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Discovery of the leinamycin family of natural products by mining actinobacterial genomes

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Abstract
Nature's ability to generate diverse natural products from simple building blocks has inspired combinatorial biosynthesis. The knowledge-based approach to combinatorial biosynthesis has allowed the production of designer analogs by rational metabolic pathway engineering. While successful, structural alterations are limited, with designer analogs often produced in compromised titers. The discovery-based approach to combinatorial biosynthesis complements the knowledge-based approach by exploring the vast combinatorial biosynthesis repertoire found in Nature. Here we showcase the discovery-based approach to combinatorial biosynthesis by targeting the domain of unknown function and cysteine lyase domain (DUF-SH) didomain, specific for sulfur incorporation from the leinamycin (LNM) biosynthetic machinery, to discover the LNM family of natural products. By mining bacterial genomes from public databases and the actinomycetes strain collection at The Scripps Research Institute, we discovered 49 potential producers that could be grouped into 18 distinct clades based on phylogenetic analysis of the DUF-SH didomains. Further analysis of the representative genomes from each of the clades identified 28 lnm-type gene clusters. Structural diversities encoded by the LNM-type biosynthetic machineries were predicted based on bioinformatics and confirmed by in vitro characterization of selected adenylation proteins and isolation and structural elucidation of the guangnanmycins and weishanmycins. These findings demonstrate the power of the discovery-based approach to combinatorial biosynthesis for natural product discovery and structural diversity and highlight Nature's rich biosynthetic repertoire. Comparative analysis of the LNM-type biosynthetic machineries provides outstanding opportunities to dissect Nature's biosynthetic strategies and apply these findings to combinatorial biosynthesis for natural product discovery and structural diversity.
Keywords
BIFUNCTIONAL ACYLTRANSFERASE/DECARBOXYLASE LNMK, NONRIBOSOMAL PEPTIDE, SYNTHETASE, POLYKETIDE SYNTHASE, ANTITUMOR-ACTIVITY, BIOSYNTHESIS, STREPTOMYCES, DERIVATIVES, INSIGHTS, DISCRETE, BIOLOGY, combinatorial biosynthesis, leinamycin, natural products discovery, structural diversity, genome mining

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Citation

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Chicago
Pan, Guohui, Zhengren Xu, Zhikai Guo, Hindra Hindra, Ming Ma, Dong Yang, Hao Zhou, et al. 2017. “Discovery of the Leinamycin Family of Natural Products by Mining Actinobacterial Genomes.” Proceedings of the National Academy of Sciences of the United States of America 114 (52): E11131–E11140.
APA
Pan, G., Xu, Z., Guo, Z., Hindra, H., Ma, M., Yang, D., Zhou, H., et al. (2017). Discovery of the leinamycin family of natural products by mining actinobacterial genomes. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 114(52), E11131–E11140.
Vancouver
1.
Pan G, Xu Z, Guo Z, Hindra H, Ma M, Yang D, et al. Discovery of the leinamycin family of natural products by mining actinobacterial genomes. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA. 2017;114(52):E11131–E11140.
MLA
Pan, Guohui, Zhengren Xu, Zhikai Guo, et al. “Discovery of the Leinamycin Family of Natural Products by Mining Actinobacterial Genomes.” PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 114.52 (2017): E11131–E11140. Print.
@article{8544211,
  abstract     = {Nature's ability to generate diverse natural products from simple building blocks has inspired combinatorial biosynthesis. The knowledge-based approach to combinatorial biosynthesis has allowed the production of designer analogs by rational metabolic pathway engineering. While successful, structural alterations are limited, with designer analogs often produced in compromised titers. The discovery-based approach to combinatorial biosynthesis complements the knowledge-based approach by exploring the vast combinatorial biosynthesis repertoire found in Nature. Here we showcase the discovery-based approach to combinatorial biosynthesis by targeting the domain of unknown function and cysteine lyase domain (DUF-SH) didomain, specific for sulfur incorporation from the leinamycin (LNM) biosynthetic machinery, to discover the LNM family of natural products. By mining bacterial genomes from public databases and the actinomycetes strain collection at The Scripps Research Institute, we discovered 49 potential producers that could be grouped into 18 distinct clades based on phylogenetic analysis of the DUF-SH didomains. Further analysis of the representative genomes from each of the clades identified 28 lnm-type gene clusters. Structural diversities encoded by the LNM-type biosynthetic machineries were predicted based on bioinformatics and confirmed by in vitro characterization of selected adenylation proteins and isolation and structural elucidation of the guangnanmycins and weishanmycins. These findings demonstrate the power of the discovery-based approach to combinatorial biosynthesis for natural product discovery and structural diversity and highlight Nature's rich biosynthetic repertoire. Comparative analysis of the LNM-type biosynthetic machineries provides outstanding opportunities to dissect Nature's biosynthetic strategies and apply these findings to combinatorial biosynthesis for natural product discovery and structural diversity.},
  author       = {Pan, Guohui and Xu, Zhengren and Guo, Zhikai and Hindra, Hindra and Ma, Ming and Yang, Dong and Zhou, Hao and Gansemans, Yannick and Zhu, Xiangcheng and Huang, Yong and Zhao, Li-Xing and Jiang, Yi and Cheng, Jinhua and Van Nieuwerburgh, Filip and Suh, Joo-Won and Duan, Yanwen and Shen, Ben},
  issn         = {0027-8424},
  journal      = {PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA},
  keyword      = {BIFUNCTIONAL ACYLTRANSFERASE/DECARBOXYLASE LNMK,NONRIBOSOMAL PEPTIDE,SYNTHETASE,POLYKETIDE SYNTHASE,ANTITUMOR-ACTIVITY,BIOSYNTHESIS,STREPTOMYCES,DERIVATIVES,INSIGHTS,DISCRETE,BIOLOGY,combinatorial biosynthesis,leinamycin,natural products discovery,structural diversity,genome mining},
  language     = {eng},
  number       = {52},
  pages        = {E11131--E11140},
  title        = {Discovery of the leinamycin family of natural products by mining actinobacterial genomes},
  url          = {http://dx.doi.org/10.1073/pnas.1716245115},
  volume       = {114},
  year         = {2017},
}

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