Biotechnology and Bioprocess Engineering 2020; 25(6): 795-809  
Engineering Heterologous Hosts for the Enhanced Production of Non-ribosomal Peptides
Komal Sharma, Mohammad Rifqi Ghiffary, Hyun Uk Kim, and Sang Yup Lee
Komal Sharma, Mohammad Rifqi Ghiffary, Hyun Uk Kim*
Systems Biology and Medicine Laboratory, Department of Chemical and Biomolecular Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Korea
Tel: +82-42-350-8811
E-mail: ehukim@kaist.ac.kr
Komal Sharma, Mohammad Rifqi Ghiffary, Hyun Uk Kim, Sang Yup Lee*
Systems Metabolic Engineering and Systems Healthcare Cross-Generation Collaborative Laboratory, KAIST, Daejeon 34141, Korea
Tel: +82-42-350-3930
E-mail: leesy@kaist.ac.kr
Sang Yup Lee
Metabolic and Biomolecular Engineering National Research Laboratory, Department of Chemical and Biomolecular Engineering, KAIST Institute for BioCentury, KAIST, Daejeon 34141, Korea
Hyun Uk Kim, Sang Yup Lee
KAIST Institute for Artificial Intelligence, BioProcess Engineering Research Center and BioInformatics Research Center, KAIST, Daejeon 34141, Korea
Received: March 16, 2020; Revised: April 25, 2020; Accepted: April 29, 2020; Published online: December 31, 2020.
© The Korean Society for Biotechnology and Bioengineering. All rights reserved.

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
Non-ribosomal peptides (NRPs) are a family of secondary metabolites with the highest number among entire secondary metabolite types. They are biosynthesized by a multi-modular enzyme complex called non-ribosomal peptide synthetase (NRPS), which is encoded by a biosynthetic gene cluster (BGC) in plants and a special group of microorganisms. NRPs are structurally and functionally diverse with numerous industrial applications. However, native producers of these valuable NRPs have several biotechnological limitations for efficient production, including their slow growth, inefficient genetic manipulations, and silent BGCs. Heterologous expression of NRPS can address these challenges, especially using an array of model organisms with well-studied metabolic networks and readily available genetic engineering tools. Here, we review the applications of representative bacterial heterologous hosts, namely representative model Streptomyces species, Escherichia coli, Pseudomonas putida, and Bacillus subtilis, which have been engineered for the enhanced production of NRPs.
Keywords: biosynthetic gene cluster, heterologous expression, heterologous production host, metabolic engineering, nonribosomal peptide, secondary metabolite


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