Chemistry:Tb1 (toxin)
Tb1 (or Tb-gamma) is a neurotoxin that is naturally found in the venom of the Brazilian scorpion Tityus bahiensis. Presumably by acting on voltage-gated sodium channels, it triggers excessive glutamate release, which can lead to both behavioral and electrographic epileptiform alterations, as well as neuronal injury.
| Tb-gamma | |||||||
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| Organism | |||||||
| Symbol | Tb1 | ||||||
| UniProt | P5661 | ||||||
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Etymology
‘Tb’ is an acronym for the scorpion Tityus bahiensis in whose venom the toxin is found. For all Tityus toxins, the number ‘1’ refers to the fact that the toxin is gamma-like.[1] Tb1 is also known as Tb-gamma[2] or gamma-bahiensis.[1] The use of ‘gamma’ in this terminology refers to the fact that Tb1 is more than 95% identical to the Tityus serrulatus gamma toxin.[1][3]
Sources
Tb1 is naturally found in the venom of the Brazilian scorpion T. bahiensis, known as the brown scorpion. This scorpion is found in South America and is medically important in Brazil.[3] Tb1 is the most prevalent toxin found in the venom of T. bahiensis, accounting for 10% of the entire soluble venom content.[1]
Chemistry
Structure
The Tb1 peptide in mature form contains 61 amino acids (21K-81C),[1] where the cysteine at the C-terminus is a modified residue.[2] The mature form has a molecular mass of 6868.03 Da.[3] The unprocessed amino acid sequence of the Tb1 peptide is:[2]
1 MKGMILFISC LLLIGIVVEC 20 21 KEGYLMDHEG CKLSCFIRPS 40 41 GYCGSECKIK KGSSGYCAWP 60 61 ACYCYGLPNW VKVWDRATNK 80 81 CGKK 84
The unprocessed form of the peptide has a signal peptide of 20 amino acids at the N-terminus. Furthermore, this unprocessed sequence of Tb1 has a three-amino acid tail following the modified residue at the C-terminus. Thus, this unprocessed sequence contains 84 amino acids and has a molecular mass of 9,384 Da.[2] Like most sodium-channel scorpion toxins,[4] the Tb1 peptide has four disulfide bonds.[2] For Tb1, these are located between amino acids 31 and 81, 35 and 57, 43 and 62, and 47 and 64. The domain of the Tb1 protein is characterized by an alpha-helix connected to antiparallel beta-sheets by these disulfide bonds.[2]
Homology
Tb1 is homologous to the gamma toxin from the T. serrulatus venom. This gamma toxin is also known as Ts1, TsTX-I, TsVII, or toxin γ.[5] Tb1 and the gamma toxin from the T. serrulatus venom are 96.72% identical, except for two amino acids.[3]
Family
Tb1 is a sodium channel scorpion toxin (NaScTx) and belongs to the beta toxin subfamily.[2] Within the NaScTx family, Tb1 is part of the NaTx6 cluster. This cluster consists of four toxins found in the venom of scorpions that inhabit the Southern area of the Amazonian rainforest: Tco-gamma, Tst1, Tb1 and the previously mentioned Ts1.[6]
Target
Tb1 is a beta-type scorpion toxin. Beta toxins bind voltage-independently at site 4[7] of the voltage-gated sodium channels[8] in neurons. Considering family and homology, it is likely that Tb1 has the same target.
Mode of action
By binding at site 4[7] of voltage-dependent sodium channels,[8] beta-type scorpion toxins shift the activation voltage toward more negative potentials.[9][3] Beta-type scorpion toxins also reduce the amplitude of the sodium current.[9] Since Tb1 is also a beta-type scorpion toxin, it is likely that Tb1 has the same working mechanism.
Toxicity
Intrahippocampal injection of Tb1 in rats causes an excessive release of glutamate, leading to increased glutamate levels.[3] Toxins derived from T. bahiensis can induce seizures in rats and cause damage to hippocampal areas when administered intracerebrally.[10] This injection causes significant respiratory difficulty, myoclonus, wet dog shakes (WDS) and spikes and discharges on EEG.[3] A different study found that, when injected intraperitoneally, 50 µg of purified Tb1 peptide is lethal to mice.[1]
Therapeutic use
Tb1 could serve as a valuable tool for researching the role of sodium channels in seizures, contributing to our comprehension of how these channels participate in the clinical manifestations resulting from abnormal cell excitability. Given the importance of identifying new active compounds to advance the understanding and treatment of channelopathies, this toxin could be an asset for such investigations.[3]
References
- ↑ 1.0 1.1 1.2 1.3 1.4 1.5 Becerril, B.; Corona, M.; Coronas, F. I.; Zamudio, F.; Calderon-Aranda, E. S.; Fletcher, P. L.; Martin, B. M.; Possani, L. D. (1996-02-01). "Toxic peptides and genes encoding toxin gamma of the Brazilian scorpions Tityus bahiensis and Tityus stigmurus". The Biochemical Journal 313 ( Pt 3) (Pt 3): 753–760. doi:10.1042/bj3130753. ISSN 0264-6021. PMID 8611151.
- ↑ 2.0 2.1 2.2 2.3 2.4 2.5 2.6 "UniProt". https://www.uniprot.org/uniprotkb/P56611/entry.
- ↑ 3.0 3.1 3.2 3.3 3.4 3.5 3.6 3.7 Beraldo Neto, Emidio; Freitas, Lucas Alves de; Pimenta, Daniel Carvalho; Lebrun, Ivo; Nencioni, Ana L. A. (2020-01-21). "Tb1, a Neurotoxin from Tityus bahiensis Scorpion Venom, Induces Epileptic Seizures by Increasing Glutamate Release". Toxins 12 (2): 65. doi:10.3390/toxins12020065. ISSN 2072-6651. PMID 31973132.
- ↑ Possani, Lourival D.; Becerril, Baltazar; Delepierre, Muriel; Tytgat, Jan (1999-06-09). "Scorpion toxins specific for Na + ‐channels" (in en). European Journal of Biochemistry 264 (2): 287–300. doi:10.1046/j.1432-1327.1999.00625.x. ISSN 0014-2956. PMID 10491073.
- ↑ Corrêa, M. M.; Sampaio, S. V.; Lopes, R. A.; Mancuso, L. C.; Cunha, O. A.; Franco, J. J.; Giglio, J. R. (1996-11-21). "Biochemical and histopathological alterations induced in rats by Tityus serrulatus scorpion venom and its major neurotoxin tityustoxin-I". Toxicon 35 (7): 1053–1067. doi:10.1016/s0041-0101(96)00219-x. ISSN 0041-0101. PMID 9248004. https://pubmed.ncbi.nlm.nih.gov/9248004.
- ↑ Guerrero-Vargas, Jimmy A.; Mourão, Caroline B. F.; Quintero-Hernández, Verónica; Possani, Lourival D.; Schwartz, Elisabeth F. (2012). "Identification and phylogenetic analysis of Tityus pachyurus and Tityus obscurus novel putative Na+-channel scorpion toxins". PLOS ONE 7 (2): e30478. doi:10.1371/journal.pone.0030478. ISSN 1932-6203. PMID 22355312. Bibcode: 2012PLoSO...730478G.
- ↑ 7.0 7.1 Rodríguez de la Vega, Ricardo C.; Possani, Lourival D. (2005-12-15). "Overview of scorpion toxins specific for Na+ channels and related peptides: biodiversity, structure-function relationships and evolution". Toxicon 46 (8): 831–844. doi:10.1016/j.toxicon.2005.09.006. ISSN 0041-0101. PMID 16274721. https://pubmed.ncbi.nlm.nih.gov/16274721.
- ↑ 8.0 8.1 Quintero-Hernández, V.; Jiménez-Vargas, J. M.; Gurrola, G. B.; Valdivia, H. H.; Possani, L. D. (2013-12-15). "Scorpion venom components that affect ion-channels function". Toxicon 76: 328–342. doi:10.1016/j.toxicon.2013.07.012. ISSN 1879-3150. PMID 23891887.
- ↑ 9.0 9.1 Vijverberg, H. P.; Pauron, D.; Lazdunski, M. (1984-03-17). "The effect of Tityus serrulatus scorpion toxin gamma on Na channels in neuroblastoma cells". Pflügers Archiv: European Journal of Physiology 401 (3): 297–303. doi:10.1007/BF00582600. ISSN 0031-6768. PMID 6089101. https://pubmed.ncbi.nlm.nih.gov/6089101.
- ↑ Beraldo Neto, Emidio; Mariano, Douglas; Freitas, Lucas; Dorce, Ana; Martins, Adriana; Pimenta, Daniel; Portaro, Fernanda; Cajado-Carvalho, Daniela et al. (2018-06-19). "Tb II-I, a Fraction Isolated from Tityus bahiensis Scorpion Venom, Alters Cytokines': Level and Induces Seizures When Intrahippocampally Injected in Rats" (in en). Toxins 10 (6): 250. doi:10.3390/toxins10060250. ISSN 2072-6651. PMID 29921762.
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