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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Abstract
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 |
|---|---|
| Status: | Published |
| Refereed: | Yes |
| 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: | 1554-8929 |
| ISSN (Online): | 1554-8937 |
| Published Online: | 23 September 2020 |
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