taipoxin

Taipoxin and other PLA₂ toxins have evolved from the digestive PLA₂ enzymes.{{cite journal | vauthors = Davidson FF, Dennis EA | title = Evolutionary relationships and implications for the regulation of phospholipase A2 from snake venom to human secreted forms | journal = Journal of Molecular Evolution | volume = 31 | issue = 3 | pages = 228–38 | date = September 1990 | pmid = 2120459 | doi = 10.1007/BF02109500 | bibcode = 1990JMolE..31..228D | s2cid = 6203372 }} The venom still functions with the almost identical multi-disulphide-bridged protein PLA₂ scaffold, which causes the hydrolytic mechanism of the enzyme.{{cite journal | vauthors = Montecucco C, Rossetto O | title = On the quaternary structure of taipoxin and textilotoxin: the advantage of being multiple | journal = Toxicon | volume = 51 | issue = 8 | pages = 1560–2 | date = June 2008 | pmid = 18471843 | doi = 10.1016/j.toxicon.2008.03.020 }} However it is thought that under strict evolution selection pressures of prey immobilisation and therefore extended feeding lead to the PLA₂ enzyme losing its so called pancreatic loop and mutations for the toxin binding with pre-synaptic membranes of motor neuron end plates.{{cite journal | vauthors = Alape-Girón A, Persson B, Cederlund E, Flores-Díaz M, Gutiérrez JM, Thelestam M, Bergman T, Jörnvall H | display-authors = 6 | title = Elapid venom toxins: multiple recruitments of ancient scaffolds | journal = European Journal of Biochemistry | volume = 259 | issue = 1–2 | pages = 225–34 | date = January 1999 | pmid = 9914497 | doi = 10.1046/j.1432-1327.1999.00021.x | s2cid = 2136068 | doi-access = free }}{{Cite book |title=Venom Phospholipase A₂ Enzymes | vauthors = Kini RM |publisher=Wiley |year=1997 |isbn=978-0471961895 |location=Chichester }}{{cite journal | vauthors = Fletcher JE, Jiang MS | title = Presynaptically acting snake venom phospholipase A2 enzymes attack unique substrates | journal = Toxicon | volume = 33 | issue = 12 | pages = 1565–76 | date = December 1995 | pmid = 8866614 | doi = 10.1016/0041-0101(95)00108-5 }}

Taipoxin is a ternary complex consisting of three subunits of α, β and γ monomers in a 1:1:1 ratio, also called the A, B and C homologous subunits. 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-helices, a Ca²⁺ binding site and a hydrophobic channel to which the fatty acyl chains binds.

The α and β complex consist of 120 amino acid residues which are cross linked by 7 disulfide 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 4 sialic acid residues, which might be important for complex formation. The gamma subunit also seems to function as a protector of the alpha complex, preventing fast renal clearance or proteolytic degradation. It also boosts the specificity on the target and could be involved in the binding of the alpha unit.{{cite journal | vauthors = Fohlman J, Lind P, Eaker D | title = Taipoxin, an extremely potent presynaptic snake venom neurotoxin. Elucidation of the primary structure of the acidic carbohydrate-containing taipoxin-subunit, a prophospholipase homolog | journal = FEBS Letters | volume = 84 | issue = 2 | pages = 367–71 | date = December 1977 | pmid = 563806 | doi = 10.1016/0014-5793(77)80726-6 | doi-access = free }} 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 PLA₂ enzyme the PLA₂ toxin is Ca²⁺ dependent for hydrolysing fatty acyl ester bonds at the sn-2 position of glycerol-phospholipids. Depending on disulphide bridge positions and lengths of C-termini these PLA₂ enzymes/PLA₂ toxins 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 as cytotoxicity, myotoxicity, neuro-toxicity, anticoagulant activity and hypotensive effects.{{cite journal | vauthors = Lomonte B, Tarkowski A, Hanson LA | title = Broad cytolytic specificity of myotoxin II, a lysine-49 phospholipase A2 of Bothrops asper snake venom | journal = Toxicon | volume = 32 | issue = 11 | pages = 1359–69 | date = November 1994 | pmid = 7886694 | doi = 10.1016/0041-0101(94)90408-1 }}{{cite journal | vauthors = Gutiérrez JM, Lomonte B | title = Phospholipase A2 myotoxins from Bothrops snake venoms | journal = Toxicon | volume = 33 | issue = 11 | pages = 1405–24 | date = November 1995 | pmid = 8744981 | doi = 10.1016/0041-0101(95)00085-z | hdl = 10669/29394 | hdl-access = free }}

Taipoxin can be purified from the venom of the coastal taipan by gel filtration chromatography. In addition to taipoxin, the venom consists of many different components, responsible for the complex symptoms.

In the beginning taipoxin was thought to be only neurotoxic. Studies showed an increase in acetylcholine release, indicating a presynaptic activity. 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.{{cite journal | vauthors = Hyatt MC, Russell JA | title = Effects of beta-bungarotoxin and taipoxin on contractions of canine airways caused by nerve stimulation | journal = Life Sciences | volume = 29 | issue = 17 | pages = 1755–9 | date = October 1981 | pmid = 7300571 | doi = 10.1016/0024-3205(81)90185-5 }} More recent studies showed that the toxin has a myotoxic effect as well. The injection of taipoxin into the hind limbs of rats leads to oedema formation and muscle degeneration. The study also supports the findings by Fohlman, that the α subunit yields the PLA₂ potency, which is similar to the potency of notexin.{{cite journal | vauthors = Harris JB, MacDonell CA | title = Phospholipase A2 activity of notexin and its role in muscle damage | journal = Toxicon | volume = 19 | issue = 3 | pages = 419–30 | date = 1981-01-01 | pmid = 7245222 | doi = 10.1016/0041-0101(81)90046-5 }} Even so, the full potential of the raw toxin is only reached by the combination of the α and γ subunits.{{cite journal | vauthors = Harris JB, Maltin CA | title = Myotoxic activity of the crude venom and the principal neurotoxin, taipoxin, of the Australian taipan, Oxyuranus scutellatus | journal = British Journal of Pharmacology | volume = 76 | issue = 1 | pages = 61–75 | date = May 1982 | pmid = 7082907 | pmc = 2068749 | doi = 10.1111/j.1476-5381.1982.tb09191.x }}

A similar experiment{{cite journal | vauthors = Dixon RW, Harris JB | title = Nerve terminal damage by beta-bungarotoxin: its clinical significance | journal = The American Journal of Pathology | volume = 154 | issue = 2 | pages = 447–55 | date = February 1999 | pmid = 10027403 | pmc = 1850016 | doi = 10.1016/S0002-9440(10)65291-1 }} 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.{{cite journal | vauthors = Harris JB, Grubb BD, Maltin CA, Dixon R | title = The neurotoxicity of the venom phospholipases A(2), notexin and taipoxin | journal = Experimental Neurology | volume = 161 | issue = 2 | pages = 517–26 | date = February 2000 | pmid = 10686073 | doi = 10.1006/exnr.1999.7275 | s2cid = 6714210 }} In chromaffin cells taipoxin showed the ability to enter the cells via Ca²⁺ independent mechanisms. There it enhanced catecholamine release 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.{{cite journal | vauthors = Neco P, Rossetto O, Gil A, Montecucco C, Gutiérrez LM | title = Taipoxin induces F-actin fragmentation and enhances release of catecholamines in bovine chromaffin cells | journal = Journal of Neurochemistry | volume = 85 | issue = 2 | pages = 329–37 | date = April 2003 | pmid = 12675909 | doi = 10.1046/j.1471-4159.2003.01682.x | s2cid = 8907229 }}

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.{{cite journal | vauthors = Kirkpatrick LL, Matzuk MM, Dodds DC, Perin MS | title = Biochemical interactions of the neuronal pentraxins. Neuronal pentraxin (NP) receptor binds to taipoxin and taipoxin-associated calcium-binding protein 49 via NP1 and NP2 | journal = The Journal of Biological Chemistry | volume = 275 | issue = 23 | pages = 17786–92 | date = June 2000 | pmid = 10748068 | doi = 10.1074/jbc.M002254200 | doi-access = free }}{{cite journal | vauthors = Dodds DC, Omeis IA, Cushman SJ, Helms JA, Perin MS | title = Neuronal pentraxin receptor, a novel putative integral membrane pentraxin that interacts with neuronal pentraxin 1 and 2 and taipoxin-associated calcium-binding protein 49 | journal = The Journal of Biological Chemistry | volume = 272 | issue = 34 | pages = 21488–94 | date = August 1997 | pmid = 9261167 | doi = 10.1074/jbc.272.34.21488 | doi-access = free }}

The toxicity of Taipoxin or other PLA₂ toxins are often measured with their ability to cut short chain phospholipids or phospholipids-analogues.{{cite book | vauthors = Leslie CC, Gelb MH | title = Signal Transduction Protocols | chapter = Assaying Phospholipase A₂ Activity | series = Methods in Molecular Biology | volume = 284 | pages = 229–42 | year = 2004 | pmid = 15173620 | doi = 10.1385/1-59259-816-1:229 | publisher = Methods Mol. Biol. | isbn = 1-59259-816-1 }} For taipoxin PLA₂ activity was set on 0.4 mmol/min/mg, and the binding constant (K) of taipoxin would be equal to: K_Taipoxin = K_A + K_B + K_C as it consist out of 3 enzymatic domains/subunits. However no correlation was made between PLA₂ activity 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.{{cite journal | vauthors = Rigoni M, Caccin P, Gschmeissner S, Koster G, Postle AD, Rossetto O, Schiavo G, Montecucco C | display-authors = 6 | title = Equivalent effects of snake PLA2 neurotoxins and lysophospholipid-fatty acid mixtures | journal = Science | volume = 310 | issue = 5754 | pages = 1678–80 | date = December 2005 | pmid = 16339444 | doi = 10.1126/science.1120640 | citeseerx = 10.1.1.817.8280 | bibcode = 2005Sci...310.1678R | jstor = 3842969 | s2cid = 39970648 }}{{cite journal | vauthors = Caccin P, Rigoni M, Bisceglie A, Rossetto O, Montecucco C | title = Reversible skeletal neuromuscular paralysis induced by different lysophospholipids | journal = FEBS Letters | volume = 580 | issue = 27 | pages = 6317–21 | date = November 2006 | pmid = 17083939 | doi = 10.1016/j.febslet.2006.10.039 | s2cid = 38178998 | doi-access = free }}{{cite journal | vauthors = Megighian A, Rigoni M, Caccin P, Zordan MA, Montecucco C | title = A lysolecithin/fatty acid mixture promotes and then blocks neurotransmitter release at the Drosophila melanogaster larval neuromuscular junction | journal = Neuroscience Letters | volume = 416 | issue = 1 | pages = 6–11 | date = April 2007 | pmid = 17293048 | doi = 10.1016/j.neulet.2007.01.040 | s2cid = 7635663 }}

The treatment of choice is an antivenom produced by CSL Ltd in 1956 in Australia on the basis of immunised horse plasma.{{cite journal | vauthors = Kuruppu S, Chaisakul J, Smith AI, Hodgson WC | title = Inhibition of presynaptic neurotoxins in taipan venom by suramin | journal = Neurotoxicity Research | volume = 25 | issue = 3 | pages = 305–10 | date = April 2014 | pmid = 24129771 | doi = 10.1007/s12640-013-9426-z | s2cid = 16083544 }} 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.{{Cite web |url=http://www.csl.com.au/s1/cs/auhq/1217017237558/Web_Product_C/1196562644405/ProductDetail.htm |title=Taipan Antivenom |website=www.csl.com.au |access-date=2017-03-17}} Additional to neurotoxins taipan venom contains anticoagulants whose effect is also inhibited by the antivenom.

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

Notexin is a monomer from Notechis scutatus venom, β-bungarotoxin is a heterodimer from Chinese banded krait (Bungarus multicinctus) venom, and textilotoxin is a pentamer from eastern Pseudonaja textilis venom.

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Category:Neurotoxins

Category:Snake toxins

Category:Acetylcholine release inhibitors