Show simple item record

dc.contributor.authorLukat, Peer
dc.contributor.authorKatsuyama, Yohei
dc.contributor.authorWenzel, Silke
dc.contributor.authorBinz, Tina
dc.contributor.authorKönig, Claudia
dc.contributor.authorBlankenfeldt, Wulf
dc.contributor.authorBrönstrup, Mark
dc.contributor.authorMüller, Rolf
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.
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
refterms.dateFOA2018-06-13T09:21:01Z
html.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.


Files in this item

Thumbnail
Name:
Lukat et al.pdf
Size:
907.5Kb
Format:
PDF
Description:
open Access publication
Thumbnail
Name:
Supplement.pdf
Size:
6.656Mb
Format:
PDF
Description:
supplemental information

This item appears in the following Collection(s)

Show simple item record

http://creativecommons.org/licenses/by-nc-sa/4.0/
Except where otherwise noted, this item's license is described as http://creativecommons.org/licenses/by-nc-sa/4.0/