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Non-Heme Monooxygenase ThoJ Catalyzes Thioholgamide β-Hydroxylation.
Sikandar, Asfandyar Lopatniuk, Maria Luzhetskyy, Andriy Koehnke, Jesko
Sikandar, Asfandyar
Lopatniuk, Maria
Luzhetskyy, Andriy
Koehnke, Jesko
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2020-10-01
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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.
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ACS Chem Biol. 2020 Oct 16;15(10):2815-2819. doi: 10.1021/acschembio.0c00637. Epub 2020 Oct 1.
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en
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1554-8937
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Attribution-NonCommercial-ShareAlike 4.0 International