Tamulotoxin

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Tamulotoxin (or Tamulus toxin, Tamulustoxin, in short form: TmTx) is a venomous neurotoxin from the Indian Red Scorpion ( Hottentotta tamulus , Mesobuthus tamulus or Buthus tamulus).

Contents

Chemistry

Structure

The toxin has been classified as a short-chain scorpion toxin. [1] It consists of 36 amino acids and is referred to as TmTx1. [2] A peptide consisting of 35 amino acids has also been identified, [1] referred to as TmTx2. [2] It possesses three intra-molecular disulphide bonds (S-S), leading to a highly stabilized conformation. It also has six cysteine residues which is a characteristic shared by many short-chain scorpion toxins.

Family

TmTx belongs to the short scorpion toxin superfamily and the potassium channel inhibitor family. [3] Adhering to the nomenclature of Tytgat et al., [4] potassium toxins can be divided into four subgroups: alpha, beta, gamma and kappa. It belongs to the group of alpha potassium toxins (α-KTx: alpha toxin affecting potassium channels). This group contains short-chain peptides of 23-42 acids with three or four disulphide bridges. The primary targets consist of voltage-gated Shaker-related potassium channels, ether-a-go-go related gene (HERG) potassium channels in the heart and calcium activated potassium channels. Within this family, TmTx belongs to the α-KTx 16 subfamily.

Homology

TmTx shows no homology with other species of scorpion toxins in BLAST of the TmTx sequence, [1] apart from the position of its six cysteine residues. It is nevertheless categorized with other potassium channel scorpion toxins, because it shares the position of its six cysteine residues with other toxins. In phylogeny, TmTx does have similarities with other scorpion neurotoxins. [2]

Target and mode of action

A comparative model has been suggested for the 3D protein structure of TmTx by using information from homologous proteins with known structures. [5] Based on this model, it is highly likely that TmTx blocks calcium activated potassium channels by binding to the S5-S6 segment and thus blocking its pore. The active site of TmTx in this model consists of 5 amino acids, which is essential for the activity of TmTx. These amino acids would be responsible for inhibiting transport of ions. On the other hand, TmTx does not seem to inhibit [125I] apamin binding to synaptic membranes in the rat brain or ionomycin-induced 86Rb+ fluxes in C6 cells in vitro. [1] This suggests that TmTx does not have an effect on SK channels or charybdotoxin-sensitive IK channels (calcium-activated potassium channel), respectively. Another suggested target is the Kv1.6 channel, [1] a voltage-gated potassium channel. There are two suggestions for the mode of action. Either it works via blocking the open channel, or there could be a modulation of slow inactivation of this channel. Upon wash, a complete reversal of the block occurred, suggesting that the binding of the toxin to the channel is not very strong.

Toxicity

Injection of the venom of H. tamulus in rats induces hyperventilatory and hypertensive responses [6] [7] and in humans. [8] The toxicity of the venom varies with age and species. [9]

Treatment

Based on the structure, biological compounds can be identified which could have a maximum binding affinity to the active site of TmTx toxin protein and thereby preventing the toxin to bind to the ionic pore of the channel. [10] Therefore, these compounds could in future be used as an antidote for TmTx. Three bioactive compounds have been identified from the plants Andrographis paniculata and Ocimum basilicum . Based on computer models, separate ligands have also been identified, which could block TmTx. [11]

Related Research Articles

Charybdotoxin

Charybdotoxin (CTX) is a 37 amino acid neurotoxin from the venom of the scorpion Leiurus quinquestriatus hebraeus (deathstalker) that blocks calcium-activated potassium channels. This blockade causes hyperexcitability of the nervous system. It is a close homologue of agitoxin and both toxins come from Leiurus quinquestriatus hebraeus. It is named after Charybdis, a sea monster from Greek myth.

Iberiotoxin (IbTX) is an ion channel toxin purified from the Eastern Indian red scorpion Hottentotta tamulus. Iberiotoxin selectively inhibits the current through large-conductance calcium-activated potassium channels.

Tamapin is a toxin from the Indian Red Scorpion, which is a selective and potent blocker of SK2 channels.

Scorpion toxin

Scorpion toxins are proteins found in the venom of scorpions. Their toxic effect may be mammal- or insect-specific and acts by binding with varying degrees of specificity to members of the Voltage-gated ion channel superfamily; specifically, voltage-gated sodium channels, voltage-gated potassium channels, and Transient Receptor Potential (TRP) channels. The result of this action is to activate or inhibit the action of these channels in the nervous and cardiac organ systems. For instance, α-scorpion toxins MeuNaTxα-12 and MeuNaTxα-13 from Mesobuthus eupeus are neurotoxins that target voltage-gated Na+ channels (Navs), inhibiting fast inactivation. In vivo assays of MeuNaTxα-12 and MeuNaTxα-13 effects on mammalian and insect Navs show differential potency. These recombinants exhibit their preferential affinity for mammalian and insect Na+ channels at the α-like toxins' active site, site 3, in order to inactivate the cell membrane depolarization faster[6]. The varying sensitivity of different Navs to MeuNaTxα-12 and MeuNaTxα-13 may be dependent on the substitution of a conserved Valine residue for a Phenylalanine residue at position 1630 of the LD4:S3-S4 subunit or due to various changes in residues in the LD4:S5-S6 subunit of the Navs. Ultimately, these actions can serve the purpose of warding off predators by causing pain or to subdue predators.

BmTx3 is a neurotoxin, which is a component of the venom of the scorpion Buthus Martensi Karsch. It blocks A-type potassium channels in the central nervous system and hERG-channels in the heart.

Lq2

Lq2 is a component of the venom of the scorpion Leiurus quinquestriatus. It blocks various potassium channels, among others the inward-rectifier potassium ion channel ROMK1.

Birtoxin is a neurotoxin from the venom of the South African Spitting scorpion. By changing sodium channel activation, the toxin promotes spontaneous and repetitive firing much like pyrethroid insecticides do

BmKAEP is a neurotoxin from the venom of the Manchurian scorpion (Mesobuthus martensii). It is a β-toxin, which shift the activation voltage of sodium channels towards more negative potentials.

In molecular biology, the BmKK2 toxins are a family of scorpion toxins. They belong to the scorpion toxin subfamily alpha-KTx 14. They include a novel short-chain peptide from the Asian scorpion Mesobuthus martensii Karsch, a potassium channel blocker composed of 31 amino acid residues. The peptide adopts a classical alpha/beta-scaffold for alpha-KTxs. BmKK2 selectively inhibits the delayed rectifier K+ current, but does not affect the fast transient K+ current.

<i>Mesobuthus eupeus</i> Species of scorpion

Mesobuthus eupeus is a polymorphic scorpion species belonging to the well-known family Buthidae. Commonly known as the lesser Asian scorpion or the mottled scorpion. It is thought to be the most widely dispersed species of the genus Mesobuthus, perhaps even of the family Buthidae.

BeKm-1 is a toxin from the Central Asian scorpion Buthus eupeus. BeKm-1 acts by selectively inhibiting the human Ether-à-go-go Related Gene (hERG) channels, which are voltage gated potassium ion channels.

Butantoxin (BuTX) is a compound of the venom of three Brazilian and an Argentinean scorpion species of the genus Tityus. Butantoxin reversibly blocks the voltage-gated K+ channels Shaker B and Kv1.2, and the Ca2+-activated K+ channelsKCa 1.1 and KCa 3.1.

Pandinus imperator (Pi3) toxin

Pi3 toxin is a purified peptide derivative of the Pandinus imperator scorpion venom. It is a potent blocker of voltage-gated potassium channel, Kv1.3 and is closely related to another peptide found in the venom, Pi2.

HsTx1 is a toxin from the venom of the scorpion Heterometrus spinifer. HsTx1 is a very potent inhibitor of the rat Kv1.3 voltage-gated potassium channel.

Limbatustoxin, is an ion channel toxin from the venom of the Centruroides limbatus scorpion. This toxin is a selective blocker of BK channels, calcium-activated potassium channels.

Noxiustoxin

Noxiustoxin (NTX) is a toxin from the venom of the Mexican scorpion Centruroides noxius Hoffmann which block voltage-dependent potassium channels and calcium-activated potassium channels.

AaTX1 is a scorpion toxin of the α-KTx15 subfamily originally found in the venom of Androctonus australis. The toxin acts as a specific blocker on Kv4.3 voltage-gated potassium channel, thereby abolishing the A-type potassium currents.

ImKTx88

ImKTx88 is a selective inhibitor of the Kv1 ion channel family that can be isolated from the venom of the Isometrus maculatus. This peptide belongs to the α-KTx subfamily and is classified as a pore-blocking toxin.

BmP02, also known as α-KTx 9.1 or Bmkk(6), is a toxin from the Buthus Martensi Karsch (BmK) scorpion. The toxin acts on potassium channels, blocking Kv1.3 and slowing the deactivation of Kv4.2. BmP02 is not toxic to humans or mice.

BmK NSPK is a toxin isolated from the venom of the Chinese armor-tail scorpion, which specifically targets voltage gated potassium channels (Kv), resulting in a direct inhibition of outward potassium current.

References

  1. 1 2 3 4 5 Strong, PN; Clark, GS; Armugam, A; De-Allie, FA; Joseph, JS; Yemul, V; Deshpande, JM; Kamat, R; Gadre, SV; Gopalakrisnakone, P; Kini, RM; Owen, DG; Jeyaseelan, K (1 January 2001). "Tamulustoxin: A Novel Potassium Channel Blocker from the Venom of the Indian Red Scorpion Mesobuthus tamulus". Archives of Biochemistry and Biophysics. 385 (1): 138–144. doi:10.1006/abbi.2000.2135. PMID   11361010.
  2. 1 2 3 Rodríguez de la Vega, RC; Possani, LD (15 June 2004). "Current views on scorpion toxins specific for K+-channels". Toxicon. 43 (8): 865–875. doi:10.1016/j.toxicon.2004.03.022. PMID   15208019.
  3. ↑ "Animal Toxin Database" . Retrieved 13 October 2014.
  4. ↑ Tytgat, J; Chandy, KG; Garcia, ML; Gutman, GA; Martin-Eauclaire, MF; Van der Walt, JJ; Possani, LD (1 November 1999). "A unified nomenclature for short-chain peptides isolated from scorpion venoms: α-KTx molecular subfamilies". Trends in Pharmacological Sciences. 20 (11): 444–447. doi:10.1016/S0165-6147(99)01398-X. PMID   10542442.
  5. ↑ Kumar, RB; Suresh, MX (10 January 2013). "Homology modeling, molecular dynamics simulation and protein-protein interaction studies on calcium activated potassium channel blocker, Tamulotoxin from Buthus tamulus". Advanced BioTech. 12 (7): 11–14. Archived from the original on 13 October 2014. Retrieved 13 October 2014.
  6. ↑ Singh, SK; Deshpande, SB (13 June 2008). "Injection of Mesobuthus tamulus venom in distal segment of femoral artery evokes hyperventilatory and hypertensive responses in anaesthetised rats". Neuroscience Letters. 438 (1): 64–66. doi:10.1016/j.neulet.2008.04.037. PMID   18472330. S2CID   25722401.
  7. ↑ Pandey, R; Deshpande, SB (August 2004). "Protective effects of aprotinin on respiratory and cardiac abnormalities induced by Mesobuthus tamulus venom in adult rats". Toxicon. 44 (2): 201–205. doi:10.1016/j.toxicon.2004.05.025. PMID   15246770.
  8. ↑ Bawaskar, HS; Bawaskar, PH (January 2012). "Scorpion sting: update". The Journal of Association of Physicians in India. 60: 46–55. PMID   22715546 . Retrieved 13 October 2014.
  9. ↑ Tiwari, AK; Deshpande, SB (December 1993). "Toxicity of scorpion (Buthus tamulus) venom in mammals is influenced by the age and species". Toxicon. 31 (12): 1619–1622. doi:10.1016/0041-0101(93)90346-K. PMID   8146875.
  10. ↑ Kumar, RB; Suresh, MX (April 2013). "Computational analysis of bioactive phytochemicals as potential inhibitors for calcium activated potassium channel blocker, tamulotoxin from Mesobuthus tamulus". Pharmacognosy Journal. 5 (2): 41–45. doi:10.1016/j.phcgj.2013.02.001.
  11. ↑ Kumar, RB; Suresh, MX (April 2013). "Pharmacophore mapping based inhibitor selection and molecular interaction studies for identification of potential drugs on calcium activated potassium channel blockers, tamulotoxin". Pharmacognosy Magazine. 9 (34): 89–95. doi:10.4103/0973-1296.111239. PMC   3680861 . PMID   23772102.
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