2.50
Hdl Handle:
http://hdl.handle.net/10033/621184
Title:
Biosynthesis of methyl-proline containing griselimycins, natural products with anti-tuberculosis activity.
Authors:
Lukat, Peer; Katsuyama, Yohei; Wenzel, Silke; Binz, Tina; König, Claudia; Blankenfeldt, Wulf; Brönstrup, Mark; Müller, Rolf ( 0000-0002-1042-5665 )
Abstract:
Griselimycins (GMs) are depsidecapeptides with superb anti-tuberculosis activity. They contain up to three (2S,4R)-4-methyl-prolines (4-MePro), of which one blocks oxidative degradation and increases metabolic stability in animal models. The natural congener with this substitution is only a minor component in fermentation cultures. We showed that this product can be significantly increased by feeding the reaction with 4-MePro and we investigated the molecular basis of 4-MePro biosynthesis and incorporation. We identified the GM biosynthetic gene cluster as encoding a nonribosomal peptide synthetase and a sub-operon for 4-MePro formation. Using heterologous expression, gene inactivation, and in vitro experiments, we showed that 4-MePro is generated by leucine hydroxylation, oxidation to an aldehyde, and ring closure with subsequent reduction. The crystal structures of the leucine hydroxylase GriE have been determined in complex with substrates and products, providing insight into the stereospecificity of the reaction.
Affiliation:
Helmholtz-Institut für pharmazeutische Forschung Saarland, Universitätscampus E8.1, 66123 Saarbrücken, Germany.
Citation:
Biosynthesis of methyl-proline containing griselimycins, natural products with anti-tuberculosis activity. 2017, 8 (11):7521-7527 Chem Sci
Journal:
Chemical science
Issue Date:
1-Nov-2017
URI:
http://hdl.handle.net/10033/621184
DOI:
10.1039/c7sc02622f
PubMed ID:
29163906
Type:
Article
Language:
en
ISSN:
2041-6520
Appears in Collections:
Publications of the research group Chemical Biology (CBIO); publications of the department of microbial natural substances ([HIPS]MINS); Publications of the Dept. Structure and Functions of Proteins(SFPR)

Full metadata record

DC FieldValue Language
dc.contributor.authorLukat, Peeren
dc.contributor.authorKatsuyama, Yoheien
dc.contributor.authorWenzel, Silkeen
dc.contributor.authorBinz, Tinaen
dc.contributor.authorKönig, Claudiaen
dc.contributor.authorBlankenfeldt, Wulfen
dc.contributor.authorBrönstrup, Marken
dc.contributor.authorMüller, Rolfen
dc.date.accessioned2017-11-27T15:04:00Z-
dc.date.available2017-11-27T15:04:00Z-
dc.date.issued2017-11-01-
dc.identifier.citationBiosynthesis of methyl-proline containing griselimycins, natural products with anti-tuberculosis activity. 2017, 8 (11):7521-7527 Chem Scien
dc.identifier.issn2041-6520-
dc.identifier.pmid29163906-
dc.identifier.doi10.1039/c7sc02622f-
dc.identifier.urihttp://hdl.handle.net/10033/621184-
dc.description.abstractGriselimycins (GMs) are depsidecapeptides with superb anti-tuberculosis activity. They contain up to three (2S,4R)-4-methyl-prolines (4-MePro), of which one blocks oxidative degradation and increases metabolic stability in animal models. The natural congener with this substitution is only a minor component in fermentation cultures. We showed that this product can be significantly increased by feeding the reaction with 4-MePro and we investigated the molecular basis of 4-MePro biosynthesis and incorporation. We identified the GM biosynthetic gene cluster as encoding a nonribosomal peptide synthetase and a sub-operon for 4-MePro formation. Using heterologous expression, gene inactivation, and in vitro experiments, we showed that 4-MePro is generated by leucine hydroxylation, oxidation to an aldehyde, and ring closure with subsequent reduction. The crystal structures of the leucine hydroxylase GriE have been determined in complex with substrates and products, providing insight into the stereospecificity of the reaction.en
dc.language.isoenen
dc.rights.urihttp://creativecommons.org/licenses/by-nc-sa/4.0/*
dc.titleBiosynthesis of methyl-proline containing griselimycins, natural products with anti-tuberculosis activity.en
dc.typeArticleen
dc.contributor.departmentHelmholtz-Institut für pharmazeutische Forschung Saarland, Universitätscampus E8.1, 66123 Saarbrücken, Germany.en
dc.identifier.journalChemical scienceen
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