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강학수 한국공업화학회 2016 한국공업화학회 연구논문 초록집 Vol.2016 No.1
Microbial natural products have long been one of the major sources of clinically important drugs. Culture-based extract screening in combination with bioactivity-guided isolation has been the major platform for the discovery of biologically active compounds from microbial sources for the past century. However, recent (meta)genome sequencings have revealed that most of biosynthetic gene clusters remain silent in standard culture conditions, and yet there are a significant number of uncultured bacteria present in nature. eDNA are therefore a large reservoir of previously uncharacterized biosynthetic gene clusters. Metagenomics provides a way to access this hidden biosynthetic diversity present in nature with the aid of next generation sequencing, bioinformatics and synthetic biology tools. In this seminar, I will present some examples of how new biologically active small molecules are discovered using metagenomics in combination with synthetic biology tools.
강학수 한국공업화학회 2016 한국공업화학회 연구논문 초록집 Vol.2016 No.1
DNA sequence is increasingly being used to guide the discovery of biosynthetic gene clusters capable of encoding for novel natural products. When studying cultured bacteria, it is possible to carry out detailed analyses of complete biosynthetic gene clusters. However, this is not possible when exploring complex metagenomes because of their immense sizes. To circumvent this limitation, we have used highly-conserved natural product biosynthetic genes as phylogenetic markers for guiding the discovery of functionally novel natural product biosynthetic gene clusters from metagenome. In this approach, biosynthetic genes are PCR-amplified, and the resulting amplicon sequences are aligned with sequences from functionally characterized gene clusters to identify sequences that encode for novel secondary metabolties. Here, I demonstrate the use of a single gene phylogeny-based mining approach to guide the discovery of new aromatic polyketides from achieved metagenomic libraries.
Promoter engineering of microbial secondary metabolite biosynthetic gene clusters
강학수 한국공업화학회 2019 한국공업화학회 연구논문 초록집 Vol.2019 No.0
Production of secondary metabolites requires the concerted expression of biosynthetic enzymes that are clustered together in microbial genomes and comprise several biosynthetic operons. As their biosynthesis is a highly energy-demanding process, the transcription of biosynthetic operons is tightly controlled by host transcriptional regulatory systems. Due to the complexity underlying the mechanism of transcriptional regulations, it is often challenging to achieve optimal culture conditions that maximize the production yield of target metabolites. Promoter engineering in combination with synthetic biology tools that enable multiplex engineering of biosynthetic gene clusters might provide a potential solution to this problem. Here, we present the development of a CRISPR/Cas9-based synthetic biology platform that allows the complete refactoring of native transcriptional regulatory systems with an aim to maximize the transcription of biosynthetic operons without affecting cell growth.