Tamulotoxin

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).

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]

References
  1. 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. 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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