Bestoxin

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The amino acid sequence of Bestoxin
N - Ala - Asp - Val - Pro - Gly - Asn - Tyr - Pro - Leu - Asp - Lys - Asp - Gly - Asn - Thr - Tyr - Thr - Cys - Leu - Glu - Leu - Gly - Glu - Asn - Lys - Asp - Cys - Gln - Lys - Val - Cys - Lys - Leu - His - Gly - Val - Gln - Tyr - Gly - Tyr - Cys - Tyr - Ala - Phe - Ser - Cys - Trp - Cys - Lys - Glu - Tyr - Leu - Asp - Asp - Lys - Asp - Ser - Val - OH

Bestoxin is a neurotoxin from the venom of the South African spitting (or fattail) scorpion Parabuthus transvaalicus . Most likely, it targets sodium channel function, thus promoting spontaneous and repetitive neuronal firing. Following injection into mice, it causes non-lethal writhing behaviour.

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South African spitting scorpion (Parabuthus transvaalicus) Parabuthus transvaalicus (male).jpg
South African spitting scorpion (Parabuthus transvaalicus)

Bestoxin is one of the many components that can be isolated from the venom of the South African spitting scorpion. Other peptide toxins also found in the venom include dortoxin, birtoxin, and altitoxin. [1] Together with birtoxin, dorotoxin, altitoxin and ikitoxin, this mammal-specific ion channel toxin is a member of the birtoxin polypeptide family. These birtoxin-like polypeptides contribute significantly to the venom's toxicity, since they constitute at least 30% of the peptides in the venom of this scorpion. [2]

Chemistry

Although the birtoxin-like polypeptides, including bestoxin, are 58 amino acids long and have only three disulfide bridges, they resemble long chain neurotoxins, which typically have a length of 60–70 amino acids and four disulfide bridges. [1] Bestoxin, as most of the known scorpion toxins, has α-helixes that are lined up with basic amino acid residues. Furthermore, bestoxin has localized positively and negatively charged surfaces, a unique property of the birtoxin polypeptide family. [2]

Target & mode of action

Based on its resemblance to long chain β-neurotoxins, bestoxin most likely binds to neurotoxin receptor site 4 of the sodium channel. Binding of long chain β-neurotoxins is voltage-independent, and results in a shift of the voltage-activation curve towards more negative potentials, inducing abnormal sodium channel permeability and promoting spontaneous and repetitive firing. [3] [4] [5]

Toxicity

Mice injected with bestoxin show intense writhing. This abnormal behavior is characterized by twisting of the neck, followed by the body, and making a full turn around the body axis. The intensity of this behavior increases over time and the mice start to spin around. After approximately 24 hours the amount of writhing decreases and the twisting behavior gradually slows down to one turn per two seconds. Furthermore, there is no lethality observed. The dosage that produces a desired effect in 99% of the test population, or ED99, of bestoxin is 100 ng of peptide per 20 g mouse bodyweight. [1] No data is available on the effect of bestoxin in humans or primates.

Treatment

Bestoxin is one of the many neurotoxic peptidic components in the venom of the South African spitting scorpion. The birtoxin-like peptides share an N-terminus of eighteen amino acid residues. Neutralization of this domain results in a decrease of toxicity of the venom. [6] Mass spectrometry and western blotting confirmed that these neurotoxins react with polyclonal antibodies and it is proposed that polyclonal antibodies will neutralize the N-terminus domain and finally the venom in a dose dependent manner. Moreover, previous work has proven that this polyclonal antibody approach is an effective strategy for antivenom production. [6]

Related Research Articles

Poneratoxin is a paralyzing neurotoxic peptide made by the bullet ant Paraponera clavata. It prevents inactivation of voltage gated sodium channels and therefore blocks the synaptic transmission in the central nervous system. Specifically, poneratoxin acts on voltage gated sodium channels in skeletal muscle fibers, causing paralysis, and nociceptive fibers, causing pain. It is rated as a 4 plus on the Schmidt sting pain index, the highest possible rating with that system, and its effects can cause waves of pain up to twelve hours after a single sting. Schmidt describes it as "pure, intense, brilliant pain...like walking over flaming charcoal with a three-inch nail embedded in your heel." It is additionally being studied for its uses in biological insecticides.

Delta atracotoxin

Delta atracotoxin is a low-molecular-weight neurotoxic polypeptide found in the venom of the Sydney funnel-web spider.

Calciseptine

Calciseptine (CaS) is a natural neurotoxin isolated from the black mamba Dendroaspis p. polylepis venom. This toxin consists of 60 amino acids with four disulfide bonds. Calciseptine specifically blocks L-type calcium channels, but not other voltage-dependent Ca2+ channels such as N-type and T-type channels.

Tityustoxin is a toxin found in the venom of scorpions from the subfamily Tityinae. By binding to voltage-dependent sodium ion channels and potassium channels, they cause sialorrhea, lacrimation and rhinorrhea.

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.

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.

Altitoxin is a neurotoxin found in the South African scorpion Parabuthus transvaalicus. Injection of altitoxin in mice leads to akinesia, depression and death.

Dortoxin is a lethal peptide toxin which is secreted by the South African spitting scorpion Parabuthus transvaalicus. Injection of pure dortoxin in mice leads to hyperactivity that lasts until death.

Bukatoxin is an α-scorpion toxin found in the venom of the Chinese scorpion Buthus martensi Karsch. By blocking the inactivation of sodium ion channels, α-scorpion toxins prolong action potentials.

Ikitoxin is a neurotoxin from the venom of the South African Spitting scorpion that targets voltage-sensitive sodium channels. It causes unprovoked jumps in mice following intracerebroventricular injections.

<i>delta</i>-Palutoxin

delta-Palutoxins (δ-palutoxins) consist of a homologous group of four insect-specific toxins from the venom of the spider Pireneitega luctuosa. They show a high toxicity against Spodoptera litura larvae by inhibiting sodium channels, leading to strong paralytic activity and eventually to the death of the insect.

Raventoxins are neurotoxins from the venom of the spider Macrothele raveni.

Halcurin is a polypeptide neurotoxin from the sea anemone Halcurias sp. Based on sequence homology to type 1 and type 2 sea anemone toxins it is thought to delay channel inactivation by binding to the extracellular site 3 on the voltage gated sodium channels in a membrane potential-dependent manner.

Cangitoxin, also known as CGTX or CGX, is a toxin purified from the venom of the sea anemone Bunodosoma cangicum, which most likely acts by prolonging the inactivation of voltage-gated sodium channels.

Cll1 Scorpion protein

Toxin Cll1 is a toxin from the venom of the Mexican scorpion Centruroides limpidus limpidus, which changes the activation threshold of sodium channels by binding to neurotoxin binding site 4, resulting in increased excitability.

Spinoxin is a 34-residue peptide neurotoxin isolated from the venom of the Malaysian black scorpion Heterometrus spinifer. It is part of the α-KTx6 subfamily and exerts its effects by inhibiting voltage-gated potassium channels, specifically Kv1.2 and Kv1.3.

LmαTX3 is an α-scorpion toxin from Lychas mucronatus. that inhibits fast inactivation of voltage gated sodium-channels (VGSCs).

Beta-mammal toxin Cn2, also known as Cn2 toxin, is a single chain β-scorpion neurotoxic peptide and the primary toxin in the venom of the Centruroides noxius Hoffmann scorpion. The toxin specifically targets mammalian Nav1.6 voltage-gated sodium channels (VGSC).

LmαTX5 is an α-scorpion toxin which inhibits the fast inactivation of voltage-gated sodium channels. It has been identified through transcriptome analysis of the venom gland of Lychas mucronatus, also known as the Chinese swimming scorpion – a scorpion species which is widely distributed in Southeast Asia.

References

  1. 1 2 3 Inceoglu, B; J Lango; I Pessah; B Hammock (2005). "Three structurally related, highly potent, peptides from the venom of possess divergent biological activity". Toxicon. 45 (6): 727–733. doi:10.1016/j.toxicon.2005.01.020. ISSN   0041-0101. PMID   15804521.
  2. 1 2 Zeng, Xian-Chun; Luo, Feng; Wen-Xin, Li (2006). "Molecular dissection of venom from Chinese scorpion Mesobuthus martensii: Identification and Characterization of four novel disulfide-bridged venom peptides". Peptides. 27 (7): 1745–1754. doi:10.1016/j.peptides.2006.01.012. PMID   16513212. S2CID   12636773.
  3. ↑ Possani, Lourival; Merino, Enrique; Corona, Miguel; Bolivar, Francisco; Becerril, Baltazar (2000). "Peptides and genes coding for scorpion toxins that affect ion-channels". Biochimie. 82 (9–10): 861–868. doi:10.1016/S0300-9084(00)01167-6. PMID   11086216.
  4. ↑ Couraud, F; Jover, E; Dubois, J.M; Rochat, H (1982). "Two types of scorpion toxin receptor sites, one related to the activation, the other to the inactivation of the action potential sodium channel". Toxicon. 20 (1): 9–16. doi:10.1016/0041-0101(82)90138-6. PMID   6281941.
  5. ↑ https://www.uniprot.org/uniprot/P0C1B6 - Bestoxin - Parabuthus transvaalicus (South African fattail scorpion)
  6. 1 2 Inceoglu, Bora; Lango, Jozsef; Rabinovich, Alina; Whetstone, Paul; Hammock, Bruce D. (2006). "The neutralizing effect of a polyclonal antibody raised against the N-terminal eighteen-aminoacid residues of birtoxin towards the whole venom of Parabuthus transvaalicus". Toxicon. 47 (2): 144–149. doi:10.1016/j.toxicon.2005.08.018. PMID   16356521.
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