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Open AccessArticle

Characterization of the Ohmyungsamycin Biosynthetic Pathway and Generation of Derivatives with Improved Antituberculosis Activity

1
Department of Chemistry and Nanoscience, Ewha Womans University, Seoul 03760, Korea
2
Natural Products Research Institute, College of Pharmacy, Seoul National University, Seoul 08826, Korea
3
Division of Applied Life Science (BK21plus Program), Gyeongsang National University, Jinju 52828, Korea
4
iNtRON Biotechnology, Inc., Seongnam-si, Gyeonggi-do 13202, Korea
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Biomolecules 2019, 9(11), 672; https://doi.org/10.3390/biom9110672
Received: 19 September 2019 / Revised: 26 October 2019 / Accepted: 28 October 2019 / Published: 30 October 2019
(This article belongs to the Special Issue Recent Advance of Actinomycetes)
The cyclic depsipeptides ohmyungsamycin (OMS) A (1) and B (2), isolated from the marine-derived Streptomyces sp. SNJ042, contain two non-proteinogenic amino acid residues, β-hydroxy-l-phenylalanine (β-hydroxy-l-Phe) and 4-methoxy-l-tryptophan (4-methoxy-l-Trp). Draft genome sequencing of Streptomyces sp. SNJ042 revealed the OMS biosynthetic gene cluster consisting of a nonribosomal peptide synthetase (NRPS) gene and three genes for amino acid modification. By gene inactivation and analysis of the accumulated products, we found that OhmL, encoding a P450 gene, is an l-Phe β-hydroxylase. Furthermore, OhmK, encoding a Trp 2,3-dioxygenase homolog, and OhmJ, encoding an O-methyltransferase, are suggested to be involved in hydroxylation and O-methylation reactions, respectively, in the biosynthesis of 4-methoxy-l-Trp. In addition, the antiproliferative and antituberculosis activities of the OMS derivatives dehydroxy-OMS A (4) and demethoxy-OMS A (6) obtained from the mutant strains were evaluated in vitro. Interestingly, dehydroxy-OMS A (4) displayed significantly improved antituberculosis activity and decreased cytotoxicity compared to wild-type OMS A. View Full-Text
Keywords: ohmyungsamycin; marine natural product; nonribosomal peptide synthetase; biosynthetic gene cluster; antituberculosis activity ohmyungsamycin; marine natural product; nonribosomal peptide synthetase; biosynthetic gene cluster; antituberculosis activity
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Kim, E.; Shin, Y.-H.; Kim, T.H.; Byun, W.S.; Cui, J.; Du, Y.E.; Lim, H.-J.; Song, M.C.; Kwon, A.S.; Kang, S.H.; Shin, J.; Lee, S.K.; Jang, J.; Oh, D.-C.; Yoon, Y.J. Characterization of the Ohmyungsamycin Biosynthetic Pathway and Generation of Derivatives with Improved Antituberculosis Activity. Biomolecules 2019, 9, 672.

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