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Biosynthesis of methyl-proline containing griselimycins, natural products with anti-tuberculosis activity

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 show that this product can be significantly increased by feeding 4-MePro and investigated the molecular basis of 4-MePro biosynthesis and incorporation. We identified the GM biosynthetic gene cluster encoding a nonribosomal peptide synthetase and a sub-operon for 4-MePro formation. Using heterologous expression, gene inactivation and in vitro experiments, we show that 4-MePro is generated by leucine hydroxylation, oxidation to an aldehyde and ring closure with subsequent reduction. Crystal structures of the leucine hydroxylase GriE have been determined in complex with substrates and products, providing insight into the stereospecificity the reaction.

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Publication details

The article was received on 12 Jun 2017, accepted on 01 Aug 2017 and first published on 03 Aug 2017


Article type: Edge Article
DOI: 10.1039/C7SC02622F
Citation: Chem. Sci., 2017, Accepted Manuscript
  • Open access: Creative Commons BY license
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    Biosynthesis of methyl-proline containing griselimycins, natural products with anti-tuberculosis activity

    P. Lukat, Y. Katsuyama, S. C. Wenzel, T. Binz, C. König, W. Blankenfeldt, M. Brönstrup and R. Müller, Chem. Sci., 2017, Accepted Manuscript , DOI: 10.1039/C7SC02622F

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