Non-heme monooxygenase ThoJ catalyzes thioholgamide β-hydroxylation

Sikandar, A., Lopatniuk, M., Luzhetskyy, A. and Koehnke, J. (2020) Non-heme monooxygenase ThoJ catalyzes thioholgamide β-hydroxylation. ACS Chemical Biology, 15(10), pp. 2815-2819. (doi: 10.1021/acschembio.0c00637) (PMID:32965102)

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Thioviridamide-like compounds, including thioholgamides, are ribosomally synthesized and post-translationally modified peptide natural products with potent anticancer cell activity and an unprecedented structure. Very little is known about their biosynthesis, and we were intrigued by the β-hydroxy-N1, N3-dimethylhistidinium moiety found in these compounds. Here we report the construction of a heterologous host capable of producing thioholgamide with a 15-fold increased yield compared to the wild-type strain. A knockout of thoJ, encoding a predicted nonheme monooxygenase, shows that ThoJ is essential for thioholgamide β-hydroxylation. The crystal structure of ThoJ exhibits a typical mono/dioxygenase fold with conserved key active-site residues. Yet, ThoJ possesses a very large substrate binding pocket that appears suitable to receive a cyclic thioholgamide intermediate for hydroxylation. The improved production of the heterologous host will enable the dissection of the individual biosynthetic steps involved in biosynthesis of this exciting RiPP family.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Koehnke, Professor Jesko
Authors: Sikandar, A., Lopatniuk, M., Luzhetskyy, A., and Koehnke, J.
College/School:College of Science and Engineering > School of Chemistry
Journal Name:ACS Chemical Biology
Publisher:American Chemical Society
ISSN (Online):1554-8937
Published Online:23 September 2020

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