Lysoquinone-TH1, a New Polyphenolic Tridecaketide Produced by Expressing the Lysolipin Minimal PKS II in Streptomyces albus
The structural repertoire of bioactive naphthacene quinones is expanded by engineering Streptomyces albus to express the lysolipin minimal polyketide synthase II (PKS II) genes from Streptomyces tendae Tü 4042 (llpD-F) with the corresponding cyclase genes llpCI-CIII. Fermentation of the rec...
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| Format: | Article |
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MDPI AG
2018-06-01
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| Series: | Antibiotics |
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| Online Access: | http://www.mdpi.com/2079-6382/7/3/53 |
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| author | Torben Hofeditz Claudia Eva-Maria Unsin Jutta Wiese Johannes F. Imhoff Wolfgang Wohlleben Stephanie Grond Tilmann Weber |
| author_facet | Torben Hofeditz Claudia Eva-Maria Unsin Jutta Wiese Johannes F. Imhoff Wolfgang Wohlleben Stephanie Grond Tilmann Weber |
| author_sort | Torben Hofeditz |
| collection | DOAJ |
| description | The structural repertoire of bioactive naphthacene quinones is expanded by engineering Streptomyces albus to express the lysolipin minimal polyketide synthase II (PKS II) genes from Streptomyces tendae Tü 4042 (llpD-F) with the corresponding cyclase genes llpCI-CIII. Fermentation of the recombinant strain revealed the two new polyaromatic tridecaketides lysoquinone-TH1 (7, identified) and TH2 (8, postulated structure) as engineered congeners of the dodecaketide lysolipin (1). The chemical structure of 7, a benzo[a]naphthacene-8,13-dione, was elucidated by NMR and HR-MS and confirmed by feeding experiments with [1,2-13C2]-labeled acetate. Lysoquinone-TH1 (7) is a pentangular polyphenol and one example of such rare extended polyaromatic systems of the benz[a]napthacene quinone type produced by the expression of a minimal PKS II in combination with cyclases in an artificial system. While the natural product lysolipin (1) has antimicrobial activity in nM-range, lysoquinone-TH1 (7) showed only minor potency as inhibitor of Gram-positive microorganisms. The bioactivity profiling of lysoquinone-TH1 (7) revealed inhibitory activity towards phosphodiesterase 4 (PDE4), an important target for the treatment in human health like asthma or chronic obstructive pulmonary disease (COPD). These results underline the availability of pentangular polyphenolic structural skeletons from biosynthetic engineering in the search of new chemical entities in drug discovery. |
| first_indexed | 2024-04-12T19:03:51Z |
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| id | doaj.art-f54a4a889f2f4633aad2c06e009b7490 |
| institution | Directory Open Access Journal |
| issn | 2079-6382 |
| language | English |
| last_indexed | 2024-04-12T19:03:51Z |
| publishDate | 2018-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Antibiotics |
| spelling | doaj.art-f54a4a889f2f4633aad2c06e009b74902022-12-22T03:20:05ZengMDPI AGAntibiotics2079-63822018-06-01735310.3390/antibiotics7030053antibiotics7030053Lysoquinone-TH1, a New Polyphenolic Tridecaketide Produced by Expressing the Lysolipin Minimal PKS II in Streptomyces albusTorben Hofeditz0Claudia Eva-Maria Unsin1Jutta Wiese2Johannes F. Imhoff3Wolfgang Wohlleben4Stephanie Grond5Tilmann Weber6Institut für Organische Chemie, Eberhard Karls Universität Tübingen, Auf der Morgenstelle 18, 72076 Tübingen, GermanyInterfakultäres Institut für Mikrobiologie und Infektionsmedizin, Eberhard Karls Universität Tübingen, Auf der Morgenstelle 28, 72076 Tübingen, GermanyGEOMAR, Helmholtz-Zentrum für Ozeanforschung Kiel, Düsternbrooker Weg 20, 24105 Kiel, GermanyGEOMAR, Helmholtz-Zentrum für Ozeanforschung Kiel, Düsternbrooker Weg 20, 24105 Kiel, GermanyInterfakultäres Institut für Mikrobiologie und Infektionsmedizin, Eberhard Karls Universität Tübingen, Auf der Morgenstelle 28, 72076 Tübingen, GermanyInstitut für Organische Chemie, Eberhard Karls Universität Tübingen, Auf der Morgenstelle 18, 72076 Tübingen, GermanyInterfakultäres Institut für Mikrobiologie und Infektionsmedizin, Eberhard Karls Universität Tübingen, Auf der Morgenstelle 28, 72076 Tübingen, GermanyThe structural repertoire of bioactive naphthacene quinones is expanded by engineering Streptomyces albus to express the lysolipin minimal polyketide synthase II (PKS II) genes from Streptomyces tendae Tü 4042 (llpD-F) with the corresponding cyclase genes llpCI-CIII. Fermentation of the recombinant strain revealed the two new polyaromatic tridecaketides lysoquinone-TH1 (7, identified) and TH2 (8, postulated structure) as engineered congeners of the dodecaketide lysolipin (1). The chemical structure of 7, a benzo[a]naphthacene-8,13-dione, was elucidated by NMR and HR-MS and confirmed by feeding experiments with [1,2-13C2]-labeled acetate. Lysoquinone-TH1 (7) is a pentangular polyphenol and one example of such rare extended polyaromatic systems of the benz[a]napthacene quinone type produced by the expression of a minimal PKS II in combination with cyclases in an artificial system. While the natural product lysolipin (1) has antimicrobial activity in nM-range, lysoquinone-TH1 (7) showed only minor potency as inhibitor of Gram-positive microorganisms. The bioactivity profiling of lysoquinone-TH1 (7) revealed inhibitory activity towards phosphodiesterase 4 (PDE4), an important target for the treatment in human health like asthma or chronic obstructive pulmonary disease (COPD). These results underline the availability of pentangular polyphenolic structural skeletons from biosynthetic engineering in the search of new chemical entities in drug discovery.http://www.mdpi.com/2079-6382/7/3/53lysolipinminimal PKS IIcyclasesbenz[a]naphthacene quinonetridecaketidearomatic polyketidepentacyclic angular polyphenolextended polyketide chain |
| spellingShingle | Torben Hofeditz Claudia Eva-Maria Unsin Jutta Wiese Johannes F. Imhoff Wolfgang Wohlleben Stephanie Grond Tilmann Weber Lysoquinone-TH1, a New Polyphenolic Tridecaketide Produced by Expressing the Lysolipin Minimal PKS II in Streptomyces albus Antibiotics lysolipin minimal PKS II cyclases benz[a]naphthacene quinone tridecaketide aromatic polyketide pentacyclic angular polyphenol extended polyketide chain |
| title | Lysoquinone-TH1, a New Polyphenolic Tridecaketide Produced by Expressing the Lysolipin Minimal PKS II in Streptomyces albus |
| title_full | Lysoquinone-TH1, a New Polyphenolic Tridecaketide Produced by Expressing the Lysolipin Minimal PKS II in Streptomyces albus |
| title_fullStr | Lysoquinone-TH1, a New Polyphenolic Tridecaketide Produced by Expressing the Lysolipin Minimal PKS II in Streptomyces albus |
| title_full_unstemmed | Lysoquinone-TH1, a New Polyphenolic Tridecaketide Produced by Expressing the Lysolipin Minimal PKS II in Streptomyces albus |
| title_short | Lysoquinone-TH1, a New Polyphenolic Tridecaketide Produced by Expressing the Lysolipin Minimal PKS II in Streptomyces albus |
| title_sort | lysoquinone th1 a new polyphenolic tridecaketide produced by expressing the lysolipin minimal pks ii in streptomyces albus |
| topic | lysolipin minimal PKS II cyclases benz[a]naphthacene quinone tridecaketide aromatic polyketide pentacyclic angular polyphenol extended polyketide chain |
| url | http://www.mdpi.com/2079-6382/7/3/53 |
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