Building Microbial Factories for the Production of Aromatic Amino Acid
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Chemical and Biological Engineering Publications Chemical and Biological Engineering 8-10-2019 Building microbial factories for the production of aromatic amino acid pathway derivatives: From commodity chemicals to plant-sourced natural products Mingfeng Cao Iowa State University Meirong Gao Iowa State University, [email protected] Miguel Suastegui Iowa State University See next page for additional authors Follow this and additional works at: https://lib.dr.iastate.edu/cbe_pubs Part of the Biochemical and Biomolecular Engineering Commons, and the Biology and Biomimetic Materials Commons The ompc lete bibliographic information for this item can be found at https://lib.dr.iastate.edu/ cbe_pubs/386. For information on how to cite this item, please visit http://lib.dr.iastate.edu/ howtocite.html. This Article is brought to you for free and open access by the Chemical and Biological Engineering at Iowa State University Digital Repository. It has been accepted for inclusion in Chemical and Biological Engineering Publications by an authorized administrator of Iowa State University Digital Repository. For more information, please contact [email protected]. Building microbial factories for the production of aromatic amino acid pathway derivatives: From commodity chemicals to plant-sourced natural products Abstract The ra omatic amino acid biosynthesis pathway, together with its downstream branches, represents one of the most commercially valuable biosynthetic pathways, producing a diverse range of complex molecules with many useful bioactive properties. Aromatic compounds are crucial components for major commercial segments, from polymers to foods, nutraceuticals, and pharmaceuticals, and the demand for such products has been projected to continue to increase at national and global levels. Compared to direct plant extraction and chemical synthesis, microbial production holds promise not only for much shorter cultivation periods and robustly higher yields, but also for enabling further derivatization to improve compound efficacy by tailoring new enzymatic steps. This review summarizes the biosynthetic pathways for a large repertoire of commercially valuable products that are derived from the aromatic amino acid biosynthesis pathway, and it highlights both generic strategies and specific os lutions to overcome certain unique problems to enhance the productivities of microbial hosts. Keywords Aromatic amino acid biosynthesis, Shikimate pathway, de novo biosynthesis, Microbial production, Flavonoids, Stilbenoids, Benzylisoquinoline alkaloids Disciplines Biochemical and Biomolecular Engineering | Biology and Biomimetic Materials Comments This is a manuscript of an article published as Cao, Mingfeng, Meirong Gao, Miguel Suastegui, Yanzhen Mei, and Zengyi Shao. "Building microbial factories for the production of aromatic amino acid pathway derivatives: From commodity chemicals to plant-sourced natural products." Metabolic Engineering (2019). DOI: 10.1016/ j.ymben.2019.08.008. Creative Commons License This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License. Authors Mingfeng Cao, Meirong Gao, Miguel Suastegui, Yanzhen Mei, and Zengyi Shao This article is available at Iowa State University Digital Repository: https://lib.dr.iastate.edu/cbe_pubs/386 Journal Pre-proof Building microbial factories for the production of aromatic amino acid pathway derivatives: From commodity chemicals to plant-sourced natural products Mingfeng Cao, Meirong Gao, Miguel Suastegui, Yanzhen Mei, Zengyi Shao PII: S1096-7176(19)30163-6 DOI: https://doi.org/10.1016/j.ymben.2019.08.008 Reference: YMBEN 1587 To appear in: Metabolic Engineering Received Date: 15 April 2019 Revised Date: 3 August 2019 Accepted Date: 7 August 2019 Please cite this article as: Cao, M., Gao, M., Suastegui, M., Mei, Y., Shao, Z., Building microbial factories for the production of aromatic amino acid pathway derivatives: From commodity chemicals to plant-sourced natural products, Metabolic Engineering (2019), doi: https://doi.org/10.1016/ j.ymben.2019.08.008. 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Submitted to Metabolic Engineering on August 2 nd , 2019 Building microbial factories for the production of aromatic amino acid pathway derivatives: from commodity chemicals to plant-sourced natural products Mingfeng Cao 1, 2, †, Meirong Gao 1, 2, †, Miguel Suastegui 1, 2 , Yanzhen Mei 5, and Zengyi Shao 1, 2, 3, 4, * 1 Department of Chemical and Biological Engineering 2 NSF Engineering Research Center for Biorenewable Chemicals (CBiRC) 3 Interdepartmental Microbiology Program 4 The Ames Laboratory 4140 Biorenewables Research Laboratory, Iowa State University, Ames, IA 50011, USA 5School of Life Sciences No.1 Wenyuan Road, Nanjing Normal University, Qixia District, Nanjing, China, 210023 †Contributed equally to this work *Correspondence to: Dr. Zengyi Shao, 4140 Biorenewables Research Laboratory, Iowa State University, Ames, IA 50011, USA Phone: 515-294-1132 Email: [email protected] 1 Abstract The aromatic amino acid biosynthesis pathway, together with its downstream branches, represents one of the most commercially valuable biosynthetic pathways, producing a diverse range of complex molecules with many useful bioactive properties. Aromatic compounds are crucial components for major commercial segments, from polymers to foods, nutraceuticals, and pharmaceuticals, and the demand for such products has been projected to continue to increase at national and global levels. Compared to direct plant extraction and chemical synthesis, microbial production holds promise not only for much shorter cultivation periods and robustly higher yields, but also for enabling further derivatization to improve compound efficacy by tailoring new enzymatic steps. This review summarizes the biosynthetic pathways for a large repertoire of commercially valuable products that are derived from the aromatic amino acid biosynthesis pathway, and it highlights both generic strategies and specific solutions to overcome certain unique problems to enhance the productivities of microbial hosts. Keywords: aromatic amino acid biosynthesis, shikimate pathway, de novo biosynthesis, microbial production, flavonoids, stilbenoids, benzylisoquinoline alkaloids 2 Highlights • The aromatic amino acid biosynthesis pathway yields commercially valuable products. • The broad scope of products from aromatic amino acid biosynthesis is described. • Biosynthetic pathways and interconnections among the sub-branches are presented. • High-level organization of enzymes of the upstream module is illustrated. • The exemplary sophisticated regulations in the upstream pathway at various levels are highlighted. 3 1. Introduction Over the past two decades, technologies arising from synthetic biology and systems biology have revolutionized metabolic engineering to establish bio-based production in engineered microorganisms. The aromatic amino acid biosynthesis pathway, together with its downstream branches, represents one of the most valuable biosynthetic pathways. The products derived from this pathway range widely, from various high-volume low-value commodity chemicals to the realm of specialty chemicals and complex natural products (Suastegui and Shao, 2016; Thompson et al., 2015; Zhang et al., 2018). The pathways leading up to the synthesis of L-tryptophan ( L-Trp), L-phenylalanine ( L-Phe), and L-tyrosine ( L-Tyr) nodes are ubiquitous in all microorganisms, constituting the backbone reactions for the synthesis of a diverse class of compounds. This portion of the pathway can be subdivided into the shikimate pathway, the L-Tyr branch, the L-Phe branch, and the L-Trp branch. The model hosts Escherichia coli and Saccharomyces cerevisiae have been manipulated to produce this group of compounds in most studies, but other species such as Scheffersomyces stipitis , Pseudomonas putida , and Corynebacterium glutamicum have also been engineered as production hosts, and in many cases, they outperform E. coli and S. cerevisiae thanks to their special biochemical and metabolic features. The downstream pathways beyond the biosynthesis of the three aromatic amino acids open a treasure trove of high-value molecules with extremely diverse structures, the majority of which are produced by plants. These natural products encompass a billion dollar market (Pandal, 2014; Rawat et al., 2013; Rinner and Hudlicky, 2012; Winter and Tang, 2012), but their extraction from plant tissues requires immense quantities of biomass and cumbersome separation processes. Open-field plant growth and the associated costs are also susceptible to environmental factors, 4 which are associated with variability in product yield and composition. In addition, the complex and delicate chemistry involved in forming these aromatics makes their de novo chemical synthesis very challenging and economically unviable at commercial scales. The implementation