocation domain (heavy-chain N-terminal translocation domain [HCN]/HCT) and receptor-binding domain (heavy-chain C-terminal receptor binding domain [HCC]/HCR). LC is a zinc metalloprotease (cleaving soluble N-ethylmaleimide-sensitive factor attachment protein receptors [SNAREs]). Enzyme structure, detailed overview
-
additional information
-
secondary beta-sheet structure of tetanus toxin fragment C by circular dichroism, overview
-
additional information
-
trypsin enzymatic digestion and peptide mapping, of tetanus toxin, overview. MALDI-TOF mass spectrometry and proteomic analysis of nTeNT and iTeNT peptides
-
additional information
-
tetanus toxin (TT) is a clostridial neurotoxin (CNT), Clostridia produce CNTs as 150-kDa single-chain proteins, which are cleaved into di-chain proteins that remain linked by an interchain disulfide bond. Di-chain CNT is composed of light chain (LC), which is a Zn2x03 metalloprotease, and heavy chain (HC), which contains a translocation domain (heavy-chain N-terminal translocation domain [HCN]/HCT) and receptor-binding domain (heavy-chain C-terminal receptor binding domain [HCC]/HCR). LC is a zinc metalloprotease (cleaving soluble N-ethylmaleimide-sensitive factor attachment protein receptors [SNAREs]). Enzyme structure, detailed overview
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POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
glycolipoprotein
-
gangliosides are bound to the C-terminal receptor-binding domain via two carbohydrate-binding sites, termed the lactose-binding site or the W pocket, and the sialic acid-binding site or the R pocket, GM1a bound to the W pocket, and GD3 bound to the R pocket
proteolytic modification
-
TeNT is produced as a 150-kDa protein that is cleaved to a di-chain protein, comprising an N-terminal light chain and a C-terminal heavy chain domain linked through a single disulfide bond
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CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
in complex with ganglioside GD1a, hanging drop vapor diffusion method, using 20% (w/v) polyethylene glycol 3350, 0.1xa0M Bis-Tris propane pH 6.5, 0.2xa0M potassium thiocyanate. In complex with ganglioside GM1a, sitting drop vapor diffusion method, using 20% (w/v) polyethylene glycol 6000, 0.1xa0M MES pH 6.0, 0.2xa0M sodium chloride
purified C-terminal receptor binding domain with bound ganglioside GT2 in presence and absence of lactose, 10 mg/ml protein in 20 mM Tris-HCl buffer, pH 7.9, containing 100 mM NaCl are mixed with the carbohydrate moiety of GT2 at 1:8 molar ratio, vapor diffusion hanging drop method, 0.002 ml of protein-ligand solution are mixed with 0.002 ml of well solution containing 100 mM bis(trispropane) buffer, pH 7.0, 25% polyethylene glycol 2000 and 300 mM ammonium sulfate, equilibration against 0.5 ml well solution at 19°C, X-ray diffraction structure determination and analysis at 2.0-2.1 A resolution, molecular replacement method
-
sitting drop vapor diffusion method. The structure provides insight into the active site, the importance of the nucleophilic water and the role of the zinc ion
tetanus neurotoxin C fragment, vapor-diffusion method, hanging drops and sitting drops, thick rod-shaped crystals, space group P2(1)2(1)2(1), unit cell dimensions a : 67.4 A, b : 79.7 A, c : 91.1 A
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PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
R372A/Y375F
Y1290F
additional information
R372A/Y375F
-
the enzyme activity is about125,000fold reduced in toxicity relative to native protein
additional information
-
construction of mutated forms of HCR/T that lack one or both carbohydrate-binding pocket, loss of gangliosides binding ability leads to loss of neuron binding ability of the toxin, both of the W and R pockets are necessary for high affinity binding to neuronal and non-neuronal cells, overview
additional information
aliquots of TeNT (0.001374 mg/ml) in aqueous solution are irradiated by cobalt-60 gamma radiation with doses ranging from 1 kGy to 8 kGy at a dose rate of 765 Gy/h using a GammaCell. Ionizing radiation promotes structural changes in the tetanus toxin such as fragmentation and/or aggregation and attenuation of enzymatic activity as the dose increases, but antigenic recognition of the toxin remains at good levels indicating its possible use as an immunogen
additional information
usagex02of beta-lactamase-tetanus toxin (betalac-TT), a discovery-based, live-cell imaging reporter system in cells to map regions of the N-terminal translocation domain of the heavy chain (HCN) that contribute to LC translocation and identification of a helix-loop-helix within HCN (cis-loop) required for LC translocation, independently of pore formation. Mutations within alpha12 of betalac-TT that target a localized group of aspartic acids or three conserved aromatic amino acids translocated betalac-TT [betalac-TT(F612A, W615A, F623A) and betalac-TT(D618K, D621K, D622K)] have a number of beta-lac translocation events similar to the number seen with betalac-TT. betalac-TT(767DAE769) and betalac-TT(767AKA769) do not cleave cytosolic beta-lactamase substrate CCF2 indicating that the presence of 768K is necessary but not sufficient for reporter translocation. betalac-TT(767AAA769) retains protein structure and cell binding function. betalac-TT and cis-loop variants traffic to similar vesicles within Neuro-2a cells
additional information
development of a DNA vaccine using scFv6.C4, a carcinoembryonic antigen (CEA, main tumor-associated antigen of colorectal cancers) surrogate, against CEA-expressing tumors. Construction of the uP/PS-scFv6.C4-FrC plasmid vector, scFv6.C4 DNA vaccine is able to both mimic CEA functionally and induce anti-CEA humoral and cellular immune responses, 40% of the vaccinated mice are tumor-free after tumor challenge. In order to enhance vaccine efficacy, fragment C of tetanus toxin (FrC) is tested as adjuvant. Addition of the adjuvant leads to higher CD4+ and CD8+ proliferative responses and strong CD8+ CTL response against MC38-CEA cells. DNA immunization with scFv6.C4 and FrC increases antitumor effect via induction of high and specific humoral and cellular immune responses to CEA, immunocytochemistry of HCT?8, MC38, and MC38-CEA cells, overview
additional information
-
aliquots of TeNT (0.001374 mg/ml) in aqueous solution are irradiated by cobalt-60 gamma radiation with doses ranging from 1 kGy to 8 kGy at a dose rate of 765 Gy/h using a GammaCell. Ionizing radiation promotes structural changes in the tetanus toxin such as fragmentation and/or aggregation and attenuation of enzymatic activity as the dose increases, but antigenic recognition of the toxin remains at good levels indicating its possible use as an immunogen
-
additional information
-
usagex02of beta-lactamase-tetanus toxin (betalac-TT), a discovery-based, live-cell imaging reporter system in cells to map regions of the N-terminal translocation domain of the heavy chain (HCN) that contribute to LC translocation and identification of a helix-loop-helix within HCN (cis-loop) required for LC translocation, independently of pore formation. Mutations within alpha12 of betalac-TT that target a localized group of aspartic acids or three conserved aromatic amino acids translocated betalac-TT [betalac-TT(F612A, W615A, F623A) and betalac-TT(D618K, D621K, D622K)] have a number of beta-lac translocation events similar to the number seen with betalac-TT. betalac-TT(767DAE769) and betalac-TT(767AKA769) do not cleave cytosolic beta-lactamase substrate CCF2 indicating that the presence of 768K is necessary but not sufficient for reporter translocation. betalac-TT(767AAA769) retains protein structure and cell binding function. betalac-TT and cis-loop variants traffic to similar vesicles within Neuro-2a cells
-
additional information
-
development of a DNA vaccine using scFv6.C4, a carcinoembryonic antigen (CEA, main tumor-associated antigen of colorectal cancers) surrogate, against CEA-expressing tumors. Construction of the uP/PS-scFv6.C4-FrC plasmid vector, scFv6.C4 DNA vaccine is able to both mimic CEA functionally and induce anti-CEA humoral and cellular immune responses, 40% of the vaccinated mice are tumor-free after tumor challenge. In order to enhance vaccine efficacy, fragment C of tetanus toxin (FrC) is tested as adjuvant. Addition of the adjuvant leads to higher CD4+ and CD8+ proliferative responses and strong CD8+ CTL response against MC38-CEA cells. DNA immunization with scFv6.C4 and FrC increases antitumor effect via induction of high and specific humoral and cellular immune responses to CEA, immunocytochemistry of HCT?8, MC38, and MC38-CEA cells, overview
-
additional information
-
aliquots of TeNT (0.001374 mg/ml) in aqueous solution are irradiated by cobalt-60 gamma radiation with doses ranging from 1 kGy to 8 kGy at a dose rate of 765 Gy/h using a GammaCell. Ionizing radiation promotes structural changes in the tetanus toxin such as fragmentation and/or aggregation and attenuation of enzymatic activity as the dose increases, but antigenic recognition of the toxin remains at good levels indicating its possible use as an immunogen
-
additional information
-
usagex02of beta-lactamase-tetanus toxin (betalac-TT), a discovery-based, live-cell imaging reporter system in cells to map regions of the N-terminal translocation domain of the heavy chain (HCN) that contribute to LC translocation and identification of a helix-loop-helix within HCN (cis-loop) required for LC translocation, independently of pore formation. Mutations within alpha12 of betalac-TT that target a localized group of aspartic acids or three conserved aromatic amino acids translocated betalac-TT [betalac-TT(F612A, W615A, F623A) and betalac-TT(D618K, D621K, D622K)] have a number of beta-lac translocation events similar to the number seen with betalac-TT. betalac-TT(767DAE769) and betalac-TT(767AKA769) do not cleave cytosolic beta-lactamase substrate CCF2 indicating that the presence of 768K is necessary but not sufficient for reporter translocation. betalac-TT(767AAA769) retains protein structure and cell binding function. betalac-TT and cis-loop variants traffic to similar vesicles within Neuro-2a cells
-
additional information
-
development of a DNA vaccine using scFv6.C4, a carcinoembryonic antigen (CEA, main tumor-associated antigen of colorectal cancers) surrogate, against CEA-expressing tumors. Construction of the uP/PS-scFv6.C4-FrC plasmid vector, scFv6.C4 DNA vaccine is able to both mimic CEA functionally and induce anti-CEA humoral and cellular immune responses, 40% of the vaccinated mice are tumor-free after tumor challenge. In order to enhance vaccine efficacy, fragment C of tetanus toxin (FrC) is tested as adjuvant. Addition of the adjuvant leads to higher CD4+ and CD8+ proliferative responses and strong CD8+ CTL response against MC38-CEA cells. DNA immunization with scFv6.C4 and FrC increases antitumor effect via induction of high and specific humoral and cellular immune responses to CEA, immunocytochemistry of HCT?8, MC38, and MC38-CEA cells, overview
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pH STABILITY
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
the purified recombinant enzyme is stable at weakly alkaline conditions
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TEMPERATURE STABILITY
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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OXIDATION STABILITY
ORGANISM
UNIPROT
LITERATURE
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STORAGE STABILITY
ORGANISM
UNIPROT
LITERATURE
-80°C, in 10 mM HEPES buffer, pH 7.2, 50 mM NaCl, after freezing in liquid N2, stable
-
37°C, enzyme diluted in water supplemented with 5 mg/ml protease-free bovine serum albumin, 3 days, 90% loss of activity
-
37°C, enzyme diluted in water supplemented with 5 mg/ml protease-free bovine serum albumin, 35-45 days, complete loss of activity
-
4°C, both native and recombinant TeNT L-chains show significant decreases after 3-4 days of storage
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PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
recombinant His6-tagged C-terminal domain of the heavy chain of tetanus toxin from Escherichia coli strain BL21(DE3) by cobalt affinity chromatography
recombinant tetanus toxin fragment C from Escherichia coli strain BL21(DE3) by anion and cation exchange chromatography
recombinant tetanus toxin Hc domain from Escherichia coli strain BL21(DE3) by mixed-mode chromatography and hydrophobic interaction chromatography, followed by dialysis
very toxic! Booster injection of tetanus toxoid before starting research with tetanus toxin advisable, human anti-tetanus neurotoxin antibodies available
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CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
expressed in Escherichia coli JM101 using three different plasmid vectors
-
mutant enzyme R372A/Y375F fused to beta-lactamase, expressed in Escherichia coli BL21(DE3) cells
-
recombinant expression of His6-tagged C-terminal domain of the heavy chain of tetanus toxin in Escherichia coli strain BL21(DE3)
recombinant expression of the Hc domain of the tetanus toxin (THc) in Escherichia coli strain BL21(DE3)
recombinant expression of the tetanus toxin fragment C in Escherichia coli strain BL21(DE3)
the C-terminal domain bound to Bcl-2 protein is expressed in COS-7 cells and Escherichia coli BL21(DE3)pLysS cells
-
the heavy chain fragment is expressed in Escherichia coli BL21(DE3) cells
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APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
medicine
additional information
medicine
-
sole causal agent of the pathological condition known as tetanus
medicine
-
very powerful neurotoxin, agent responsible for all clinical symptoms of tetanus
medicine
-
monoclonal antibody MAb 5C4 is the only anti-fragment C (heavy chain) antibody which is capable of blocking the binding of recombinant fragment C to GT1b gangliosides
medicine
-
the antibodies 2-7G, 2-2D, and S-4-7H can effectively inhibit the binding between the heavy chain fragment of the enzyme (TeNT-Hc) and differentiated PC-12 cells in vitro. Moreover, 2-7G inhibits TeNT-Hc binding to the receptor via carbohydrate-binding sites of the W pocket while 2-2D and S-4-7H inhibit binding of the R pocket. Although no single antibody completely protect mice from the toxin, they can prolong survival
medicine
-
treatment of T cells with recombinant carboxy-subdomain of the heavy chain results in development of Th1 lineage phenotype, which might lead to a specific and protective antibody mediated response against the enzyme
medicine
-
HuscFv antibodies specific for heavy chain can protect against tetanus neurotoxin by inhibiting binding of the enzyme to ganglioside GT1b
medicine
the tetanus toxin fragment C is a candidate vaccine for replacement of the existing tetanus toxoid vaccine due to its strong immunogenicity
medicine
tetanus toxin blocks the release of the inhibitory neurotransmitters in the central nervous system and causes tetanus and its main form of prevention is through vaccination. The vaccine is produced by inactivation of tetanus toxin with formaldehyde, which may cause side effects. An alternative way is the use of ionizing radiation for inactivation of the toxin and also to improve the potential immunogenic response and to reduce the post-vaccination side effects. Analysis of the tetanus toxin structure after different doses of ionizing radiation of 60Co, overview. Ionizing radiation promotes structural changes in the tetanus toxin such as fragmentation and/or aggregation and attenuation of enzymatic activity as the dose increases, but antigenic recognition of the toxin remains at good levels indicating its possible use as an immunogen
medicine
the current vaccine against tetanus is based on inactivated tetanus toxin (TeNT). To develop a recombinant TeNT vaccine suitable for replacement of full-length tetanus toxoid (TT) vaccine for use in humans, a recombinant non-tagged isoform of the Hc domain of the tetanus toxin (THc) is expressed in Escherichia coli and purified by sequential chromatography steps. The immunogenicity and protective effect of the THc antigen were explored and compared with those of TT in Balb/c mice. The THc-based subunit vaccine provided complete protection against TeNT challenge following a high dosage as a toxoid vaccine. The anti-THc and neutralising antibody titres are higher for the THc-based vaccine than the TT vaccine because protective epitopes are located on the THc domain. The ability of anti-THc antibodies to block the binding of THc to gangliosides is assessed using a solid phase assay
medicine
-
very powerful neurotoxin, agent responsible for all clinical symptoms of tetanus
-
medicine
-
the tetanus toxin fragment C is a candidate vaccine for replacement of the existing tetanus toxoid vaccine due to its strong immunogenicity
-
medicine
-
tetanus toxin blocks the release of the inhibitory neurotransmitters in the central nervous system and causes tetanus and its main form of prevention is through vaccination. The vaccine is produced by inactivation of tetanus toxin with formaldehyde, which may cause side effects. An alternative way is the use of ionizing radiation for inactivation of the toxin and also to improve the potential immunogenic response and to reduce the post-vaccination side effects. Analysis of the tetanus toxin structure after different doses of ionizing radiation of 60Co, overview. Ionizing radiation promotes structural changes in the tetanus toxin such as fragmentation and/or aggregation and attenuation of enzymatic activity as the dose increases, but antigenic recognition of the toxin remains at good levels indicating its possible use as an immunogen
-
medicine
-
the current vaccine against tetanus is based on inactivated tetanus toxin (TeNT). To develop a recombinant TeNT vaccine suitable for replacement of full-length tetanus toxoid (TT) vaccine for use in humans, a recombinant non-tagged isoform of the Hc domain of the tetanus toxin (THc) is expressed in Escherichia coli and purified by sequential chromatography steps. The immunogenicity and protective effect of the THc antigen were explored and compared with those of TT in Balb/c mice. The THc-based subunit vaccine provided complete protection against TeNT challenge following a high dosage as a toxoid vaccine. The anti-THc and neutralising antibody titres are higher for the THc-based vaccine than the TT vaccine because protective epitopes are located on the THc domain. The ability of anti-THc antibodies to block the binding of THc to gangliosides is assessed using a solid phase assay
-
medicine
-
the tetanus toxin fragment C is a candidate vaccine for replacement of the existing tetanus toxoid vaccine due to its strong immunogenicity
-
medicine
-
tetanus toxin blocks the release of the inhibitory neurotransmitters in the central nervous system and causes tetanus and its main form of prevention is through vaccination. The vaccine is produced by inactivation of tetanus toxin with formaldehyde, which may cause side effects. An alternative way is the use of ionizing radiation for inactivation of the toxin and also to improve the potential immunogenic response and to reduce the post-vaccination side effects. Analysis of the tetanus toxin structure after different doses of ionizing radiation of 60Co, overview. Ionizing radiation promotes structural changes in the tetanus toxin such as fragmentation and/or aggregation and attenuation of enzymatic activity as the dose increases, but antigenic recognition of the toxin remains at good levels indicating its possible use as an immunogen
-
medicine
-
the current vaccine against tetanus is based on inactivated tetanus toxin (TeNT). To develop a recombinant TeNT vaccine suitable for replacement of full-length tetanus toxoid (TT) vaccine for use in humans, a recombinant non-tagged isoform of the Hc domain of the tetanus toxin (THc) is expressed in Escherichia coli and purified by sequential chromatography steps. The immunogenicity and protective effect of the THc antigen were explored and compared with those of TT in Balb/c mice. The THc-based subunit vaccine provided complete protection against TeNT challenge following a high dosage as a toxoid vaccine. The anti-THc and neutralising antibody titres are higher for the THc-based vaccine than the TT vaccine because protective epitopes are located on the THc domain. The ability of anti-THc antibodies to block the binding of THc to gangliosides is assessed using a solid phase assay
-
additional information
the intramuscular injection of recombinant Hc-TeTx protein can be internalized in the neuromuscular junction (NMJ) and transported retrogradely to the spinal cord and is an effective method of delivery of a potentially neuroprotective agent with high affnity and specificity for spinal motoneurons (MNs) for studies in vivo. Recombinant protein Hc-TeTx cannot diffuse to other muscles, such as neighboring gastrocnemius muscles (GM), or muscles more remote from the injection site, such as the left tibialis anterior (TA) and GM, and it remains inside the NMJ
additional information
-
the intramuscular injection of recombinant Hc-TeTx protein can be internalized in the neuromuscular junction (NMJ) and transported retrogradely to the spinal cord and is an effective method of delivery of a potentially neuroprotective agent with high affnity and specificity for spinal motoneurons (MNs) for studies in vivo. Recombinant protein Hc-TeTx cannot diffuse to other muscles, such as neighboring gastrocnemius muscles (GM), or muscles more remote from the injection site, such as the left tibialis anterior (TA) and GM, and it remains inside the NMJ
-
additional information
-
the intramuscular injection of recombinant Hc-TeTx protein can be internalized in the neuromuscular junction (NMJ) and transported retrogradely to the spinal cord and is an effective method of delivery of a potentially neuroprotective agent with high affnity and specificity for spinal motoneurons (MNs) for studies in vivo. Recombinant protein Hc-TeTx cannot diffuse to other muscles, such as neighboring gastrocnemius muscles (GM), or muscles more remote from the injection site, such as the left tibialis anterior (TA) and GM, and it remains inside the NMJ
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REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Fairweather, N.F.; Lyness, V.A.
The complete nucleotide sequence of tetanus toxin
Nucleic Acids Res.
14
7809-7813
1986
Clostridium tetani
brenda
Rossetto, O.; Schiavo, G.; Polverino de Laureto, P.; Fabbiani, S.; Montecucco, C.
Surface topography of histidine residues of tetanus toxin probed by immobilized-metal-ion affinity chromatography
Biochem. J.
285
9-12
1992
Clostridium tetani
brenda
Eisel, U.; Jarusch, W.; Goretzki, K.; Henschen, A.; Engels, J.; Weller, U.; Hudel, M.; Habermann, E.; Niemann, H.
Tetanus toxin: primary structure, expression in E. coli, and homology with botulinum toxins
EMBO J.
5
2495-2502
1986
Clostridium tetani
brenda
Schiavo, G.; Benfenati, F.; Poulain, B.; Rossetto, O.; Polverino de Laureto, P.; DasGupta, B.R.; Montecucco, C.
Tetanus and botulinum-B neurotoxins block neurotransmitter release by proteolytic cleavage of synaptobrevin
Nature
359
832-835
1992
Clostridium tetani
brenda
Montecucco, C.; Schiavo, G.
Mechanism of action of tetanus and botulinum neurotoxins
Mol. Microbiol.
13
1-8
1994
Clostridium tetani
brenda
Schiavo, G.; Montecucco, C.
Tetanus and botulism neurotoxins: isolation and assay
Methods Enzymol.
248
643-652
1995
Clostridium tetani, Clostridium tetani Harvard
brenda
Umland, T.C.; Wingert, L.; Swaminathan, S.; Schmidt, J.J.; Sax, M.
Crystallization and preliminary X-ray analysis of tetanus neurotoxin C fragment
Acta Crystallogr. Sect. D
54
273-275
1998
Clostridium tetani
brenda
Meneghini, C.; Morante, S.
The active site structure of tetanus neurotoxin resolved by multiple scattering analysis in X-Ray absorption spectroscopy
Biophys. J.
75
1953-1963
1998
Clostridium tetani
brenda
Sutton, J.M.; Chow-Worn, O.; Spaven, L.; Silman, N.J.; Hallis, B.; Shone, C.C.
Tyrosine-1290 of tetanus neurotoxin plays a key role in its binding to gangliosides and functional binding to neurones
FEBS Lett.
493
45-49
2001
Clostridium tetani
brenda
Rummel, A.; Bade, S.; Alves, J.; Bigalke, H.; Binz, T.
Two carbohydrate binding sites in the H(CC)-domain of tetanus neurotoxin are required for toxicity
J. Mol. Biol.
326
835-847
2003
Clostridium tetani
brenda
Tonello, F.; Pellizzari, R.; Pasqualato, S.; Grandi, G.; Peggion, E.; Montecucco, C.
Recombinant and truncated tetanus neurotoxin light chain: cloning, expression, purification, and proteolytic activity
Protein Expr. Purif.
15
221-227
1999
Clostridium tetani, Clostridium tetani Y-IV-3
brenda
Brueggemann, H.; Gottschalk, G.
Insights in metabolism and toxin production from the complete genome sequence of Clostridium tetani
Anaerobe
10
53-68
2004
Clostridium tetani (Q93N27), Clostridium tetani
brenda
Raffestin, S.; Marvaud, J.C.; Cerrato, R.; Dupuy, B.; Popoff, M.R.
Organization and regulation of the neurotoxin genes in Clostridium botulinum and Clostridium tetani
Anaerobe
10
93-100
2004
Clostridium tetani
brenda
Fratelli, F.; Siquini, T.J.; Prado, S.M.; Higashi, H.G.; Converti, A.; de Carvalho, J.C.
Effect of medium composition on the production of tetanus toxin by Clostridium tetani
Biotechnol. Prog.
21
756-761
2005
Clostridium tetani
brenda
Rao, K.N.; Kumaran, D.; Binz, T.; Swaminathan, S.
Structural analysis of the catalytic domain of tetanus neurotoxin
Toxicon
45
929-939
2005
Clostridium tetani (P04958)
brenda
Kegel, B.; Behrensdorf-Nicol, H.A.; Bonifas, U.; Silberbach, K.; Klimek, J.; Kraemer, B.; Weisser, K.
An in vitro assay for detection of tetanus neurotoxin activity: Using antibodies for recognizing the proteolytically generated cleavage product
Toxicol. in Vitro
21
1641-1649
2007
Clostridium tetani
brenda
Indrawattana, N.; Sookrung, N.; Kulkeaw, K.; Seesuay, W.; Kongngoen, T.; Chongsa-nguan, M.; Tungtrongchitr, A.; Chaicumpa, W.
Human monoclonal ScFv that inhibits cellular entry and metalloprotease activity of tetanus neurotoxin
Asian Pac. J. Allergy Immunol.
28
85-93
2010
Clostridium tetani
brenda
Chen, C.; Fu, Z.; Kim, J.J.; Barbieri, J.T.; Baldwin, M.R.
Gangliosides as high affinity receptors for tetanus neurotoxin
J. Biol. Chem.
284
26569-26577
2009
Clostridium tetani
brenda
Yu, R.; Yi, S.; Yu, C.; Fang, T.; Liu, S.; Yu, T.; Song, X.; Fu, L.; Hou, L.; Chen, W.
A conformational change of C fragment of tetanus neurotoxin reduces its ganglioside-binding activity but does not destroy its immunogenicity
Clin. Vaccine Immunol.
18
1668-1672
2011
Clostridium tetani
brenda
Behrensdorf-Nicol, H.A.; Weisser, K.; Kraemer, B.
"BINACLE" assay for in vitro detection of active tetanus neurotoxin in toxoids
ALTEX
32
137-142
2015
Clostridium tetani
brenda
Watanabe, Y.; Matsuba, T.; Nakanishi, M.; Une, M.; Hanajima, R.; Nakashima, K.
Tetanus toxin fragments and Bcl-2 fusion proteins cytoprotection and retrograde axonal migration
BMC Biotechnol.
18
39
2018
Clostridium tetani, Clostridium tetani KZ1174
brenda
Ferecsko, A.; Jiruska, P.; Foss, L.; Powell, A.; Chang, W.; Sik, A.; Jefferys, J.
Structural and functional substrates of tetanus toxin in an animal model of temporal lobe epilepsy
Brain Struct. Funct.
220
1013-1029
2015
Clostridium tetani
-
brenda
Rossetto, O.; Pirazzini, M.; Lista, F.; Montecucco, C.
The role of the single interchains disulfide bond in tetanus and botulinum neurotoxins and the development of antitetanus and antibotulism drugs
Cell. Microbiol.
21
e13037
2019
Clostridium tetani
brenda
Torabi Goudarzi, S.; Hajivalili, M.; Hosseini, M.; Ghafari Khamene, M.; Yazdani, Y.; Sadreddini, S.; Miahipour, A.; Younesi, V.; Yousefi, M.
Tetanus neurotoxin HCC protein commits T cells to IFN-gamma producing cells
Cell. Mol. Biol.
62
20-24
2016
Clostridium tetani
brenda
Masuyer, G.; Conrad, J.; Stenmark, P.
The structure of the tetanus toxin reveals pH-mediated domain dynamics
EMBO Rep.
18
1306-1317
2017
Clostridium tetani (P04958), Clostridium tetani, Clostridium tetani E88 (P04958)
brenda
Zuverink, M.; Chen, C.; Przedpelski, A.; Blum, F.; Barbieri, J.
A heterologous reporter defines the role of the tetanus toxin interchain disulfide in light-chain translocation
Infect. Immun.
83
2714-2724
2015
Clostridium tetani
brenda
Nagoba, B.; Dharne, M.; Gohil, K.N.
Molecular methods for identification of Clostridium tetani by targeting neurotoxin
Methods Mol. Biol.
1600
37-47
2017
Clostridium tetani
brenda
Khalili, E.; Lakzaei, M.; Rasaee, M.J.; Aminian, M.
Production of Recombinant human scFv against tetanus toxin heavy chain by phage display technology
Monoclon. Antib. Immunodiagn. Immunother.
34
303-309
2015
Clostridium tetani
brenda
Ghotloo, S.; Golsaz-Shirazi, F.; Amiri, M.M.; Jeddi-Tehrani, M.; Shokri, F.
Epitope mapping of tetanus toxin by monoclonal antibodies implication for immunotherapy and vaccine design
Neurotox. Res.
37
239-249
2019
Clostridium tetani
brenda
Moeller, J.; Kraner, M.E.; Burkovski, A.
More than a toxin Protein inventory of Clostridium tetani toxoid vaccines
Proteomes
7
15
2019
Clostridium tetani (P04958), Clostridium tetani, Clostridium tetani E88 (P04958)
brenda
Pirazzini, M.; Azarnia Tehran, D.; Zanetti, G.; Rossetto, O.; Montecucco, C.
Hsp90 and thioredoxin-thioredoxin reductase enable the catalytic activity of Clostridial neurotoxins inside nerve terminals
Toxicon
147
32-37
2018
Clostridium tetani
brenda
Surana, S.; Tosolini, A.P.; Meyer, I.F.G.; Fellows, A.D.; Novoselov, S.S.; Schiavo, G.
The travel diaries of tetanus and botulinum neurotoxins
Toxicon
147
58-67
2018
Clostridium tetani
brenda
Bano, L.; Tonon, E.; Drigo, I.; Pirazzini, M.; Guolo, A.; Farina, G.; Agnoletti, F.; Montecucco, C.
Detection of Clostridium tetani neurotoxins inhibited in vivo by botulinum antitoxin B Potential for misleading mouse test results in food controls
Toxins
10
248
2018
Clostridium tetani, Clostridium tetani ATCC 10779, Clostridium tetani TV1277
brenda
Wang, H.; Yu, R.; Fang, T.; Yu, T.; Chi, X.; Zhang, X.; Liu, S.; Fu, L.; Yu, C.; Chen, W.
Tetanus neurotoxin neutralizing antibodies screened from a human immune scFv antibody phage display library
Toxins
8
266
2016
Clostridium tetani
brenda
Carle, S.; Pirazzini, M.; Rossetto, O.; Barth, H.; Montecucco, C.
High conservation of tetanus and botulinum neurotoxins cleavage sites on human SNARE proteins suggests that these pathogens exerted little or no evolutionary pressure on humans
Toxins
9
404
2017
Clostridium tetani
brenda
Behrensdorf-Nicol, H.A.; Kraemer, B.
Is the test for irreversibility of tetanus toxoids still relevant?
Vaccine
37
1721-1724
2019
Clostridium tetani
brenda
Zanetti, B.F.; Ferreira, C.P.; de Vasconcelos, J.R.C.; Han, S.W.
scFv6.C4 DNA vaccine with fragment C of tetanus toxin increases protective immunity against CEA-expressing tumor
Gene Ther.
26
441-454
2019
Clostridium tetani (P04958), Clostridium tetani E88 (P04958), Clostridium tetani Massachusetts (P04958)
brenda
Sartori, G.P.; da Costa, A.; Macarini, F.L.D.S.; Mariano, D.O.C.; Pimenta, D.C.; Spencer, P.J.; Nali, L.H.D.S.; Galisteo, A.J.
Characterization and evaluation of the enzymatic activity of tetanus toxin submitted to cobalt-60 gamma radiation
J. Venom. Anim. Toxins Incl. Trop. Dis.
27
e20200140
2021
Clostridium tetani (P04958), Clostridium tetani E88 (P04958), Clostridium tetani Massachusetts (P04958)
brenda
Zuverink, M.; Bluma, M.; Barbieri, J.T.
Tetanus toxin cis-loop contributes to light-chain translocation
mSphere
5
e00244-20
2020
Clostridium tetani (P04958), Clostridium tetani E88 (P04958), Clostridium tetani Massachusetts (P04958)
brenda
Patricio, F.; Parra, I.; Martinez, I.; Perez-Severiano, F.; Montes, S.; Aguilera, J.; Limon, I.D.; Tizabi, Y.; Mendieta, L.
Effectiveness of fragment C domain of tetanus toxin and pramipexole in an animal model of Parkinsons disease
Neurotox. Res.
35
699-710
2019
Clostridium tetani (P04958), Clostridium tetani E88 (P04958), Clostridium tetani Massachusetts (P04958)
brenda
Chai, P.; Pu, X.; Li, J.; Xia, X.; Ge, J.; Luo, A.; Su, H.; Zhang, W.; Ma, J.
Expression and purification of tetanus toxin fragment C in Escherichia coli BL21(DE3)
Protein Pept. Lett.
27
1132-1140
2020
Clostridium tetani (P04958), Clostridium tetani E88 (P04958), Clostridium tetani Massachusetts (P04958)
brenda
Liu, F.J.; Shi, D.Y.; Li, Z.Y.; Lu, J.S.; Wang, R.; Pang, X.B.; Yang, Z.X.; Yu, Y.Z.
Evaluation of a recombinant tetanus toxin subunit vaccine
Toxicon
187
75-81
2020
Clostridium tetani (P04958), Clostridium tetani E88 (P04958), Clostridium tetani Massachusetts (P04958)
brenda
Herrando-Grabulosa, M.; Casas, C.; Talbot, K.; Aguilera, J.
Neurotrophic properties of C-terminal domain of the heavy chain of tetanus toxin on motor neuron disease
Toxins
12
666
2020
Clostridium tetani (P04958), Clostridium tetani E88 (P04958), Clostridium tetani Massachusetts (P04958)
brenda
EXTERNAL LINKS (specific for EC-Number 3.4.24.68)
Transporter Classification Database (TCDB): 1.C.8.1.2
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