Agatoxin

NMR structure (PDB 1OAV) of Omega-agatoxin IVA. The peptide backbone is depicted by a curved cartoon diagram while the amino acid side chains are represented by capped sticks. Carbon atoms are colored grey, nitrogen blue, oxygen red, and sulfur atoms yellow.

Agatoxins are a class of chemically diverse polyamine and peptide toxins which are isolated from the venom of various spiders. Their mechanism of action includes blockade of glutamate-gated ion channels, voltage-gated sodium channels, or voltage-dependent calcium channels. Agatoxin is named after the funnel web spider (Agelenopsis aperta) which produces a venom containing several agatoxins.[1]

Isolation

The venom of the Agelenopsis aperta is located in two glands, which are located in the two fang bases. Ejection of the venom takes place via contraction of surrounding muscles. To obtain this venom, the spider is milked by electrical stimulation. The crude venom is dissolved in an EDTA plasma to avoid proteolysis. Purification of the agatoxin is accomplished by a HPLC procedure.[2][3]

Structure

Agatoxins may be divided into three major structural subclasses:[1]

Alpha-agatoxins

Alpha-agatoxins are composed of polyamines which are attached to an aromatic moiety (see for example AG 489).

Mu-agatoxins

Mu-agatoxins are C-terminally amidated peptides, consisting of 35-37 amino acids and are constrained by four intramolecular disulfide bonds.

Subtype Amino acid length MW (kDa) UniProt
1 36 4273 UniProt: P11057
2 37 4110 UniProt: P11058
3 38 4197 UniProt: P60178
4 37 4208 UniProt: P60178
5 37 4208 UniProt: P11061
6 37 4168 UniProt: P11062

Omega-agatoxins

Omega-agatoxins in turn are subdivided in four classes based on their primary structures, biochemical properties and calcium channels specificity.[1]

Subtype Amino acid length MW (kDa) UniProt
IA 112 12808 UniProt: P15969
IB UniProt: P15969
IIA UniProt: P15971
IIIA 76 8518 UniProt: P33034
IIIB 76 8620 UniProt: P81744
IIIC UniProt: P81745
IIID UniProt: P81746
IVA 48 5210 UniProt: P30288
IVA 83 9167 UniProt: P37045

In several of the omega-agatoxins contain one or more D-amino acids which are produced from L-amino acids through the action of peptide isomerases.[4]

Molecular targets

Mechanism of action

Toxicity

Alpha-agatoxin causes a rapid reversible paralysis in insects, while mu-agatoxin cause a slow long-lasting paralysis. When the two toxins will be injected at the same time, they are synergistic. So co-injection of these toxins leads to a paralysis for a very long, possible everlasting, period of time.[1] Omega-agatoxin injection causes spasms leading to a progressive paralysis which will eventually lead to death in insects. Because insects have a much smaller repertoire of voltage-gated calcium channels and have a different pharmacology than vertebrates the effects can vary between species.[6]

References

  1. 1.0 1.1 1.2 1.3 1.4 1.5 1.6 Adams ME (2004). "Agatoxins: ion channel specific toxins from the American funnel web spider, Agelenopsis aperta". Toxicon 43 (5): 509–25. doi:10.1016/j.toxicon.2004.02.004. PMID 15066410.
  2. Kozlov S, Malyavka A, McCutchen B, Lu A, Schepers E, Herrmann R, Grishin E (2005). "A novel strategy for the identification of toxinlike structures in spider venom". Proteins 59 (1): 131–40. doi:10.1002/prot.20390. PMID 15688451.
  3. Skinner WS, Adams ME, Quistad GB, Kataoka H, Cesarin BJ, Enderlin FE, Schooley DA (1989). "Purification and characterization of two classes of neurotoxins from the funnel web spider, Agelenopsis aperta". J. Biol. Chem. 264 (4): 2150–5. PMID 2914898.
  4. Shikata Y, Ohe H, Mano N, Kuwada M, Asakawa N (1998). "Structural analysis of N-linked carbohydrate chains of funnel web spider (Agelenopsis aperta) venom peptide isomerase". Biosci. Biotechnol. Biochem. 62 (6): 1211–5. doi:10.1271/bbb.62.1211. PMID 9692206.
  5. Doering CJ, Zamponi GW (2003). "Molecular pharmacology of high voltage-activated calcium channels". J. Bioenerg. Biomembr. 35 (6): 491–505. doi:10.1023/B:JOBB.0000008022.50702.1a. PMID 15000518.
  6. King GF (2007). "Modulation of insect Ca(v) channels by peptidic spider toxins". Toxicon 49 (4): 513–30. doi:10.1016/j.toxicon.2006.11.012. PMID 17197008.

External links