Azemiopsin

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Azemiopsin, a toxin obtained from the Azemiops feae viper venom, is a polypeptide that consists of 21 amino acid residues. It does not contain cysteine residues or disulfide bridges. The polypeptide can block skeletal muscle contraction by blocking nicotinic acetylcholine receptors.

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The toxin is derived from the venomous glands of the Azemiops feae viper species. The Azemiops feae viper is the only species within the Azemiopinae subfamily, which, together with Crotalinae and Viperinae subfamilies, belongs to the Viperidae family. [1]

Chemistry

Structure

Azemiopsin is a polypeptide molecule consisting of 21 residues, which does not contain cysteine residues or disulfide bridges. [2] Its amino acid sequence is DNWWPKPPHQGPRPPRPRPKP [1] and its molecular weight 2540 Da. Azemiopsin predominantly contains beta-structures: 62% consists of beta-structure (beta sheet + beta-turn), 34% consists of unordered structure, and the remaining 4% consist of alpha helix. [1] This suggests that the polypeptide may likely adopt a hairpin-like structure.

Homology

Azemiopsin is structurally similar to waglerins, which are peptides from the venom produced by Tropidolaemus wagleri . This resemblance is especially apparent in the C-terminal part, which includes alternating prolines and positively charged residues. [1] However, the absence of disulfide bridges in azemiopsin makes this toxin less stable compared to other acetylcholine receptor-blocking peptides.

Target

Azemiopsin is a high-affinity selective inhibitor of muscle-type nicotinic acetylcholine receptors and it can thus block synaptic transmission at the neuromuscular junction. The peptide can inhibit (IC50 ≈19 nM) the muscle nicotinic acetylcholine receptor, assessed by measuring acetylcholine-evoked calcium responses in muscles. The peptide efficiently competes with bungarotoxin for binding to the Torpedo nicotinic acetylcholine receptor (IC50 0.18 ± 0.03 μM). Additionally, it has shown an inhibitory effect on mouse muscle type α1β1εδ nicotinic acetylcholine receptor in nanomolar range (IC50 = 19 ± 8 nM). The peptide is less effective (IC50 ≈3 μM) at α7 nicotinic acetylcholine receptors. The peptide displayed low affinity to α4β2 and α3-containing muscle nicotinic acetylcholine receptor. The peptide showed no effect on the GABA receptor and the 5-HT receptor at concentrations up to respectively 100 μm and 10 μm. [3] [1] [2] In conclusion, azemiopsin shows high selectivity in inhibiting certain nicotinic acetylcholine receptor subtypes.

Mode of Action

Azemiopsin is a blocker of the nicotinic acetylcholine receptor in muscle. [1]

Toxicity

Research has been done on the toxicity of azemiopsin for three different routes of administration in mice: intraperitoneal, intravenous and intramuscular. For intraperitoneal administration LD50 was 2.6 ± 0.3 mg/kg, [1] for intravenous administration LD50 was 0.51 +/- 0.06 mg/kg, and for intramuscular injection, it was 0.732 +/- 0.13 mg/kg. [3] intramuscular injection of Azemiopsin at a dosis between 0.3 mg/kg and 0.7 mg/kg results in various symptoms, including impaired coordination of movements, loss of muscle tone, decreased motor activity, impaired breathing, and decreased response to external stimuli. The symptoms appeared roughly 5 to 7 minutes after injection and were the most severe between 10 and 20 minutes. After a period of 60 minutes, most mice showed almost complete recovery but still had lowered motor activity and muscle tone [3]

Therapeutic Use

Azemiopsin has potential to be used therapeutically as a muscle relaxant because of its ability to selectively inhibit the nicotinic acetylcholine receptors. Moreover, the peptide is not inferior to the relaxants that are currently used but it is still in the preclinical study phase. [3]

Related Research Articles

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Cobratoxin Chemical compound

α-Cobratoxin is a substance of the venom of certain Naja cobras. It is a nicotinic acetylcholine receptor (nAChR) antagonist which causes paralysis by preventing the binding of acetylcholine to the nAChR.

Imperatoxin I (IpTx) is a peptide toxin derived from the venom of the African scorpion Pandinus imperator.

BeKm-1 is a toxin from the Central Asian scorpion Buthus eupeus. BeKm-1 acts by selectively inhibiting the human Ether-à-go-go Related Gene (hERG) channels, which are voltage gated potassium ion channels.

Alpha-neurotoxin Group of neurotoxic peptides found in the venom of snakes

α-Neurotoxins are a group of neurotoxic peptides found in the venom of snakes in the families Elapidae and Hydrophiidae. They can cause paralysis, respiratory failure, and death. Members of the three-finger toxin protein family, they are antagonists of post-synaptic nicotinic acetylcholine receptors (nAChRs) in the neuromuscular synapse that bind competitively and irreversibly, preventing synaptic acetylcholine (ACh) from opening the ion channel. Over 100 α-neurotoxins have been identified and sequenced.

Hainantoxins (HNTX) are neurotoxins from the venom of the Chinese bird spider Haplopelma hainanum. Hainantoxins specifically inhibit tetrodotoxin-sensitive Voltage-gated sodium channels, thereby causing blockage of neuromuscular transmission and paralysis. Currently, 13 different hainantoxins are known, but only HNTX-I, -II, -III, -IV and -V have been investigated in detail.

Huwentoxins (HWTX) are a group of neurotoxic peptides found in the venom of the Chinese bird spider Haplopelma schmidti. The species was formerly known as Haplopelma huwenum, Ornithoctonus huwena and Selenocosmia huwena. While structural similarity can be found among several of these toxins, HWTX as a group possess high functional diversity.

κ-Bungarotoxin Protein neurotoxin of the bungarotoxin family

κ-Bungarotoxin is a protein neurotoxin of the bungarotoxin family that is found in the venom of the many-banded krait, a snake found in Taiwan. κ-Bungarotoxin is a high affinity antagonist of nicotinic acetylcholine receptors (nAChRs), particularly of CHRNA3; it causes a post-synaptic blockade of neurotransmission. Although there is significant variability in the clinical effects of snake bites, neuromuscular paralysis and respiratory failure are associated with krait bites.

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

Three-finger toxin Toxin protein

Three-finger toxins are a protein superfamily of small toxin proteins found in the venom of snakes. Three-finger toxins are in turn members of a larger superfamily of three-finger protein domains which includes non-toxic proteins that share a similar protein fold. The group is named for its common structure consisting of three beta strand loops connected to a central core containing four conserved disulfide bonds. The 3FP protein domain has no enzymatic activity and is typically between 60-74 amino acid residues long. Despite their conserved structure, three-finger toxin proteins have a wide range of pharmacological effects. Most members of the family are neurotoxins that act on cholinergic intercellular signaling; the alpha-neurotoxin family interacts with muscle nicotinic acetylcholine receptors (nAChRs), the kappa-bungarotoxin family with neuronal nAChRs, and muscarinic toxins with muscarinic acetylcholine receptors (mAChRs).

Long neurotoxin 1 (LNTX-1) is a neurotoxin that binds antagonistically to all types of muscular and neuronal nicotinic acetylcholine receptors. LNTX-1 is found in the venom of the king cobra.

Crotoxin (CTX) is the main toxic compound in the snake venom of the South American rattlesnake, Crotalus durissus terrificus. Crotoxin is a heterodimeric beta-neurotoxin, composed of an acidic, non-toxic and non-enzymatic subunit (CA), and a basic, weakly toxic, phospholipase A2 protein (CB). This neurotoxin causes paralysis by both pre- and postsynaptic blocking of acetylcholine signalling.

References

  1. 1 2 3 4 5 6 7 Utkin, Yuri N. (2012). "Azemiopsin from Azemiops feae Viper Venom, a Novel Polypeptide Ligand of Nicotinic Acetylcholine Receptor". Journal of Biological Chemistry. 287 (32): 27079–86. doi: 10.1074/jbc.m112.363051 . PMC   3411050 . PMID   22613724.
  2. 1 2 Kudryavtsev, D (2015). "Natural compounds interacting with nicotinic acetylcholine receptors: from low-molecular weight ones to peptides and proteins". Toxins. 7 (5): 1683–1701. doi: 10.3390/toxins7051683 . PMC   4448168 . PMID   26008231.
  3. 1 2 3 4 Shelukhina, I.V. (2018). ")". Toxins. 34 (10).
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