BmKAEP

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BmKAEP (or anti-epilepsy peptide) 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.


Etymology[edit]

BmK is the abbreviation for Buthus martensi Karsch, an old name for the scorpion that is the source of BmKAEP; AEP is an abbreviation for anti-epilepsy peptide. At the NCBI Protein Database, the full name of this peptide is listed as "Toxin BmKAEP".[1]

Source[edit]

Manchurian scorpion (Mesobuthus martensii)

BmKAEP is one of the components of Mesobuthus martensii′s venom,[2] a well-known scorpion belonging to the Buthidae family, which is found distributed throughout Eastern Asia and China.

Chemistry[edit]

BmKAEP is an inhibitory β-toxin and thus, a Na+ channel inhibitor. As with other mammal and insect toxins, BmKAEP is classified according to species and mechanism of action.[3]

BmKAEP is a 61-amino-acid protein derived from an 85-amino-acid precursor. The mature protein contains 8 cysteine residues that establish 4 disulfide bridges (4C-C).[3] 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.[3] Its lysine residue, at position 51, also has a special feature: it interacts with mammalian Na+ channels.[4]

BmKAEP primary sequence [Source: UniProt P15228]

01 mklflllvis asmlidglvn adgyirgsng
31 ckvsclwgne gcnkeckafg ayygycwtwg
61 lacwceglpd dktwksesnt cggkk

Target and Mode of Action[edit]

Because of its sequence homology with other β-toxins, BmKAEP is predicted to bind to site 4 (S4) of voltage-gated Na+ channels, at domains I, III and IV.[5] Its interaction with the S4 loop causes the loop to be maintained at the outward activated position. Therefore, activation of the Na+ channels shifts towards more negative values,[6] enhancing the channel's activation and promoting spontaneous and repetitive firing. Subsequently, the sodium current amplitude decreases, due to the membrane potential depolarization, thus suppressing action potentials.[2]

Toxicity[edit]

BmK venom induces a transient phase of contraction followed by a slow progressive flaccid paralysis in insect larvae.[7] However, since it requires a high dosage to be effective, its toxicity is weak, both in insects and mammals.[8]

Toxicity parameters
LD50 2,4 mg/kg (mice; intraperitoneal injection)[3]
MLD (minimum lethal dose) 0,074 mg/kg (mice; Intracerebroventricular injection)[2]
CPU (concentration paralysis unit) 1 µg/body (larvae)[2]
NOAEL (No observed adverse effect) <2 µg (insects); <20 µg (mice)[3]

Therapeutic use[edit]

Though 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 0,057 µg/g.[8]

Mesobuthus martensii, especially its tail, has been used in Chinese traditional medicine to treat several neuronal diseases, such as several types of paralysis, apoplexy and epilepsy.[2]

References[edit]

  1. ^ "Toxin BmKAEP". NCBI Protein database. Retrieved 25 October 2010. 
  2. ^ a b c d e Goudet, C; Chi, CW; Tytgat, J (2002). "An overview of toxins and genes from the venom of the Asian scorpion Buthus martensi Karsch". Toxicon 40 (9): 1239–58. doi:10.1016/S0041-0101(02)00142-3. PMID 12220709. 
  3. ^ a b c d e Wang, Chun-Guang; He, Xiao-Lin; Shao, Feng; Liu, Wei; Ling, Min-Hua; Wang, Da-Cheng; Chi, Cheng-Wu (2001). "Molecular characterization of an anti-epilepsy peptide from the scorpion Buthus martensi Karsch". European Journal of Biochemistry 268 (8): 2480–5. doi:10.1046/j.1432-1327.2001.02132.x. PMID 11298767. 
  4. ^ Yuan, Yuzhe; Luo, Lan; Peigneur, Steve; Tytgat, Jan; Zhu, Shunyi (2010). "Two recombinant depressant scorpion neurotoxins differentially affecting mammalian sodium channels". Toxicon 55 (8): 1425–33. doi:10.1016/j.toxicon.2010.02.019. PMID 20219516. 
  5. ^ Cestèle, S; Catterall, WA (2000). "Molecular mechanisms of neurotoxin action on voltage-gated sodium channels". Biochimie 82 (9–10): 883–92. doi:10.1016/S0300-9084(00)01174-3. PMID 11086218. 
  6. ^ Cestele, S; Qu, Y; Rogers, J; Rochat, H; Scheuer, T; Catterall, W (1998). "Voltage Sensor–TrappingEnhanced Activation of Sodium Channels by β-Scorpion Toxin Bound to the S3–S4 Loop in Domain II". Neuron 21 (4): 919–31. doi:10.1016/S0896-6273(00)80606-6. PMID 9808476. 
  7. ^ Gurevitz, Michael; Froy, Oren; Zilberberg, Noam; Turkov, Michael; Strugatsky, David; Gershburg, Eduard; Lee, Daewoo; Adams, Michael E. et al. (1998). "Sodium channel modifiers from scorpion venom: Structure–activity relationship, mode of action and application". Toxicon 36 (11): 1671–82. doi:10.1016/S0041-0101(98)00160-3. PMID 9792184. 
  8. ^ a b Zhou, XH; Yang, D; Zhang, JH; Liu, CM; Lei, KJ (1989). "Purification and N-terminal partial sequence of anti-epilepsy peptide from venom of the scorpion Buthus martensii Karsch". The Biochemical journal 257 (2): 509–17. PMC 1135608. PMID 2930463. 

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