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	{{chembox		{{chembox
	| verifiedrevid = 400318226		| verifiedrevid = 421043852
	|ImageFile=mycolactone 2.png		| ImageFile=mycolactone 2.png
	|ImageSize=		| ImageSize=
	|IUPACName= -7,9-dimethyl-2-oxo-1-oxacyclododec-9-en-6-yl] (''2E,4E,6E,8E,10E,12S,13S,15S'')-12,13,15-trihydroxy-4,6,10-trimethylhexadeca-2,4,6,8,10-pentaenoate		| PIN= (6''S'',7''S'',9''E'',12''R'')-12--7,9-dimethyl-2-oxo-1-oxacyclododec-9-en-6-yl (2''E'',4''E'',6''E'',8''E'',10''E'',12''S'',13''S'',15''S'')-12,13,15-trihydroxy-4,6,10-trimethylhexadeca-2,4,6,8,10-pentaenoate
	|Section1= {{Chembox Identifiers		|Section1={{Chembox Identifiers
	| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}		| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
	| ChemSpiderID = 4445303		| ChemSpiderID = 4445303
	| InChI = 1/C44H70O9/c1-28(13-11-14-29(2)25-39(48)40(49)27-37(10)46)21-30(3)18-20-44(51)52-41-15-12-16-43(50)53-42(19-17-31(4)22-34(41)7)35(8)24-32(5)23-33(6)38(47)26-36(9)45/h11,13-14,17-18,20-21,23,25,33-42,45-49H,12,15-16,19,22,24,26-27H2,1-10H3/b14-11+,20-18+,28-13+,29-25+,30-21+,31-17+,32-23+/t33-,34+,35+,36-,37+,38-,39+,40+,41+,42-/m1/s1		| InChI = 1/C44H70O9/c1-28(13-11-14-29(2)25-39(48)40(49)27-37(10)46)21-30(3)18-20-44(51)52-41-15-12-16-43(50)53-42(19-17-31(4)22-34(41)7)35(8)24-32(5)23-33(6)38(47)26-36(9)45/h11,13-14,17-18,20-21,23,25,33-42,45-49H,12,15-16,19,22,24,26-27H2,1-10H3/b14-11+,20-18+,28-13+,29-25+,30-21+,31-17+,32-23+/t33-,34+,35+,36-,37+,38-,39+,40+,41+,42-/m1/s1
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	| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}		| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
	| StdInChIKey = WKTLNJXZVDLRTJ-QRRXZRELSA-N		| StdInChIKey = WKTLNJXZVDLRTJ-QRRXZRELSA-N
			| CASNo_Ref = {{cascite|correct|??}}
	| CASNo=222050-77-3		| CASNo=222050-77-3
	| PubChem=5282079		| PubChem=5282079
	| SMILES = O=C1O(C/C=C(/C((OC(=O)\C=C\C(=C\C(=C\C=C\C(=C\(O)(O)C(O)C)C)C)C)CCC1)C)C)(C)CC(=C/(C)(O)C(O)C)/C		| SMILES = O=C1O(C/C=C(/C((OC(=O)\C=C\C(=C\C(=C\C=C\C(=C\(O)(O)C(O)C)C)C)C)CCC1)C)C)(C)CC(=C/(C)(O)C(O)C)/C
	| MeSHName=Mycolactone		| MeSHName=Mycolactone
	}}		}}
	|Section2= {{Chembox Properties		|Section2={{Chembox Properties
	| Formula=C<sub>44</sub>H<sub>70</sub>O<sub>9</sub>		| Formula=C<sub>44</sub>H<sub>70</sub>O<sub>9</sub>
	| MolarMass=743.021		| MolarMass=743.021
	| Appearance=		| Appearance=
	| Density=		| Density=
	| MeltingPt=		| MeltingPt=
	| BoilingPt=		| BoilingPt=
	| Solubility=		| Solubility=
	}}		}}
	|Section3= {{Chembox Hazards		|Section3={{Chembox Hazards
	| MainHazards=		| MainHazards=
	| FlashPt=		| FlashPt=
			| AutoignitionPt =
	| Autoignition=
	}}		}}
	}}		}}
	'''Mycolactone''' is a ]-derived ] produced and secreted by a group of very closely related ] ] that have been assigned a variety of species names including, '']'', '']'' (an unofficial designation), '']'', and some strains of '']''. These mycobacteria are collectively referred to as mycolactone-producing mycobacteria or MPM. <ref name=Yip>{{cite journal		'''Mycolactone''' is a ]-derived ] produced and secreted by a group of very closely related ] ] species including '']'', '']'' (an unofficial designation), '']'', and some strains of '']''. These mycobacteria are collectively referred to as mycolactone-producing mycobacteria or MPM.<ref name=Yip>{{cite journal
	| author = Yip MJ, Porter JL, Fyfe JA, Lavender CJ, ''et al.''		|vauthors=Yip MJ, Porter JL, Fyfe JA, Lavender CJ, etal | title = Evolution of ''Mycobacterium ulcerans'' and other mycolactone-producing mycobacteria from a common ''Mycobacterium marinum'' progenitor.
		⚫	| journal = J. Bacteriol.
	| title = Evolution of "Mycobacterium ulcerans" and other mycolactone-producing mycobacteria from a common "Mycobacterium marinum" progenitor.
			| date=March 2007
⚫	| journal = J Bacteriol.
	| year = 2007 |month=March
	| volume = 189		| volume = 189
	| pages = 2021–29		| pages = 2021–29
Line 44:		Line 44:
	| doi = 10.1128/JB.01442-06		| doi = 10.1128/JB.01442-06
	| issue = 5		| issue = 5
	| pmc = 1855710}}</ref><ref name=Käser>{{cite journal		| pmc = 1855710}}</ref><ref name="Käser">{{cite journal
		⚫	|author1=Käser M |author2=Hauser J |author3=Small P |author4=Pluschke G. | title = Large sequence polymorphisms unveil the phylogenetic relationship of environmental and pathogenic mycobacteria related to "Mycobacterium ulcerans".
	| author = Käser M, Hauser J, Small P, Pluschke G.
		⚫	| journal = Appl Environ Microbiol
⚫	| title = Large sequence polymorphisms unveil the phylogenetic relationship of environmental and pathogenic mycobacteria related to "Mycobacterium ulcerans".
			| date=September 2009
⚫	| journal = Appl Environ Microbiol.
	| year = 2009 |month=September
	| volume = 75		| volume = 75
	| pages = 5667–75.		| pages = 5667–75
	| pmid = 19592526		| pmid = 19592526
	| doi = 10.1128/AEM.00446-09		| doi = 10.1128/AEM.00446-09
	| issue = 17		| issue = 17
	| pmc = 2737907}}</ref>		| pmc = 2737907|bibcode=2009ApEnM..75.5667K }}</ref>
			In humans, mycolactone is the toxin responsible for ]s, doing so by damaging tissues and inhibiting the immune response.<ref>{{cite web|url=https://www.who.int/mediacentre/factsheets/fs199/en/|title=Buruli ulcer disease|date=March 2007|work=Fact sheets|publisher=WHO|access-date=24 March 2012}}</ref>
	Mycolactone is produced by MPM through condensation of two polyketide chains (known as the core and acyl side chain). Different MPM produce characteristic mixtures of mycolactone congeners. The structural heterogeneity of mycolactones is due to variations in the acyl side chain. The structure of the mycolactone core is invariant.<ref name=Pidot>{{cite journal
			__TOC__
	| author = Pidot SJ, Hong H, Seemann T, Porter JL, ''et al.''
			==Variants==
⚫	| title = Deciphering the genetic basis for polyketide variation among mycobacteria producing mycolactones.
		⚫	Five distinct, naturally occurring mycolactone structural variants have been described so far:
		⚫	* Mycolactone A/B (''M. ulcerans'' from Africa, Malaysia, Japan<ref name=Pidot>{{cite journal
		⚫	|vauthors=Pidot SJ, Hong H, Seemann T, Porter JL, etal | title = Deciphering the genetic basis for polyketide variation among mycobacteria producing mycolactones.
	| journal = BMC Genomics		| journal = BMC Genomics
	| year = 2008 |month=October		| date=October 2008
	| volume = 9		| volume = 9
	| pages = 462		| pages = 462
	| pmc=2569948		| pmc=2569948
	| doi = 10.1186/1471-2164-9-462		| doi = 10.1186/1471-2164-9-462
	| pmid = 18840298}}</ref>		| pmid = 18840298
			| doi-access = free
			}}</ref>
	The genes required for mycolactone biosynthesis form a contiguous 110-kb cluster on a large ]<ref name=Stinear>{{cite journal
			* Mycolactone C (''M. ulcerans'' from Australia)<ref>{{cite journal |last1=Mve-Obiang |first1=Armand |last2=Lee |first2=Richard E. |last3=Portaels |first3=Françoise |last4=Small |first4=P. L. C. |title=Heterogeneity of Mycolactones Produced by Clinical Isolates of Mycobacterium ulcerans : Implications for Virulence |journal=Infection and Immunity |date=February 2003 |volume=71 |issue=2 |pages=774–783 |doi=10.1128/IAI.71.2.774-783.2003 |pmid=12540557 |pmc=145382 }}</ref>
	| author = Stinear TP, Mve-Obiang A, Small PL, Frigui W, ''et al.''
⚫	| title = Giant plasmid-encoded polyketide synthases produce the macrolide toxin of "Mycobacterium ulcerans".
⚫	| journal = PNAS
	| year = 2004 |month=February
⚫	| volume = 101
⚫	| issue = 6
⚫	| pages = 1345–9
⚫	| pmid = 14736915
⚫	| doi = 10.1073/pnas.0305877101
	| pmc = 337055}}</ref>. The lactone core is produced by two polyketide synthases (PKS) that are encoded by the genes, mlsA1 and mlsA2, and a third polyketide synthase, encoded by the mlsB gene, produces the ]-acyl side chain. Three putative accessory genes are found in the mycolactone cluster. One of these, MUP053, encodes a p450 monooxygenase that is thought to produce the hydroxyl at C′-12 on the fatty acid side chain. The gene encoding a FabH-like, type III ketosynthase (KS), located upstream of mlsA1, encodes a putative “joinase” (MUP045), and a type II thioesterase (TE II) gene (MUP038) is located between mlsA2 and mlsB.<ref name=Stinear />
⚫	Five distinct, naturally-occurring mycolactone structural variants have been described so far:
⚫	* Mycolactone A/B (''M. ulcerans'' from Africa, Malaysia, Japan<ref name=Pidot />)
	* Mycolactone C (''M. ulcerans'' from Australia)
	* Mycolactone D (''M. ulcerans'' from China)		* Mycolactone D (''M. ulcerans'' from China)
	* Mycolactone E (''M. liflandii'')<ref name=Mve-Obiang>{{cite journal		* Mycolactone E (''M. liflandii'' from Sub-Saharan Africa)<ref name=Mve-Obiang>{{cite journal
		⚫	|vauthors=Mve-Obiang A, Lee RE, Umstot ES, Trott KA, etal | title = A newly discovered mycobacterial pathogen isolated from laboratory colonies of ''Xenopus'' species with lethal infections produces a novel form of mycolactone, the ''Mycobacterium ulcerans'' macrolide toxin.
	| author = Mve-Obiang A, Lee RE, Umstot ES, Trott KA, ''et al.''
		⚫	| journal = Infect. Immun.
⚫	| title = A newly discovered mycobacterial pathogen isolated from laboratory colonies of "Xenopus" species with lethal infections produces a novel form of mycolactone, the "Mycobacterium ulcerans" macrolide toxin.
			| date=June 2005
⚫	| journal = Infect Immun.
		⚫	| volume = 73
	| year = 2005 |month=June
⚫	| volume = 7
	| pages = 3307–12		| pages = 3307–12
	| pmc = 1111873		| pmc = 1111873
	| doi = 10.1128/IAI.73.6.3307-3312.2005		| doi = 10.1128/IAI.73.6.3307-3312.2005
	| pmid = 15908356		| pmid = 15908356
	| issue = 6}}</ref> <ref name=Hong>{{cite journal		| issue = 6}}</ref><ref name=Hong>{{cite journal
	| author = Hong H, Stinear T, Skelton P, Spencer JB, Leadlay PF.		|author1=Hong H |author2=Stinear T |author3=Skelton P |author4=Spencer JB |author5=Leadlay PF. | title = Structure elucidation of a novel family of mycolactone toxins from the frog pathogen ''Mycobacterium'' sp. MU128FXT by mass spectrometry.
		⚫	| journal = Chem Commun
	| title = Structure elucidation of a novel family of mycolactone toxins from the frog pathogen "Mycobacterium" sp. MU128FXT by mass spectrometry.
			| date=Sep 2005
⚫	| journal = Chem Commun (Camb)
			| volume = 34
	| year = 2005 |month=Sept
⚫	| volume = 34 4306-8
	| pages = 4306–8		| pages = 4306–8
	| pmc =
	| doi = 10.1039/b506835e		| doi = 10.1039/b506835e
	| pmid = 16113730		| pmid = 16113730
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	* Mycolactone F (''M. pseudoshottsii'' and ''M. marinum'' from around the world)<ref>		* Mycolactone F (''M. pseudoshottsii'' and ''M. marinum'' from around the world)<ref>
	{{cite journal		{{cite journal
	| author = Ranger BS, Mahrous EA, Mosi L, ''et al.''		|vauthors=Ranger BS, Mahrous EA, Mosi L, etal | title = Globally distributed mycobacterial fish pathogens produce a novel plasmid-encoded toxic macrolide, mycolactone F.
	| title = Globally distributed mycobacterial fish pathogens produce a novel plasmid-encoded toxic macrolide, mycolactone F.
	| journal = Infect. Immun.		| journal = Infect. Immun.
	| year = 2006 |month=November		| date=November 2006
	| volume =74		| volume =74
	| issue =11		| issue =11
	| pages =6037–45		| pages =6037–45
		⚫	| url= | doi = 10.1128/IAI.00970-06
	| url= http://iai.asm.org/cgi/gca?sendit=Get+All+Checked+Abstract%28s%29&SEARCHID=1&TITLEABSTRACT=globally+mycolactone+F&FIRSTINDEX=0&hits=10&RESULTFORMAT=&gca=iai%3BIAI.00970-06v1
⚫	| doi = 10.1128/IAI.00970-06
	| pmid = 16923788 |pmc=1695495}}		| pmid = 16923788 |pmc=1695495}}
	</ref> <ref name=Stragier>{{cite journal		</ref><ref name=Stragier>{{cite journal
	| author = Stragier P, Hermans K, Stinear T, Portaels F.		|author1=Stragier P |author2=Hermans K |author3=Stinear T |author4=Portaels F. | title = First report of a mycolactone-producing Mycobacterium infection in fish agriculture in Belgium.
		⚫	| journal = FEMS Microbiol. Lett.
	| title = First report of a mycolactone-producing Mycobacterium infection in fish agriculture in Belgium.
			| date=September 2008
⚫	| journal = FEMS Microbiol Lett.
	| year = 2008 |month=September
	| volume = 286		| volume = 286
	| pages = 93–5		| pages = 93–5
	| pmid = 18631185		| pmid = 18631185
	| doi = 10.1111/j.1574-6968.2008.01264.x		| doi = 10.1111/j.1574-6968.2008.01264.x
	| issue = 1}}</ref>		| issue = 1| doi-access = free}}</ref>
	== Biosynthesis ==		== Biosynthesis ==
	Mycolactone consists of a 12-membered ] core with an ]-linked ] chain. Three ]-encoded ] (PKS) enzymes are responsible for its production: MLSA 1 and MLSA 2 which generate the core, and MLSB is responsible for the synthesis of the polyketide chain. As shown in Figure 1, MLSB (1.2 MDa) contains seven consecutive extension modules and MLSA 1 (1.8 MDa) consists of eight. The remaining PKS enzyme, MLSA 2, contains the ninth module of MLSA <ref name=Stinear />. The C-terminal domains of both MLSA2 and MLSB includes a ] (TE) that was thought to catalyze the formation of the mycolactone core but appears inactive.<ref>{{cite journal |author=Meier J L, Barrows-Yano T, Foley T L, Wike C L, and Burkart M D |title=The unusual macrocycle forming thioesterase of mycolactone |journal=Mol. Biosyst. |volume=4 |pages=663–671 |year=2008 |month=April |doi=10.1039/b801397g |url=http://www.rsc.org/delivery/_ArticleLinking/ArticleLinking.asp?JournalCode=MB&Year=2008&ManuscriptID=b801397g&Iss=6 |pmid=18493665 |issue=6}}</ref> Each module consists of either ] or ] ] (AT) that allows for chain extension, a ketosynthase (KS), which catalyzes chain elongation, and an ] (ACP) where the growing polyketide chain is attached. Modules may also consist of any of the following modifying domains: a dehydratase (DH), an enoyl reductase (ER) and one of two types of ketoreductase (KR) domains. Type A and B KRs refer to the two directions of ketoreduction that are correlated with specific ] in the ]. Four of the DH domains are predicted to be inactive based on a ] found in the active site sequence.<ref name=Stinear /><ref>{{cite journal |author= Bali S, Weissman K J |title=Ketoreduction in Mycolactone Biosynthesis: Insight into Substrate Specificity and Stereocontrol from Studies of Discrete Ketoreductase Domains in vitro |journal=ChemBioChem |volume=7 |issue=12 |pages=1935–1942 |year=2006 |month=October |doi=10.1002/cbic.200600285|url=http://www3.interscience.wiley.com/cgi-bin/fulltext/113390907/HTMLSTART |pmid= 17031885}}</ref>		Mycolactone consists of a 12-membered ] core with an ]-linked ] chain. Three ]-encoded ] (PKS) enzymes are responsible for its production: MLSA 1 and MLSA 2 which generate the core, and MLSB is responsible for the synthesis of the polyketide chain. As shown in Figure 1, MLSB (1.2 MDa) contains seven consecutive extension modules and MLSA 1 (1.8 MDa) consists of eight. The remaining PKS enzyme, MLSA 2, contains the ninth module of MLSA.<ref name=Stinear>{{cite journal
		⚫	|vauthors=Stinear TP, Mve-Obiang A, Small PL, Frigui W, etal | title = Giant plasmid-encoded polyketide synthases produce the macrolide toxin of "Mycobacterium ulcerans".
⚫	]
		⚫	| journal = PNAS
⚫	'''Figure 1.''' Domain Organization of Mycolactone<ref name=Stinear />.
			| date=February 2004
		⚫	| volume = 101
		⚫	| issue = 6
		⚫	| pages = 1345–9
		⚫	| pmid = 14736915
		⚫	| doi = 10.1073/pnas.0305877101
			| pmc = 337055| doi-access = free
			}}</ref> The C-terminal domains of both MLSA2 and MLSB includes a ] (TE) that was thought to catalyze the formation of the mycolactone core but appears inactive.<ref>{{cite journal |last1=Meier |first1=Jordan L. |last2=Barrows-Yano |first2=Tiffany |last3=Foley |first3=Timothy L. |last4=Wike |first4=Candice L. |last5=Burkart |first5=Michael D. |title=The unusual macrocycle forming thioesterase of mycolactone |journal=Molecular BioSystems |date=2008 |volume=4 |issue=6 |pages=663–671 |doi=10.1039/b801397g |pmid=18493665 }}</ref> Each module consists of either ] or ] ] (AT) that allows for chain extension, a ketosynthase (KS), which catalyzes chain elongation, and an ] (ACP) where the growing polyketide chain is attached. Modules may also consist of any of the following modifying domains: a dehydratase (DH), an enoyl reductase (ER) and one of two types of ketoreductase (KR) domains. Type A and B KRs refer to the two directions of ketoreduction that are correlated with specific ] in the ]. Four of the DH domains are predicted to be inactive based on a ] found in the active site sequence.<ref name=Stinear /><ref>{{cite journal |last1=Bali |first1=Shilpa |last2=Weissman |first2=Kira J. |title=Ketoreduction in Mycolactone Biosynthesis: Insight into Substrate Specificity and Stereocontrol from Studies of Discrete Ketoreductase Domains in vitro |journal=ChemBioChem |date=4 December 2006 |volume=7 |issue=12 |pages=1935–1942 |doi=10.1002/cbic.200600285 |pmid=17031885 |s2cid=40596187 }}</ref>
		⚫	{{wide image|Mycolactone3.jpg|1266px|Domain organization of mycolactone.}}
		⚫	'''Figure 1.''' Domain Organization of Mycolactone.<ref name=Stinear />
	== References ==		== References ==
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	]		]
	]		]
			]