Deciphering the genetic basis for polyketide variation among mycobacteria producing mycolactones
<p>Abstract</p> <p>Background</p> <p>Mycolactones are immunosuppressive and cytotoxic polyketides, comprising five naturally occurring structural variants (named A/B, C, D, E and F), produced by different species of very closely related mycobacteria including the human...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2008-10-01
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| Series: | BMC Genomics |
| Online Access: | http://www.biomedcentral.com/1471-2164/9/462 |
| _version_ | 1818382508924862464 |
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| author | Wilson Peter Johnson Matthew Men Artem Yip Marcus J Porter Jessica L Seemann Torsten Hong Hui Pidot Sacha J Davies John K Leadlay Peter F Stinear Timothy P |
| author_facet | Wilson Peter Johnson Matthew Men Artem Yip Marcus J Porter Jessica L Seemann Torsten Hong Hui Pidot Sacha J Davies John K Leadlay Peter F Stinear Timothy P |
| author_sort | Wilson Peter |
| collection | DOAJ |
| description | <p>Abstract</p> <p>Background</p> <p>Mycolactones are immunosuppressive and cytotoxic polyketides, comprising five naturally occurring structural variants (named A/B, C, D, E and F), produced by different species of very closely related mycobacteria including the human pathogen, <it>Mycobacterium ulcerans</it>. In <it>M. ulcerans </it>strain Agy99, mycolactone A/B is produced by three highly homologous type I polyketide megasynthases (PKS), whose genes (<it>mlsA1</it>: 51 kb, <it>mlsA2</it>: 7.2 kb and <it>mlsB</it>: 42 kb) are found on a 174 kb plasmid, known as pMUM001.</p> <p>Results</p> <p>We report here comparative genomic analysis of pMUM001, the complete DNA sequence of a 190 kb megaplasmid (pMUM002) from <it>Mycobacterium liflandii </it>128FXT and partial sequence of two additional pMUM replicons, combined with liquid chromatography-tandem mass spectrometric (LC-MS/MS) analysis. These data reveal how PKS module and domain differences affecting MlsB correlate with the production of mycolactones E and F. For mycolactone E these differences from MlsB in <it>M. ulcerans </it>Agy99 include replacement of the AT domain of the loading module (acetate to propionate) and the absence of an entire extension module. For mycolactone F there is also a reduction of one extension module but also a swap of ketoreductase domains that explains the characteristic stereochemistry of the two terminal side-chain hydroxyls, an arrangement unique to mycolactone F</p> <p>Conclusion</p> <p>The mycolactone PKS locus on pMUM002 revealed the same large, three-gene structure and extraordinary pattern of near-identical PKS domain sequence repetition as observed in pMUM001 with greater than 98.5% nucleotide identity among domains of the same function. Intra- and inter-strain comparisons suggest that the extreme sequence homogeneity seen among the mls PKS genes is caused by frequent recombination-mediated domain replacement. This work has shed light on the evolution of mycolactone biosynthesis among an unusual group of mycobacteria and highlights the potential of the <it>mls </it>locus to become a toolbox for combinatorial PKS biochemistry.</p> |
| first_indexed | 2024-12-14T02:51:36Z |
| format | Article |
| id | doaj.art-5c5f9179bcbe48c2bafe1ba654a8b148 |
| institution | Directory Open Access Journal |
| issn | 1471-2164 |
| language | English |
| last_indexed | 2024-12-14T02:51:36Z |
| publishDate | 2008-10-01 |
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| series | BMC Genomics |
| spelling | doaj.art-5c5f9179bcbe48c2bafe1ba654a8b1482022-12-21T23:19:44ZengBMCBMC Genomics1471-21642008-10-019146210.1186/1471-2164-9-462Deciphering the genetic basis for polyketide variation among mycobacteria producing mycolactonesWilson PeterJohnson MatthewMen ArtemYip Marcus JPorter Jessica LSeemann TorstenHong HuiPidot Sacha JDavies John KLeadlay Peter FStinear Timothy P<p>Abstract</p> <p>Background</p> <p>Mycolactones are immunosuppressive and cytotoxic polyketides, comprising five naturally occurring structural variants (named A/B, C, D, E and F), produced by different species of very closely related mycobacteria including the human pathogen, <it>Mycobacterium ulcerans</it>. In <it>M. ulcerans </it>strain Agy99, mycolactone A/B is produced by three highly homologous type I polyketide megasynthases (PKS), whose genes (<it>mlsA1</it>: 51 kb, <it>mlsA2</it>: 7.2 kb and <it>mlsB</it>: 42 kb) are found on a 174 kb plasmid, known as pMUM001.</p> <p>Results</p> <p>We report here comparative genomic analysis of pMUM001, the complete DNA sequence of a 190 kb megaplasmid (pMUM002) from <it>Mycobacterium liflandii </it>128FXT and partial sequence of two additional pMUM replicons, combined with liquid chromatography-tandem mass spectrometric (LC-MS/MS) analysis. These data reveal how PKS module and domain differences affecting MlsB correlate with the production of mycolactones E and F. For mycolactone E these differences from MlsB in <it>M. ulcerans </it>Agy99 include replacement of the AT domain of the loading module (acetate to propionate) and the absence of an entire extension module. For mycolactone F there is also a reduction of one extension module but also a swap of ketoreductase domains that explains the characteristic stereochemistry of the two terminal side-chain hydroxyls, an arrangement unique to mycolactone F</p> <p>Conclusion</p> <p>The mycolactone PKS locus on pMUM002 revealed the same large, three-gene structure and extraordinary pattern of near-identical PKS domain sequence repetition as observed in pMUM001 with greater than 98.5% nucleotide identity among domains of the same function. Intra- and inter-strain comparisons suggest that the extreme sequence homogeneity seen among the mls PKS genes is caused by frequent recombination-mediated domain replacement. This work has shed light on the evolution of mycolactone biosynthesis among an unusual group of mycobacteria and highlights the potential of the <it>mls </it>locus to become a toolbox for combinatorial PKS biochemistry.</p>http://www.biomedcentral.com/1471-2164/9/462 |
| spellingShingle | Wilson Peter Johnson Matthew Men Artem Yip Marcus J Porter Jessica L Seemann Torsten Hong Hui Pidot Sacha J Davies John K Leadlay Peter F Stinear Timothy P Deciphering the genetic basis for polyketide variation among mycobacteria producing mycolactones BMC Genomics |
| title | Deciphering the genetic basis for polyketide variation among mycobacteria producing mycolactones |
| title_full | Deciphering the genetic basis for polyketide variation among mycobacteria producing mycolactones |
| title_fullStr | Deciphering the genetic basis for polyketide variation among mycobacteria producing mycolactones |
| title_full_unstemmed | Deciphering the genetic basis for polyketide variation among mycobacteria producing mycolactones |
| title_short | Deciphering the genetic basis for polyketide variation among mycobacteria producing mycolactones |
| title_sort | deciphering the genetic basis for polyketide variation among mycobacteria producing mycolactones |
| url | http://www.biomedcentral.com/1471-2164/9/462 |
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