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Taipoxin

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Taipoxin subunit α
Identifiers
OrganismOxyuranus scutellatus
Symbol?
UniProtP00614
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StructuresSwiss-model
DomainsInterPro
Taipoxin subunit β1
Identifiers
OrganismOxyuranus scutellatus
Symbol?
PDB3VC0
UniProtP00615
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StructuresSwiss-model
DomainsInterPro
Taipoxin subunit β2
Identifiers
OrganismOxyuranus scutellatus
Symbol?
PDB3vbz
UniProtP0CG57
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StructuresSwiss-model
DomainsInterPro
Taipoxin subunit γ
Identifiers
OrganismOxyuranus scutellatus
Symbol?
UniProtP00616
Search for
StructuresSwiss-model
DomainsInterPro

Taipoxinis a potentmyo- andneurotoxinthat was isolated from thevenomof thecoastal taipanOxyuranus scutellatusor also known as the common taipan.[1]Taipoxin like many other pre-synaptic neurotoxins arephospholipase A2(PLA2) toxins, which inhibit/complete block the release of the motor transmitter acetylcholine and lead to death by paralysis of the respiratory muscles (asphyxia).[2]It is the most lethal neurotoxin isolated from any snake venom to date.

Themolecular massof the heterotrimer is about 46,000Dalton;comprising 1:1:1 α, β and γ monomers.[3]Median lethal dose(LD50) for mice is around 1–2 μg/kg (subcutaneous injection).[4][1]

History[edit]

Taipoxin and other PLA2toxins have evolved from the digestivePLA2enzymes.[5]The venom still functions with the almost identical multi-disulphide-bridged protein PLA2scaffold, which causes the hydrolytic mechanism of theenzyme.[6]However it is thought that under strict evolution selection pressures of prey immobilisation and therefore extended feeding lead to the PLA2enzyme losing its so called pancreatic loop and mutations for the toxin binding with pre-synaptic membranes of motor neuron end plates.[7][8][9]

Structure[edit]

Taipoxin is aternary complexconsisting of three subunits of α, β and γ monomers in a 1:1:1 ratio, also called the A, B and C homologous subunits.[6]These subunits are equally distributed across the structure and together the three-dimensional structures of these three monomers form a shared core of three α helix's, a Ca2+binding site and a hydrophobic channel to which the fatty acyl chains binds.[7]

The α and β complex consist of 120amino acid residueswhich are cross linked by 7disulfide bridges.The Alpha subunit is very basic (pH(I)>10) and the only one that shows neurotoxicity. The β complex is neutral and can be separated into two isoforms. β1 and β2 are interchangeable but differ slightly in amino acid composition. The γ complex contains 135 amino acid residues which are cross linked by 8 disulfide bridges. It is very acidic due to 4sialic acid residues,which might be important for complex formation. The gamma subunit also seems to function as a protector of the Alpha complex, preventing fastrenal clearanceorproteolytic degradation.It also boosts the specificity on the target and could be involved in the binding of the Alpha unit.[10]The whole complex is slightly acidic with a pH(I) of 5, but under a lower pH and/or high ionic strength the subunits dissociate.

Just as the PLA2enzyme the PLA2toxin is Ca2+dependent for hydrolysing fatty acyl ester bonds at the sn-2 position ofglycerol-phospholipids.[7]Depending on disulphide bridge positions and lengths of C-termini these PLA2enzymes/PLA2toxins are categorized into three classes. These classes are also an indication of the toxicity of PLA2/PLA2,as PLA2s from pancreatic secretions, bee venom or the weak elapid venoms are grouped into class I, whereas PLA2s from the more potent viperid venoms which causes inflammatory exudate's are grouped into class II. However most snake venoms are capable of more than one toxic activity, such ascytotoxicity,myotoxicity,neuro-toxicity,anticoagulantactivity andhypotensiveeffects.[11][12]

Isolation process[edit]

Taipoxin can be purified from the venom of thecoastal taipanbygel filtration chromatography.[1]In addition to taipoxin, the venom consists of many different components, responsible for the complex symptoms.[13]

Mechanism of action[edit]

In the beginning taipoxin was thought to be only neurotoxic. Studies showed an increase in acetylcholine release, indicating a presynaptic activity.[1]Further experiments showed that Taipoxin inhibited the responses to electrical stimuli greater than the reaction to additionally administered acetylcholine. This led to the conclusion that taipoxin has pre- and postsynaptic effects. Additional to the increased acetylcholine release it inhibits the vesicular recycling.[14]More recent studies showed that the toxin has amyotoxiceffect as well. The injection of taipoxin into the hind limbs of rats leads tooedemaformation and muscle degeneration.[15]The study also supports the findings by Fohlman,[1]that the α subunit yields the PLA2potency, which is similar to the potency of notexin.[16]Even so, the full potential of the raw toxin is only reached by the combination of the α and γ subunits.[15]

A similar experiment[17]has been done refocusing on the neural compounds. 24 hours after the injection the innervation was compromised to the extent of being unable to identify intact axons. This showed that taipoxin like toxins lead to the depletion of transmitters from the nerve terminals and lead to the degeneration of nerve terminal and intramuscular axons.[18]Inchromaffin cellstaipoxin showed the ability to enter the cells via Ca2+independent mechanisms. There it enhancedcatecholaminerelease in depolarizing cells by disassembling F-actin in the cytoskeletal barrier. This could lead to a vesicle redistribution promoting immediate access into the subplasmalemmal area.[19]

More research studies have found potential binding partners of taipoxin, which would give more insight into how taipoxin is transported to the nerve terminals and intramuscular axons.[20][21]

Toxicity[edit]

The toxicity of Taipoxin or other PLA2toxins are often measured with their ability to cut short chain phospholipids or phospholipids-analogues.[22]For taipoxin PLA2activity was set on 0.4 mmol/min/mg, and thebinding constant(K) of taipoxin would be equal to: KTaipoxin= KA+ KB+ KCas it consist out of 3 enzymatic domains/subunits.[6]However no correlation was made between PLA2activity and toxicity, as the pharmacokinetics and the membrane binding properties are more important. A more specific membrane binding would lead to accumulation of taipoxin in the plasma membranes of motor-neurons.[23][24][25]

Treatment[edit]

The treatment of choice is anantivenomproduced by CSL Ltd in 1956 in Australia on the basis of immunised horse plasma.[26]After being bitten the majority of patients will develop systemic envenoming of which clinical evidence is usually present within two hours. This effect can be delayed by applying first aid measures, like immobilization.[13]Additional to neurotoxins taipan venom containsanticoagulantswhose effect is also inhibited by the antivenom.

Similar toxins[edit]

Similar to taipoxin are toxins with different subunits of the PLA domains:

Notexinis a monomer fromNotechis scutatusvenom,β-bungarotoxinis a heterodimer from Chinese banded krait (Bungarus multicinctus) venom, andtextilotoxinis a pentamer from easternPseudonaja textilisvenom.

References[edit]

  1. ^abcdeFohlman J, Eaker D, Karlsoon E, Thesleff S (September 1976)."Taipoxin, an extremely potent presynaptic neurotoxin from the venom of the australian snake taipan (Oxyuranus s. scutellatus). Isolation, characterization, quaternary structure and pharmacological properties".European Journal of Biochemistry.68(2): 457–69.doi:10.1111/j.1432-1033.1976.tb10833.x.PMID976268.
  2. ^Silva A, Hodgson WC, Isbister GK (October 2016)."Cross-Neutralisation of In Vitro Neurotoxicity of Asian and Australian Snake Neurotoxins and Venoms by Different Antivenoms".Toxins.8(10): 302.doi:10.3390/toxins8100302.PMC5086662.PMID27763543.
  3. ^Alomone labs:Taipoxin(pdf)
  4. ^Rossetto O, Morbiato L, Caccin P, Rigoni M, Montecucco C (June 2006)."Presynaptic enzymatic neurotoxins".Journal of Neurochemistry.97(6): 1534–45.doi:10.1111/j.1471-4159.2006.03965.x.PMID16805767.S2CID22678139.
  5. ^Davidson FF, Dennis EA (September 1990). "Evolutionary relationships and implications for the regulation of phospholipase A2 from snake venom to human secreted forms".Journal of Molecular Evolution.31(3): 228–38.Bibcode:1990JMolE..31..228D.doi:10.1007/BF02109500.PMID2120459.S2CID6203372.
  6. ^abcMontecucco C, Rossetto O (June 2008). "On the quaternary structure of taipoxin and textilotoxin: the advantage of being multiple".Toxicon.51(8): 1560–2.doi:10.1016/j.toxicon.2008.03.020.PMID18471843.
  7. ^abcAlape-Girón A, Persson B, Cederlund E, Flores-Díaz M, Gutiérrez JM, Thelestam M, et al. (January 1999)."Elapid venom toxins: multiple recruitments of ancient scaffolds".European Journal of Biochemistry.259(1–2): 225–34.doi:10.1046/j.1432-1327.1999.00021.x.PMID9914497.S2CID2136068.
  8. ^Kini RM (1997).Venom Phospholipase A2Enzymes.Chichester: Wiley.ISBN978-0471961895.
  9. ^Fletcher JE, Jiang MS (December 1995). "Presynaptically acting snake venom phospholipase A2 enzymes attack unique substrates".Toxicon.33(12): 1565–76.doi:10.1016/0041-0101(95)00108-5.PMID8866614.
  10. ^Fohlman J, Lind P, Eaker D (December 1977)."Taipoxin, an extremely potent presynaptic snake venom neurotoxin. Elucidation of the primary structure of the acidic carbohydrate-containing taipoxin-subunit, a prophospholipase homolog".FEBS Letters.84(2): 367–71.doi:10.1016/0014-5793(77)80726-6.PMID563806.
  11. ^Lomonte B, Tarkowski A, Hanson LA (November 1994). "Broad cytolytic specificity of myotoxin II, a lysine-49 phospholipase A2 of Bothrops asper snake venom".Toxicon.32(11): 1359–69.doi:10.1016/0041-0101(94)90408-1.PMID7886694.
  12. ^Gutiérrez JM, Lomonte B (November 1995). "Phospholipase A2 myotoxins from Bothrops snake venoms".Toxicon.33(11): 1405–24.doi:10.1016/0041-0101(95)00085-z.hdl:10669/29394.PMID8744981.
  13. ^ab"Taipan Antivenom".csl.au.Retrieved2017-03-17.
  14. ^Hyatt MC, Russell JA (October 1981). "Effects of beta-bungarotoxin and taipoxin on contractions of canine airways caused by nerve stimulation".Life Sciences.29(17): 1755–9.doi:10.1016/0024-3205(81)90185-5.PMID7300571.
  15. ^abHarris JB, Maltin CA (May 1982)."Myotoxic activity of the crude venom and the principal neurotoxin, taipoxin, of the Australian taipan, Oxyuranus scutellatus".British Journal of Pharmacology.76(1): 61–75.doi:10.1111/j.1476-5381.1982.tb09191.x.PMC2068749.PMID7082907.
  16. ^Harris JB, MacDonell CA (1981-01-01). "Phospholipase A2 activity of notexin and its role in muscle damage".Toxicon.19(3): 419–30.doi:10.1016/0041-0101(81)90046-5.PMID7245222.
  17. ^Dixon RW, Harris JB (February 1999)."Nerve terminal damage by beta-bungarotoxin: its clinical significance".The American Journal of Pathology.154(2): 447–55.doi:10.1016/S0002-9440(10)65291-1.PMC1850016.PMID10027403.
  18. ^Harris JB, Grubb BD, Maltin CA, Dixon R (February 2000). "The neurotoxicity of the venom phospholipases A(2), notexin and taipoxin".Experimental Neurology.161(2): 517–26.doi:10.1006/exnr.1999.7275.PMID10686073.S2CID6714210.
  19. ^Neco P, Rossetto O, Gil A, Montecucco C, Gutiérrez LM (April 2003). "Taipoxin induces F-actin fragmentation and enhances release of catecholamines in bovine chromaffin cells".Journal of Neurochemistry.85(2): 329–37.doi:10.1046/j.1471-4159.2003.01682.x.PMID12675909.S2CID8907229.
  20. ^Kirkpatrick LL, Matzuk MM, Dodds DC, Perin MS (June 2000)."Biochemical interactions of the neuronal pentraxins. Neuronal pentraxin (NP) receptor binds to taipoxin and taipoxin-associated calcium-binding protein 49 via NP1 and NP2".The Journal of Biological Chemistry.275(23): 17786–92.doi:10.1074/jbc.M002254200.PMID10748068.
  21. ^Dodds DC, Omeis IA, Cushman SJ, Helms JA, Perin MS (August 1997)."Neuronal pentraxin receptor, a novel putative integral membrane pentraxin that interacts with neuronal pentraxin 1 and 2 and taipoxin-associated calcium-binding protein 49".The Journal of Biological Chemistry.272(34): 21488–94.doi:10.1074/jbc.272.34.21488.PMID9261167.
  22. ^Leslie CC, Gelb MH (2004). "Assaying Phospholipase A2Activity ".Signal Transduction Protocols.Methods in Molecular Biology. Vol. 284. Methods Mol. Biol. pp. 229–42.doi:10.1385/1-59259-816-1:229.ISBN1-59259-816-1.PMID15173620.
  23. ^Rigoni M, Caccin P, Gschmeissner S, Koster G, Postle AD, Rossetto O, et al. (December 2005). "Equivalent effects of snake PLA2 neurotoxins and lysophospholipid-fatty acid mixtures".Science.310(5754): 1678–80.Bibcode:2005Sci...310.1678R.CiteSeerX10.1.1.817.8280.doi:10.1126/science.1120640.JSTOR3842969.PMID16339444.S2CID39970648.
  24. ^Caccin P, Rigoni M, Bisceglie A, Rossetto O, Montecucco C (November 2006)."Reversible skeletal neuromuscular paralysis induced by different lysophospholipids".FEBS Letters.580(27): 6317–21.doi:10.1016/j.febslet.2006.10.039.PMID17083939.S2CID38178998.
  25. ^Megighian A, Rigoni M, Caccin P, Zordan MA, Montecucco C (April 2007). "A lysolecithin/fatty acid mixture promotes and then blocks neurotransmitter release at the Drosophila melanogaster larval neuromuscular junction".Neuroscience Letters.416(1): 6–11.doi:10.1016/j.neulet.2007.01.040.PMID17293048.S2CID7635663.
  26. ^Kuruppu S, Chaisakul J, Smith AI, Hodgson WC (April 2014). "Inhibition of presynaptic neurotoxins in taipan venom by suramin".Neurotoxicity Research.25(3): 305–10.doi:10.1007/s12640-013-9426-z.PMID24129771.S2CID16083544.
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