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Publication Abstract from PubMed

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 beta-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 beta-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.

Non-Heme Monooxygenase ThoJ Catalyzes Thioholgamide beta-Hydroxylation.,Sikandar A, Lopatniuk M, Luzhetskyy A, Koehnke J ACS Chem Biol. 2020 Oct 1. doi: 10.1021/acschembio.0c00637. PMID:32965102^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.