Conotoxin

Last updated
Alpha conotoxin precursor
Alpha-Conotoxin from Conus pennaceus 1AKG.png
α-Conotoxin PnIB from C. pennaceus, disulfide bonds shown in yellow. From the University of Michigan's Orientations of Proteins in Membranes database, PDB: 1AKG ​.
Identifiers
SymbolToxin_8
Pfam PF07365
InterPro IPR009958
PROSITE PDOC60004
SCOP2 1mii / SCOPe / SUPFAM
OPM superfamily 148
OPM protein 1akg
Available protein structures:
Pfam   structures / ECOD  
PDB RCSB PDB; PDBe; PDBj
PDBsum structure summary
Omega conotoxin
Ziconotide 1DW5.png
Schematic diagram of the three-dimensional structure of ω-conotoxin MVIIA (ziconotide). Disulfide bonds are shown in gold. From PDB: 1DW5 ​.
Identifiers
SymbolConotoxin
Pfam PF02950
InterPro IPR004214
SCOP2 2cco / SCOPe / SUPFAM
OPM superfamily 112
OPM protein 1fyg
Available protein structures:
Pfam   structures / ECOD  
PDB RCSB PDB; PDBe; PDBj
PDBsum structure summary

A conotoxin is one of a group of neurotoxic peptides isolated from the venom of the marine cone snail, genus Conus .

Contents

Conotoxins, which are peptides consisting of 10 to 30 amino acid residues, typically have one or more disulfide bonds. Conotoxins have a variety of mechanisms of actions, most of which have not been determined. However, it appears that many of these peptides modulate the activity of ion channels. [1] Over the last few decades conotoxins have been the subject of pharmacological interest. [2]

The LD50 of conotoxin ranges from 5-25 μg/kg. [3] [4] [5]

Hypervariability

Conotoxins are hypervariable even within the same species. They do not act within a body where they are produced (endogenously) but act on other organisms. [6] Therefore, conotoxin genes experience less selection against mutations (like gene duplication and nonsynonymous substitution), and mutations remain in the genome longer, allowing more time for potentially beneficial novel functions to arise. [7] Variability in conotoxin components reduces the likelihood that prey organisms will develop resistance; thus cone snails are under constant selective pressure to maintain polymorphism in these genes because failing to evolve and adapt will lead to extinction ( Red Queen hypothesis ). [8]

Disulfide connectivities

Types of conotoxins also differ in the number and pattern of disulfide bonds. [9] The disulfide bonding network, as well as specific amino acids in inter-cysteine loops, provide the specificity of conotoxins. [10]

Types and biological activities

The number of conotoxins whose activities have been determined so far is five, and they are called the α(alpha)-, δ(delta)-, κ(kappa)-, μ(mu)-, and ω(omega)- types. Each of the five types of conotoxins attacks a different target:

Alpha

Alpha conotoxins have two types of cysteine arrangements, [18] and are competitive nicotinic acetylcholine receptor antagonists.

Delta, kappa, and omega

Omega, delta and kappa families of conotoxins have a knottin or inhibitor cystine knot scaffold. The knottin scaffold is a very special disulfide-through-disulfide knot, in which the III-VI disulfide bond crosses the macrocycle formed by two other disulfide bonds (I-IV and II-V) and the interconnecting backbone segments, where I-VI indicates the six cysteine residues starting from the N-terminus. The cysteine arrangements are the same for omega, delta and kappa families, even though omega conotoxins are calcium channel blockers, whereas delta conotoxins delay the inactivation of sodium channels, and kappa conotoxins are potassium channel blockers. [9]

Mu

Mu-conotoxin
PDB 1r9i EBI.jpg
nmr solution structure of piiia toxin, nmr, 20 structures
Identifiers
SymbolMu-conotoxin
Pfam PF05374
Pfam clan CL0083
InterPro IPR008036
SCOP2 1gib / SCOPe / SUPFAM
OPM superfamily 112
OPM protein 1ag7
Available protein structures:
Pfam   structures / ECOD  
PDB RCSB PDB; PDBe; PDBj
PDBsum structure summary

Mu-conotoxins have two types of cysteine arrangements, but the knottin scaffold is not observed. [19] Mu-conotoxins target the muscle-specific voltage-gated sodium channels, [9] and are useful probes for investigating voltage-dependent sodium channels of excitable tissues. [19] [20] Mu-conotoxins target the voltage-gated sodium channels, preferentially those of skeletal muscle, [21] and are useful probes for investigating voltage-dependent sodium channels of excitable tissues. [22]

Different subtypes of voltage-gated sodium channels are found in different tissues in mammals, e.g., in muscle and brain, and studies have been carried out to determine the sensitivity and specificity of the mu-conotoxins for the different isoforms. [23]

See also

Related Research Articles

<span class="mw-page-title-main">Ziconotide</span> Drug for chronic pain

Ziconotide, sold under the brand name Prialt, also called intrathecal ziconotide (ITZ) because of its administration route, is an atypical analgesic agent for the amelioration of severe and chronic pain. Derived from Conus magus, a cone snail, it is the synthetic form of an ω-conotoxin peptide. It is 1,000 times as powerful as morphine.

<span class="mw-page-title-main">Calciseptine</span> Neurotoxin

Calciseptine (CaS) is a natural neurotoxin isolated from the black mamba Dendroaspis p. polylepis venom. This toxin consists of 60 amino acids with four disulfide bonds. Calciseptine specifically blocks L-type calcium channels, but not other voltage-dependent Ca2+ channels such as N-type and T-type channels.

The P-type calcium channel is a type of voltage-dependent calcium channel. Similar to many other high-voltage-gated calcium channels, the α1 subunit determines most of the channel's properties. The 'P' signifies cerebellar Purkinje cells, referring to the channel's initial site of discovery. P-type calcium channels play a similar role to the N-type calcium channel in neurotransmitter release at the presynaptic terminal and in neuronal integration in many neuronal types.

<span class="mw-page-title-main">Agatoxin</span>

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 which produces a venom containing several agatoxins. There are different agatoxins. The ω‎-agatoxins are approximately 100 amino acids in length and are antagonists of voltage-sensitive calcium channels and also block the release of neurotransmitters. For instance, the ω‎-agatoxin 1A is a selective blocker and will block L-type calcium channels whereas the ω‎-agatoxin 4B will inhibit voltage sensitive P-type calcium channels. The μ‎-agatoxins only act on insect voltage-gated sodium channels.

<span class="mw-page-title-main">Contryphan</span>

The contryphans are a family of peptides that are active constituents of the potent venom produced by cone snail. The two amino acid cysteine residues in contryphans are linked by a disulfide bond. In addition, contryphans undergo an unusual degree of post-translational modification including epimerization of leucine and tryptophan, tryptophan bromination, amidation of the C-terminus, and proline hydroxylation. In the broader scheme of genetic conotoxin classification, contryphans are members of "Conotoxin Superfamily O2."

Birtoxin is a neurotoxin from the venom of the South African Spitting scorpion. By changing sodium channel activation, the toxin promotes spontaneous and repetitive firing much like pyrethroid insecticides do

Bestoxin is a neurotoxin from the venom of the South African spitting scorpion Parabuthus transvaalicus. Most likely, it targets sodium channel function, thus promoting spontaneous and repetitive neuronal firing. Following injection into mice, it causes non-lethal writhing behaviour.

BmKAEP 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.

Conantokins are a small family of helical peptides that are derived from the venom of predatory marine snails of the genus Conus. Conantokins act as potent and specific antagonists of the N-methyl-D-aspartate receptor (NMDAR). They are the only naturally-derived peptides to do so. The subtypes of conantokins exhibit a surprising variability of selectivity across the NMDAR subunits, and are therefore uniquely useful in developing subunit-specific pharmacological probes.

<i>delta</i>-Palutoxin

delta-Palutoxins (δ-palutoxins) consist of a homologous group of four insect-specific toxins from the venom of the spider Pireneitega luctuosa. They show a high toxicity against Spodoptera litura larvae by inhibiting sodium channels, leading to strong paralytic activity and eventually to the death of the insect.

Theraphosa leblondi toxin (TLTx) is a toxin occurring in three different forms (subtypes) that are purified and sequenced from the venom of the giant tarantula Theraphosa blondi. This toxin selectively inhibits Kv4.2 voltage-gated potassium channels by acting as a gating modifier.

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.

<span class="mw-page-title-main">Inhibitor cystine knot</span>

An inhibitor cystine knot is a protein structural motif containing three disulfide bridges. Knottins are one of three folds in the cystine knot motif; the other closely related knots are the growth factor cystine knot (GFCK) and the cyclic cystine knot. Types include a) cyclic mobius, b) cyclic bracelet, c) acyclic inhibitor knottins. Cystine knot motifs are found frequently in nature in a plethora of plants, animals, and fungi and serve diverse functions from appetite suppression to anti-fungal activity.

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

GTx1-15 is a toxin from the Chilean tarantula venom that acts as both a voltage-gated calcium channel blocker and a voltage-gated sodium channel blocker.

CNF-Sr3, also known as conorfamide-Sr3, is a toxin derived from the venom duct of Conus spurius. CNF-Sr3 is an inhibitor of the Shaker channel, a subtype of the voltage-gated potassium channels.

LmαTX5 is an α-scorpion toxin which inhibits the fast inactivation of voltage-gated sodium channels. It has been identified through transcriptome analysis of the venom gland of Lychas mucronatus, also known as the Chinese swimming scorpion – a scorpion species which is widely distributed in Southeast Asia.

DKK-SP1 is one of the many neurotoxins present in the scorpion Mesobuthus martensii. This toxin inhibits the voltage-gated sodium channel Nav1.8.

Cl6b (μ-THTX-Cl6b) is a peptide toxin from the venom of the spider Cyriopagopus longipes. It acts as a sodium channel blocker: Cl6b significantly and persistently reduces currents through the tetrodotoxin-sensitive sodium channels NaV1.2-1.4, NaV1.6, and NaV1.7.

Tb1 is a neurotoxin that is naturally found in the Brazilian scorpion venom Tityus bahiensis and is thought to act on voltage-gated sodium channels. This causes an excessive glutamate release, which leads to both behavioral and electrographic epileptiform alterations, as well as neuronal injury.

References

This article incorporates text from the public domain Pfam and InterPro:
  1. ↑ Terlau H, Olivera BM (2004). "Conus venoms: a rich source of novel ion channel-targeted peptides". Physiol. Rev. 84 (1): 41–68. doi:10.1152/physrev.00020.2003. PMID   14715910.
  2. ↑ Olivera BM, Teichert RW (2007). "Diversity of the neurotoxic Conus peptides: a model for concerted pharmacological discovery". Molecular Interventions. 7 (5): 251–60. doi:10.1124/mi.7.5.7. PMID   17932414.
  3. ↑ "Archived copy" (PDF). Archived (PDF) from the original on 2017-08-29. Retrieved 2017-03-31.{{cite web}}: CS1 maint: archived copy as title (link)
  4. ↑ "Biological Agent Reference Sheet - Conotoxin" (PDF). Emory University.
  5. ↑ Baker, A.L. "toxin ld50 list". PhycoKey.
  6. ↑ Olivera BM, Watkins M, Bandyopadhyay P, Imperial JS, de la Cotera EP, Aguilar MB, Vera EL, Concepcion GP, Lluisma A (September 2012). "Adaptive radiation of venomous marine snail lineages and the accelerated evolution of venom peptide genes". Ann. N. Y. Acad. Sci. 1267 (1): 61–70. Bibcode:2012NYASA1267...61O. doi:10.1111/j.1749-6632.2012.06603.x. PMC   3488454 . PMID   22954218.
  7. ↑ Wong ES, Belov K (March 2012). "Venom evolution through gene duplications". Gene. 496 (1): 1–7. doi:10.1016/j.gene.2012.01.009. PMID   22285376.
  8. ↑ Liow LH, Van Valen L, Stenseth NC (July 2011). "Red Queen: from populations to taxa and communities". Trends Ecol. Evol. 26 (7): 349–58. doi:10.1016/j.tree.2011.03.016. PMID   21511358.
  9. 1 2 3 Jones RM, McIntosh JM (2001). "Cone venom--from accidental stings to deliberate injection". Toxicon. 39 (10): 1447–1451. doi:10.1016/S0041-0101(01)00145-3. PMID   11478951.
  10. ↑ Sato K, Kini RM, Gopalakrishnakone P, Balaji RA, Ohtake A, Seow KT, Bay BH (2000). "lambda-conotoxins, a new family of conotoxins with unique disulfide pattern and protein folding. Isolation and characterization from the venom of Conus marmoreus". J. Biol. Chem. 275 (50): 39516–39522. doi: 10.1074/jbc.M006354200 . PMID   10988292.
  11. ↑ Nicke A, Wonnacott S, Lewis RJ (2004). "Alpha-conotoxins as tools for the elucidation of structure and function of neuronal nicotinic acetylcholine receptor subtypes". Eur. J. Biochem. 271 (12): 2305–2319. doi: 10.1111/j.1432-1033.2004.04145.x . PMID   15182346.
  12. ↑ Leipold E, Hansel A, Olivera BM, Terlau H, Heinemann SH (2005). "Molecular interaction of delta-conotoxins with voltage-gated sodium channels". FEBS Lett. 579 (18): 3881–3884. doi: 10.1016/j.febslet.2005.05.077 . PMID   15990094.
  13. ↑ Shon KJ, Stocker M, Terlau H, Stühmer W, Jacobsen R, Walker C, Grilley M, Watkins M, Hillyard DR, Gray WR, Olivera BM (1998). "kappa-Conotoxin PVIIA is a peptide inhibiting the shaker K+ channel". J. Biol. Chem. 273 (1): 33–38. doi: 10.1074/jbc.273.1.33 . PMID   9417043.
  14. ↑ Li RA, Tomaselli GF (2004). "Using the deadly mu-conotoxins as probes of voltage-gated sodium channels". Toxicon. 44 (2): 117–122. doi:10.1016/j.toxicon.2004.03.028. PMC   2698010 . PMID   15246758.
  15. ↑ Nielsen KJ, Schroeder T, Lewis R (2000). "Structure-activity relationships of omega-conotoxins at N-type voltage-sensitive calcium channels". J. Mol. Recognit. 13 (2): 55–70. doi:10.1002/(SICI)1099-1352(200003/04)13:2<55::AID-JMR488>3.0.CO;2-O. PMID   10822250. Archived from the original (abstract) on 2011-08-13.
  16. ↑ Bowersox SS, Luther R (1998). "Pharmacotherapeutic potential of omega-conotoxin MVIIA (SNX-111), an N-type neuronal calcium channel blocker found in the venom of Conus magus". Toxicon. 36 (11): 1651–1658. doi:10.1016/S0041-0101(98)00158-5. PMID   9792182.
  17. ↑ Prommer E (2006). "Ziconotide: a new option for refractory pain". Drugs Today. 42 (6): 369–78. doi:10.1358/dot.2006.42.6.973534. PMID   16845440.
  18. ↑ Gray WR, Olivera BM, Zafaralla GC, Ramilo CA, Yoshikami D, Nadasdi L, Hammerland LG, Kristipati R, Ramachandran J, Miljanich G (1992). "Novel alpha- and omega-conotoxins from Conus striatus venom". Biochemistry. 31 (41): 11864–11873. doi:10.1021/bi00156a009. PMID   1390774.
  19. 1 2 Nielsen KJ, Watson M, Adams DJ, Hammarström AK, Gage PW, Hill JM, Craik DJ, Thomas L, Adams D, Alewood PF, Lewis RJ (July 2002). "Solution structure of mu-conotoxin PIIIA, a preferential inhibitor of persistent tetrodotoxin-sensitive sodium channels" (PDF). J. Biol. Chem. 277 (30): 27247–55. doi: 10.1074/jbc.M201611200 . PMID   12006587.
  20. ↑ Zeikus RD, Gray WR, Cruz LJ, Olivera BM, Kerr L, Moczydlowski E, Yoshikami D (1985). "Conus geographus toxins that discriminate between neuronal and muscle sodium channels". J. Biol. Chem. 260 (16): 9280–8. doi: 10.1016/S0021-9258(17)39364-X . PMID   2410412.
  21. ↑ McIntosh JM, Jones RM (October 2001). "Cone venom--from accidental stings to deliberate injection". Toxicon. 39 (10): 1447–51. doi:10.1016/S0041-0101(01)00145-3. PMID   11478951.
  22. ↑ Cruz LJ, Gray WR, Olivera BM, Zeikus RD, Kerr L, Yoshikami D, Moczydlowski E (August 1985). "Conus geographus toxins that discriminate between neuronal and muscle sodium channels". J. Biol. Chem. 260 (16): 9280–8. doi: 10.1016/S0021-9258(17)39364-X . PMID   2410412.
  23. ↑ Floresca CZ (2003). "A comparison of the mu-conotoxins by [3H]saxitoxin binding assays in neuronal and skeletal muscle sodium channel". Toxicol Appl Pharmacol. 190 (2): 95–101. doi:10.1016/s0041-008x(03)00153-4. PMID   12878039.
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