Maitotoxin

{{Short description|Chemical compound}} {{distinguish|mitotoxin}} {{chembox | verifiedrevid = 472257619 | Name = Maitotoxin | ImageFile = Maitotoxin 2D structure.svg | ImageSize = 300 px | ImageName = | ImageFile1 = Maitotoxin-3D-vdW.png <!-- | ImageSize1 = 300px --> | ImageName1 = Space-filling model of the maitotoxin molecule | SystematicName = <small>Disodium (1²''S'',1^4a''R'',1^5a''S'',1^6a''R'',1^7a''S'',1⁸''Z'',1^10a''R'',1^11a''S'',1^12a''R'',1^13a''S'',1^14a''R'',1¹⁶''R'',1¹⁷''R'',1^18a''S'',1^19a''R'',1^21a''S'',1^22a''R'',1^23a''S'',1^24a''R'',1^25a''S'',1^26a''R'',1^27a''S'',2²''S'',2^4a''R'',2^5a''S'',2^6a''R'',2^7a''S'',2^8a''R'',2^9a''S'',2¹¹''R'',2¹²''R'',2^13a''R'',2¹⁴''S'',2^14a''S'',2^15a''R'',2^17a''S'',2^18a''R'',2^19a''S'',3²''R'',3³''R'',3^4a''S'',3⁶''S'',3⁷''R'',3⁸''R'',3^8a''S'',5''R'',7''R'',8²''S'',8³''R'',8^4a''S'',8⁶''R'',8⁷''R'',8⁸''R'',8^8a''S'',9²''R'',9³''R'',9⁴''R'',9^4a''S'',9^5a''S'',9^6a''R'',9^7a''S'',9⁸''R'',9⁹''R'',9¹⁰''S'',9^11a''R'',9^12a''S'',9^13a''R'',9¹⁴''R'',9^14a''R'',11''S'',12''R'',13²''S'',13³''R'',13⁴''S'',13^4a''S'',13^5a''R'',13^6a''S'',13^7a''R'',13⁸''S'',13^8a''S'',13¹⁰''S'',13¹¹''R'',13^12a''R'',13^13a''S'',13^14a''R'',13^15a''S'',13¹⁷''R'',13^17a''R'')-1²-[(1''S'',2''R'',4''R'',5''S'')-1,2-dihydroxy-4,5-dimethyloct-7-en-1-yl]-1¹⁷,2¹¹,2¹⁴,3³,3⁷,3⁸,5,7,8³,8⁷,8⁸,9³,9⁴,9⁸,9¹⁴,11,12,13³,13⁴,13⁸,13¹¹,13¹⁷-docosahydroxy-1^4a,1^5a,1^6a,1^14a,1¹⁶,1^19a,1^21a,1^22a,2^5a,2^7a,2^9a,2^14a,2^17a,13^13a,13^15a-pentadecamethyl-13²-[(2''R'',3''R'',4''R'',7''S'',8''R'',9''R'',11''R'',13''E'')-3,8,11,15-tetrahydroxy-4,9,13-trimethyl-12-methylidene-7-(sulfonatooxy)pentadec-13-en-2-yl]-1³,1⁴,1^4a,1^5a,1⁶,1^6a,1^7a,1¹⁰,1^10a,1^11a,1¹²,1^12a,1^13a,1¹⁴,1^14a,1¹⁶,1¹⁷,1¹⁸,1^18a,1^19a,1²⁰,1²¹,1^21a,1^22a,1²³,1^23a,1^24a,1²⁵,1^25a,1^26a,1²⁷,1^27a,2²,2³,2⁴,2^4a,2^5a,2⁶,2^6a,2^7a,2⁸,2^8a,2^9a,2¹⁰,2¹¹,2¹²,2^13a,2¹⁴,2^14a,2^15a,2¹⁶,2¹⁷,2^17a,2^18a,2¹⁹,2^19a,3²,3³,3⁴,3^4a,3⁶,3⁷,3⁸,3^8a,8²,8³,8⁴,8^4a,8⁶,8⁷,8⁸,8^8a,9³,9⁴,9^4a,9^5a,9⁶,9^6a,9^7a,9⁸,9⁹,9¹⁰,9^11a,9¹²,9^12a,9^13a,9¹⁴,9^14a,13³,13⁴,13^4a,13^5a,13⁶,13^6a,13^7a,13⁸,13^8a,13¹⁰,13¹¹,13¹²,13^12a,13^13a,13¹⁴,13^14a,13^15a,13¹⁶,13¹⁷,13^17a-octahectahydro-1²''H'',9²''H'',13²''H''-1(16)-pyrano[2′′′&nbsp;′,3′′′&nbsp;′:5′′′,6′′′]pyrano[2′′′,3′′′:6′′,7′′]oxepino[2′′,3′′:5′,6′]pyrano[2′,3′:5,6]pyrano[3,2-''b'']pyrano[2′′′,3′′′:5′′,6′′]pyrano[2′′,3′′:5′,6′]pyrano[2′,3′:5,6]pyrano[2,3-''g'']oxocina-2(2,12)-bis(pyrano[2′′,3′′:5,6]pyrano[2′,3′:5,6]pyrano)[3,2-''b'':2′,3′-''f'']oxepina-13(10)-pyrano[3,2-''b'']pyrano[2′′′,3′′′:5′′,6′′]pyrano[2′′,3′′:5′,6′]pyrano[2′,3′:5,6]pyrano[2,3-''f'']oxepina-9(2,10)-dipyrano[2,3-''e'':2′,3′-''e''′]pyrano[3,2-''b'':5,6-''b''′]dipyrana-3,8(2,6)-bis(pyrano[3,2-''b'']pyrana)tridecaphan-9⁹-yl sulfate</small> | OtherNames = | Section1 = {{Chembox Identifiers | CASNo_Ref = {{cascite|correct|??}} | CASNo = 59392-53-9 | ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} | ChemSpiderID = 25991548 | PubChem = 71460273 | UNII = 9P59GES78D | ChEMBL = 2152261 | KEGG = C16854 | SMILES = C[C@H](CC[C@@H]([C@@H]([C@H](C)C[C@H](C(=C)/C(=C/CO)/C)O)O)OS(=O)(=O)[O-])[C@H]([C@@H](C)[C@H]1[C@@H]([C@@H]([C@H]2[C@H](O1)[C@@H](C[C@]3([C@H](O2)C[C@H]4[C@H](O3)C[C@]5([C@H](O4)[C@H]([C@H]6[C@H](O5)C[C@H]([C@H](O6)[C@@H]([C@H](C[C@H]7[C@@H]([C@@H]([C@H]8[C@H](O7)C[C@H]9[C@H](O8)C[C@H]1[C@H](O9)[C@H]([C@@H]2[C@@H](O1)[C@@H]([C@H]([C@@H](O2)[C@H]1[C@@H]([C@H]([C@H]2[C@@H](O1)C[C@H]([C@@H](O2)[C@@H](C[C@H](C[C@H]1[C@@H]([C@H]([C@H]2[C@@H](O1)C[C@H]([C@@H](O2)[C@H]1[C@@H](C[C@]2([C@H](O1)[C@@H]([C@]1([C@H](O2)C[C@]2([C@H](O1)CC[C@]1([C@H](O2)C[C@]2([C@H](O1)C[C@H]1[C@H](O2)CC[C@H](O1)[C@]1([C@@H](C[C@H]2[C@](O1)(C[C@H]1[C@](O2)(CC[C@]2([C@H](O1)C[C@H]1[C@](O2)(C[C@H]2[C@H](O1)C/C=C\[C@H]1[C@H](O2)C[C@H]2[C@](O1)(C[C@]1([C@H](O2)C[C@H]2[C@](O1)(CC[C@H](O2)[C@H]([C@@H](C[C@@H](C)[C@@H](C)CC=C)O)O)C)C)C)C)C)C)C)O)C)C)C)C)C)O)C)O)O)O)O)O)O)O)O)O)O)O)O)O)OS(=O)(=O)[O-])O)O)O)O)C)C)O)O)O)O.[Na+].[Na+] | InChI = 1/C164H258O68S2.2Na/c1-24-26-65(2)68(5)41-74(168)117(179)85-33-36-152(11)106(203-85)55-109-162(21,231-152)64-161(20)105(210-109)51-89-83(220-161)28-25-27-82-99(199-89)59-157(16)108(202-82)56-107-153(12,230-157)39-38-151(10)112(211-107)61-158(17)111(224-151)54-101(176)163(22,232-158)103-32-31-84-90(204-103)53-110-156(15,219-84)62-113-150(9,223-110)37-34-102-155(14,225-113)63-114-164(23,227-102)147(192)149-159(18,226-114)58-81(175)134(218-149)133-79(173)47-93-136(216-133)120(182)119(181)92(200-93)44-72(166)43-76(170)131-77(171)46-94-137(214-131)122(184)124(186)143(207-94)145-126(188)125(187)144-146(217-145)128(190)139-97(208-144)50-88-87(206-139)49-96-138(205-88)127(189)141(229-234(196,197)198)95(201-96)45-75(169)118(180)132-78(172)48-98-140(215-132)129(191)148-160(19,221-98)60-100-91(209-148)52-104-154(13,222-100)57-80(174)135-142(212-104)123(185)121(183)130(213-135)71(8)115(177)67(4)29-30-86(228-233(193,194)195)116(178)69(6)42-73(167)70(7)66(3)35-40-165;;/h24-25,28,35,65,67-69,71-149,165-192H,1,7,26-27,29-34,36-64H2,2-6,8-23H3,(H,193,194,195)(H,196,197,198);;/q;2*+1/p-2/b28-25-,66-35+;;/t65-,67+,68+,69+,71+,72+,73+,74+,75-,76+,77+,78+,79+,80+,81+,82+,83-,84+,85-,86-,87-,88+,89+,90-,91-,92-,93-,94-,95-,96+,97-,98+,99-,100+,101+,102+,103-,104+,105-,106-,107+,108-,109+,110+,111-,112-,113+,114+,115+,116+,117-,118+,119-,120+,121+,122+,123-,124+,125+,126+,127+,128+,129-,130-,131-,132-,133+,134+,135+,136+,137+,138+,139-,140+,141-,142-,143+,144-,145+,146+,147-,148+,149+,150-,151+,152+,153-,154-,155-,156-,157+,158+,159-,160-,161+,162-,163+,164+;;/m0../s1 | InChIKey = NWQUHAJRFNRIIU-NHOVDTRNBI | StdInChI_Ref = {{stdinchicite|correct|chemspider}} | StdInChI = 1S/C164H258O68S2.2Na/c1-24-26-65(2)68(5)41-74(168)117(179)85-33-36-152(11)106(203-85)55-109-162(21,231-152)64-161(20)105(210-109)51-89-83(220-161)28-25-27-82-99(199-89)59-157(16)108(202-82)56-107-153(12,230-157)39-38-151(10)112(211-107)61-158(17)111(224-151)54-101(176)163(22,232-158)103-32-31-84-90(204-103)53-110-156(15,219-84)62-113-150(9,223-110)37-34-102-155(14,225-113)63-114-164(23,227-102)147(192)149-159(18,226-114)58-81(175)134(218-149)133-79(173)47-93-136(216-133)120(182)119(181)92(200-93)44-72(166)43-76(170)131-77(171)46-94-137(214-131)122(184)124(186)143(207-94)145-126(188)125(187)144-146(217-145)128(190)139-97(208-144)50-88-87(206-139)49-96-138(205-88)127(189)141(229-234(196,197)198)95(201-96)45-75(169)118(180)132-78(172)48-98-140(215-132)129(191)148-160(19,221-98)60-100-91(209-148)52-104-154(13,222-100)57-80(174)135-142(212-104)123(185)121(183)130(213-135)71(8)115(177)67(4)29-30-86(228-233(193,194)195)116(178)69(6)42-73(167)70(7)66(3)35-40-165;;/h24-25,28,35,65,67-69,71-149,165-192H,1,7,26-27,29-34,36-64H2,2-6,8-23H3,(H,193,194,195)(H,196,197,198);;/q;2*+1/p-2/b28-25-,66-35+;;/t65-,67+,68+,69+,71+,72+,73+,74+,75-,76+,77+,78+,79+,80+,81+,82+,83-,84+,85-,86-,87-,88+,89+,90-,91-,92-,93-,94-,95-,96+,97-,98+,99-,100+,101+,102+,103-,104+,105-,106-,107+,108-,109+,110+,111-,112-,113+,114+,115+,116+,117-,118+,119-,120+,121+,122+,123-,124+,125+,126+,127+,128+,129-,130-,131-,132-,133+,134+,135+,136+,137+,138+,139-,140+,141-,142-,143+,144-,145+,146+,147-,148+,149+,150-,151+,152+,153-,154-,155-,156-,157+,158+,159-,160-,161+,162-,163+,164+;;/m0../s1 | StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} | StdInChIKey = NWQUHAJRFNRIIU-DVGFTKJRSA-L }} | Section2 = {{Chembox Properties | Formula = C₁₆₄H₂₅₆O₆₈S₂Na₂ | MolarMass = 3422 g/mol | MeltingPt = }} }} '''Maitotoxin''' ('''MTX''') is an extremely potent toxin produced by ''Gambierdiscus toxicus'', a dinoflagellate species. Maitotoxin is so potent that it has been demonstrated that an intraperitoneal injection of 130 ng/kg was lethal in mice.<ref>{{cite journal | author=Yokoyama, A| title=Some Chemical Properties of Maitotoxin, a Putative Calcium Channel Agonist Isolated from a Marine Dinoflagellate | journal=J. Biochem. | volume=104 | issue=2 | year=1988 | pages=184–187 | pmid=3182760|display-authors=etal | doi=10.1093/oxfordjournals.jbchem.a122438| doi-access=free }}</ref> Maitotoxin was named from the ciguateric fish ''Ctenochaetus striatus''&mdash;called "maito" in Tahiti&mdash;from which maitotoxin was isolated for the first time. It was later shown that maitotoxin is actually produced by the dinoflagellate ''Gambierdiscus toxicus''.

== Mechanism of toxicity == Maitotoxin activates calcium channels, leading to an increase in levels of cytosolic Ca²⁺ ions.<ref>{{cite journal|title=Contraction and increase in tissue calcium content induced by maitotoxin, the most potent known marine toxin, in intestinal smooth muscle|journal=British Journal of Pharmacology|volume=79|issue=1|pages=3–5|pmid=6871549|pmc=2044839|year=1983|last1=Ohizumi|first1=Y|last2=Yasumoto|first2=T|doi=10.1111/j.1476-5381.1983.tb10485.x}}</ref> The exact molecular target of maitotoxin is unknown, but it has been suggested that maitotoxin binds to the plasma membrane Ca²⁺ ATPase (PMCA) and turns it into an ion channel, similar to how palytoxin turns the Na⁺/K⁺-ATPase into a sodium channel.<ref>{{cite journal|title=Maitotoxin converts the plasmalemmal Ca2+ pump into a Ca2+-permeable nonselective cation channel|journal=American Journal of Physiology. Cell Physiology|volume=297|issue=6|pages=C1533–43|doi=10.1152/ajpcell.00252.2009|pmid=19794142|pmc=2793065|year=2009|last1=Sinkins|first1=W. G|last2=Estacion|first2=M|last3=Prasad|first3=V|last4=Goel|first4=M|last5=Shull|first5=G. E|last6=Kunze|first6=D. L|last7=Schilling|first7=W. P}}</ref> Ultimately, a necroptosis cascade is activated, resulting in membrane blebbing and eventually cell lysis.<ref>{{cite journal |author1=Estacion, M |author2=Schilling, WP |name-list-style=amp | title=Maitotoxin-induced membrane blebbing and cell death in bovine aortic endothelial cells | journal=BMC Physiology | volume=1 | year=2001 | doi=10.1186/1472-6793-1-2 |pmid=11231888 |pmc=32181 | article-number=2 |doi-access=free }}</ref><ref>{{cite journal | author=Wang, K.| title=Maitotoxin induces calpain activation in SH-SY5Y neuroblastoma cells and cerebrocortical cultures | journal=Arch. Biochem. Biophys. | volume=331 | year=1996 | pages=208–214 | doi=10.1006/abbi.1996.0300 | pmid=8660700 | issue=2|display-authors=etal}}</ref> The toxicity of maitotoxin in mice is the highest for nonprotein toxins: the {{LD50}} is 50&nbsp;ng/kg.<ref name="Igarashi Aritake Yasumoto 1999 pp. 71–79">{{cite journal | last1=Igarashi | first1=Tomoji | last2=Aritake | first2=Shiro | last3=Yasumoto | first3=Takeshi | title=Mechanisms underlying the hemolytic and ichthyotoxic activities of maitotoxin | journal=Natural Toxins | publisher=Wiley | volume=7 | issue=2 | year=1999 | issn=1056-9014 | doi=10.1002/(sici)1522-7189(199903/04)7:2<71::aid-nt40>3.0.co;2-0 | pages=71–79| pmid=10495469 }}</ref>

== Molecular structure == The molecule itself is a system of 32 fused rings and is notable for being one of the largest and most complex non-protein, non-polysaccharide molecules produced by any organism. Maitotoxin includes 32 ether rings, 22 methyl groups, 28 hydroxyl groups, and 2 sulfuric acid esters and has an amphipathic structure.<ref>{{cite journal | author=Murata, M| title=Structure and partial stereochemical assignments for maitotoxin, the most toxic and largest natural non-biopolymer | journal=J. Am. Chem. Soc. | volume=116 | issue=16 | year=1994 | pages=7098–7107 | doi=10.1021/ja00095a013| bibcode=1994JAChS.116.7098M |display-authors=etal}}</ref><ref>{{cite journal | author=Sasaki, M| title=The complete structure of maitotoxin, I; Configuration of the C1-C14 side chain | journal=Angew. Chem. Int. Ed. Engl. | volume=35 | year=1996 | pages=1672–1675 | doi=10.1002/anie.199616721 | issue=15|display-authors=etal}}</ref><ref>{{cite journal | author=Kishi, Y | author-link=Kishi, Y | title=Complete structure of maitotoxin | journal=Pure Appl. Chem. | volume=70 | issue=2 | year=1998 | pages=339–344 | doi=10.1351/pac199870020339| doi-access=free }}</ref> Its structure was established through analysis using nuclear magnetic resonance at Tohoku University, Harvard University and the University of Tokyo in combination with mass spectrometry, and synthetic chemical methods. However, Andrew Gallimore and Jonathan Spencer have questioned the structure of maitotoxin at a single ring-junction (the J–K junction), based purely on biosynthetic considerations and their general model for marine polyether biogenesis.<ref name=poly>{{cite journal |vauthors=Gallimore AR, Spencer JB | title=Stereochemical Uniformity in Marine Polyether Ladders—Implications for the Biosynthesis and Structure of Maitotoxin | journal=Angew. Chem. Int. Ed. Engl. | volume=45 | issue=27 | year=2006 | pmid=16767782 | pages=4406–4413 | doi=10.1002/anie.200504284| doi-access=free }}</ref> K. C. Nicolaou and Michael Frederick argue that despite this biosynthetic argument, the originally proposed structure could still be correct. <ref>{{cite journal |vauthors=Nicolaou KC, Frederick MO |title=On the structure of maitotoxin |journal=Angew. Chem. Int. Ed. Engl. |volume=46 |issue=28 |pages=5278–82 |year=2007 |pmid=17469088 |doi=10.1002/anie.200604656 }} </ref> The controversy has yet{{update inline|date=February 2017}} to be resolved.

== Biosynthesis == The molecule is produced in nature via a polyketide synthase pathway.<ref name=poly />

==Total synthesis== Since 1996 the Nicolaou research group is involved in an effort to synthesise the molecule via total synthesis<ref>{{cite journal | author = Nicolaou K. C., Cole Kevin P., Frederick Michael O., Aversa Robert J., Denton Ross M. | year = 2007 | title = Chemical Synthesis of the GHIJK Ring System and Further Experimental Support for the Originally Assigned Structure of Maitotoxin. | journal = Angew. Chem. Int. Ed. | volume = 46 | issue = 46 | pages = 8875–8879 | doi = 10.1002/anie.200703742 | pmid = 17943950 }}</ref><ref>{{cite journal | doi = 10.1021/ja801139f | volume=130 | title=Chemical Synthesis of the GHIJKLMNO Ring System of Maitotoxin | year=2008 | journal=Journal of the American Chemical Society | pages=7466–7476 | author=Nicolaou K. C.| issue=23 | pmid=18481856 | bibcode=2008JAChS.130.7466N }}</ref><ref>{{cite journal | doi = 10.1021/ja102260q | volume=132 | title=Synthesis of the ABCDEFG Ring System of Maitotoxin | year=2010 | journal=Journal of the American Chemical Society | pages=6855–6861 | author=Nicolaou K. C.| issue=19 | pmid=20415445 | pmc=2880607 | bibcode=2010JAChS.132.6855N }}</ref><ref>{{cite journal | doi = 10.1021/ja509829e | volume=136 | title=Synthesis and Biological Evaluation of QRSTUVWXYZA′ Domains of Maitotoxin | year=2014 | journal=Journal of the American Chemical Society | pages=16444–16451 | author=Nicolaou K. C.| issue=46 | pmid=25374117 | pmc=4244842 | doi-access=free | bibcode=2014JAChS.13616444N }}</ref> although as of 2015 the project is on hold due to lack of funding.<ref>''Chemistry's toughest total synthesis challenge put on hold by lack of funds'' Katrina Kramer 15 January 2015 Chemistry World http://www.rsc.org/chemistryworld/2015/01/chemistry-grandest-total-synthesis-challenge-maitotoxin-put-hold-lack-funds</ref>

==See also== *Palytoxin * Ciguatera

== References == {{Reflist|30em}}

== Further reading == * {{cite book | last=JP JOSHI |first=Maitland | title=Organic Chemistry, Third Edition | publisher=W. W. Norton & Company |date=2004 | isbn=978-0-393-92408-4}}

{{Ion channel modulators}} {{Sodium compounds}}

Category:Oxygen heterocycles Category:Marine neurotoxins Category:Ion channel toxins Category:Phycotoxins Category:Secondary alcohols Category:Alkene derivatives Category:Tetrahydropyrans Category:Organic sodium salts Category:Polyether toxins Category:Non-protein ion channel toxins Category:Calcium channel openers Category:Conjugated dienes Category:Organosulfates Category:Heterocyclic compounds with 7 or more rings