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BmKAEP
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BmKAEP (or anti-epilepsy peptide) is a 61 amino acid neurotoxin from the venom of the scorpion Mesobuthus martensii (which historic name is Buthus Martensii Karsch) that modifies the gating process of Na+ channels by shifting the activation voltage of sodium channels toward more negative potentials.
Etymology
editBmK is the abbreviation for Buthus martensi Karsch, the scorpion that is the source of BmKAEP, whereas AEP corresponds to the anti-epilepsy peptide.
Source
editBmKAEP is one of the components of Mesobuthus martensii 's venom [1], a well-known scorpion belonging to the Buthidae family [2], which is distributed through Eastern-Asia and China.
Chemistry
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BmKAEP is a β-toxin, which inhibits Na+ channels. β-toxins act by modifying voltage-gated Na+ channels' activation process [1]. These toxins are classified according to the target-animal and to the modification they cause. Thus, there are mammal (as mice and rats) and insect β-toxins and these can be excitatory or, as BmKAEP, depressant [4].
BmKAEP is a 61 amino acid mature protein derived from an 85 amino acid precursor. The mature protein contains 8 cystein residues that establish 4 disulfide bridges (4C-C) [4]. Despite its high homology with other depressant toxins, BmKAEP differs from them at residues 6, 7 and 39, which is thought to be important in determining its unique function [4]. Its lysine residue, at position 51, also has a special feature: it interacts with mammalian Na+ channels [5].
| BmKAEP primary sequence [6] |
|---|
| 1 mklflllvis asmlidglvn adgyirgsng
31 ckvsclwgne gcnkeckafg ayygycwtwg 61 lacwceglpd dktwksesnt cggkk |
Target and Mode of Action
editBmKAEP binds to the site 4 (S4) of voltage-gated Na+ channels, at domains I, III and IV [7]. Its interaction with the S4 loop causes the loop to be maintained at the outward activated position. Therefore, Na+ channel's voltage-dependent activation shifts towards more negative values [8], enhancing the channel's activation and promoting spontaneous and repetitive firing. Subsequently, the sodium current amplitude decreases, due to the depolarized environment inside the cell, suppressing action potentials [1].
Toxicity
editBmK venom induces a transient phase of contraction followed by a slow progressive flaccid paralysis in insect larvae [9]. However, since it requires a high dosage to be effective, its toxicity is weak, both in insects and mammals [10].
| Toxicity parameters | |
|---|---|
| LD50 | 2,4mg/kg (mice; intraperitoneal injection) [4] |
| MLD (minimum lethal dose) | 0,074mg/kg (mice; Intracerebroventricular injection) [1] |
| CPU (concentration paralysis unit) | 1µg/body (larvae) [1] |
| NOAEL (No observed adverse effect) | <2µg (insects); <20µg (mice) [4] |
Therapeutic use
editThough the exact mechanism of its anti-epilepsy effect is not clear, several studies have shown that BmKAEP can inhibit coriaria lactone-induced epilepsy in rats by prolonging the latent epilepsy period, relieving the degree of seizures and shortening its average duration, at a pharmacological dosage of only 0,057µg/g [10]. This approach has not been tried in Humans.
Mesobuthus martensii, specially its tail, has been used in Chinese traditional medicine to treat several neuronal diseases, such as several types of paralysis, apoplexy and epilepsy [1].
References
edit- ^ a b c d e f Goudet C., Chi Ch., Tytgat J. (2002). An overview of toxins and genes from the venom of the Asian scorpion Buthus martensii Karsch. Toxicon 40, 1239-1256. doi:10.1016/S0041-0101(02)00142-3, PMID: 12220709
- ^ http://www.uniprot.org/taxonomy/34649
- ^ http://swissmodel.expasy.org/repository/?pid=smr03&uid=&token=&query_1_input=P15228&mid=977abc77620b952f40ece6422238d1db_1&zid=async
- ^ a b c d e Wang Ch., He X., Shao F., Liu W., Ling M., Wang Da. and Chi Ch. (2001). Molecular characterization of an anti-epilepsy peptide from the scorpion Buthus martensii Karsch. J.Biochem. 268, 2480-2485. DOI: 10.1046/j.1432-1327.2001.02132.x, PMID: 11298767
- ^ Yuan Yu., Luo L., Peigneur S., Tytgat J., Zhu Sh. (2010). Two recombinant depressant scorpion neurotoxins differentially affecting mamalian sodium channels. Toxicon 55, 1425-1433. doi:10.1016/j.toxicon.2010.02.019, PMID: 20219516
- ^ http://www.ncbi.nlm.nih.gov/protein/37999913?from=1&to=85&report=gpwithparts
- ^ Cestele, S., Catterall, W.A. (2000). Molecular mechanisms of neurotoxin action on voltage-gated sodium channels. Biochimie 82, 883–892. doi:10.1016/S0300-9084(00)01174-3, PMID: 11086218
- ^ Cestèle S., Qu Y., Rogers J.C., Rochat H., Scheuer T., Catterall W.A. (1998) Voltage sensor-trapping: enhanced activation of sodium channels by beta-scorpion toxin bound to the S3-S4 loop in domain II, Neuron 21, 919–931. doi:10.1016/S0896-6273(00)80606-6, PMID: 9808476
- ^ Gurevitz, M., Froy, O., Zilberberg, N., Turkov, M., Strugatsky, D., Gershburg, E., Lee, D., Adams, M.E., Tugarinov, V., Anglister, J., Shaanan, B., Loret, E., Stankiewicz, M., Pelhate, M., Gordon, D., Chejanovsky, N. (1998). Sodium channel modifiers from scorpion venom: structure–activity relationship, mode of action and application. Toxicon 36, 1671–1682. doi:10.1016/S0041-0101(98)00160-3, PMID: 9792184
- ^ a b Zhou, X.H., Yang, D., Zhang, J.H., Liu, C.M., Lei, K.J. (1989). Purification and N-terminal partial sequence of anti-epilepsy peptide from venom of the scorpion Buthus martensii Karsch. Biochem. J. 257, 509–517. PMID: 2930463