Raventoxin

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

Sources

Raventoxins are toxins from the venom of the spider Macrothele raveni. This is a hairy spider, a member of the genus Macrothele, that can be found in the hilly areas of Ningming County, Guangxi Province in China.[1]

Chemistry

Six different types of raventoxin have been described, named raventoxin-I to VI.[1][2][3][4] Raventoxin-I consists of 43 amino acid residues. It has a molecular mass of 4840.11 Da. The toxin is partially homologous to δ-AcTx-Hv1a and δ-AcTx-Ar1, two toxins derived from Hadronyche versuta and Atrax robustus, respectively.[1] Raventoxin-II has a molecular weight of 3021.56 Da.[2] Raventoxin-III is a basic polypeptide, consisting of 29 amino acid residues. It has a molecular mass of 3286.58 Da. Raventoxin-V has a molecular weight of 3133.48 Da.[1] Raventoxin-VI consists of 51 amino acid residues, and has a molecular weight of 5371.6 Da.[4]

Target and mode of action

All described raventoxins have shown to exert a neurotoxic effect.[1][2][3][4] At low concentration, raventoxin-I enhances muscle contraction, suggesting a direct action of the toxin on muscle, whereas at higher concentration it blocks neuromuscular transmission. No toxins have shown to act similarly.[1]

The primary structure of raventoxin-III is identical to that of Magi 5 (β-hexatoxin-Mg1a), a toxin found in the venom of the spider Macrothele gigas.[5] Magi 5 binds at site 4 of the alpha subunit of the mammalian voltage-gated sodium channel Nav1.2 (SCN2A). Binding of Magi 5 to the sodium channels shifts both activation and inactivation to more hyperpolarized voltages and slows the recovery from inactivation.[5] Combined, these effects may lead to increased inactivation of the sodium channels at rest, leading to inhibition and blockage of neuromuscular transmission. The blockage is most probably reversible.[1] Magi-5 competes with the scorpion beta-toxin Css IV for binding to the sodium channelat neurotoxin receptor site 4.[5] One other known property of Magi-5 is its binding to site 3 of the insect sodium channel, observed in lepidopteran larvae, which raises the possibility of homology between the molecular structures of the binding site 3 (in insects) and 4 (in mammals).[6]

Raventoxin-VI blocks neuromuscular transmission in a rat phrenic nerve preparation. Intracerebroventricular injection of the toxin leads to paralysis in rat.[4]

Toxicity

Raventoxin-I and raventoxin-III have both shown excitation, spastic paralysis, gasping, a fast heartbeat and exophthalmos in mice. Only raventoxin-I also shows an increase in salivation. Both toxins can cause death in mice, when sufficiently administered. The LD50 of raventoxin-I is 0.772 mg/kg when intra-abdominally injected in mice.[1] Raventoxin-I and raventoxin-III are not toxic for cockroaches.,[1] but administration of Magi-5 (raventoxin-III) in lepidopteran larvae results in temporary paralysis of the insects.[6] Raventoxin-II and raventoxin-V also have insecticidal effects.[2][3]

Therapeutic use

The effect of administering the whole venom of the Macrothele raveni spider has been studied in several diseases, especially in carcinomata. In HeLa cells, it showed necrosis, direct lysis and apoptosis.[7] The antitumor effect of the venom is also shown in a human breast carcinoma cell line, MCF-7, where cytotoxic changes, apoptosis and necrosis where caused by the venom. After administration of the venom in affected mice, the tumor size significantly decreased compared to the tumor size in control mice.[8]

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References
  1. Zeng XZ (2003). "Purification and characterization of raventoxin-I and raventoxin-III, two neurotoxic peptides from the venom of the spider Macrothele raveni". Toxicon. 41 (6): 651–6. doi:10.1016/s0041-0101(02)00361-6. PMID 12727269.
  2. Zeng, Xiong-zhi, Liang, Song-ping Purification and Preliminary Toxic Research of Raventoxin-II, a Neurotoxic Peptide from the Venom of the Spider Macrothele raveni . Life Science Research. 2001 september; 5(3): 217-220.
  3. Zeng Xiong-zhi, Liang Song-ping. Purification and Preliminary Active Characterization of Raventoxin-V, a Novel Insecticidal Toxin Isolated from the Spider Macrothele Rraveni. Journal of Huaihua University. 2007-04
  4. Zhang Peng fei, Chen Ping, Xiao Shun yong, Liang Song ping.Purification, Characterization of Raventoxin-VI from the Venom of the Spider Macrothele raveni[J];Life Science Research;2003-02
  5. Corzo G, Sabo JK, Bosmans F, Billen B, Villegas E, Tytgat J, Norton RS (2007). "Solution Structure and Alanine Scan of a Spider Toxin That Affects the Activation of Mammalian Voltage-gated Sodium Channels. (2007)". J. Biol. Chem. 282 (7): 4643–4652. doi:10.1074/jbc.m605403200. PMID 17148449.
  6. Corzo G, Gilles N, Satake H, Villegas E, Nakajima T, Haupt J (Jul 2003). "Distinct primary structures of the major peptide toxins from the venom of the spider Macrothele gigas that bind to sites 3 and 4 in the sodium channel". FEBS Lett. 547 (1–3): 43–50. doi:10.1016/s0014-5793(03)00666-5. PMID 12860384.
  7. Gao L, Shan BE, Chen J, Liu JH, Song DX, Zhu BC (Mar 2005). "Effects of spider Macrothele raven venom on cell proliferation and cytotoxicity in HeLa cells". Acta Pharmacol. Sin. 26 (3): 369–76. doi:10.1111/j.1745-7254.2005.00052.x. PMID 15715936.
  8. Gao L, Yu S, Wu Y, Shan B (Jul 2007). "Effect of spider venom on cell apoptosis and necrosis rates in MCF-7 cells". DNA Cell Biol. 26 (7): 485–9. doi:10.1089/dna.2007.0579. PMID 17630852.
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