Technical Advances to Accelerate Modular Type I Polyketide Synthase Engineering towards a Retro-biosynthetic Platform

Pang, Bo; Valencia, Luis E.; Wang, Jessica; Wan, Yao; Lal, Ravi; Zargar, Amin; Keasling, Jay D.

doi:10.1007/s12257-019-0083-9

Cited by 18 publications

(9 citation statements)

References 97 publications

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“…[ 5 ] The scope of biopolymers is expanding as a result of recent advances in the development of microbial cell factories which can produce diverse bio‐based monomers, thus, most of the polymers can now be regarded as biopolymers. [ 6–12 ] Recently, with the suggestion of environmental life cycle assessments of biopolymer regarding our recent concerns on climate change and resource depletion, drop‐in replacement of monomers based on fossil fuels with biomass‐derived monomer has been exploited for the development of feasible alternatives to conventional synthetic plastics. For example, the Coca‐Cola Company has already been using 30% bio‐based poly(ethylene glycol terephthalate) (bio‐PET) and plans to develop 100% bio‐PET.…”

Section: Introductionmentioning

confidence: 99%

Recent Advances in Sustainable Plastic Upcycling and Biopolymers

Sohn

Kim

Baritugo

et al. 2020

Biotechnology Journal

111

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Advances in scientific technology in the early twentieth century have facilitated the development of synthetic plastics that are lightweight, rigid, and can be easily molded into a desirable shape without changing their material properties. Thus, plastics become ubiquitous and indispensable materials that are used in various manufacturing sectors, including clothing, automotive, medical, and electronic industries. However, strong physical durability and chemical stability of synthetic plastics, most of which are produced from fossil fuels, hinder their complete degradation when they are improperly discarded after use. In addition, accumulated plastic wastes without degradation have caused severe environmental problems, such as microplastics pollution and plastic islands. Thus, the usage and production of plastics is not free from environmental pollution or resource depletion. In order to lessen the impact of climate change and reduce plastic pollution, it is necessary to understand and address the current plastic life cycles. In this review, "sustainable biopolymers" are suggested as a promising solution to the current plastic crisis. The desired properties of sustainable biopolymers and bio-based and bio/chemical hybrid technologies for the development of sustainable biopolymers are mainly discussed.

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Section: Introductionmentioning

confidence: 99%

Recent Advances in Sustainable Plastic Upcycling and Biopolymers

Sohn

Kim

Baritugo

et al. 2020

Biotechnology Journal

111

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“…Hence, various bio-based production methods using renewable feedstocks have recently been developed [1,2]. To address the growing demand for the production of value-added products, such as platform chemicals and biopolymers from renewable resources, several engineered microorganisms have been developed [3][4][5][6][7][8][9].…”

Section: Introductionmentioning

confidence: 99%

Effect of DR1558, a Deinococcus radiodurans response regulator, on the production of GABA in the recombinant Escherichia coli under low pH conditions

et al. 2020

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Background: Gamma aminobutyric acid (GABA) is an important platform chemical, which has been used as a food additive and drug. Additionally, GABA is a precursor of 2-pyrrolidone, which is used in nylon synthesis. GABA is usually synthesized from glutamate in a reaction catalyzed by glutamate decarboxylase (GAD). Currently, there are several reports on GABA production from monosodium glutamate (MSG) or glucose using engineered microbes. However, the optimal pH for GAD activity is 4, which is the limiting factor for the efficient microbial fermentative production of GABA as fermentations are performed at pH 7. Recently, DR1558, a response regulator in the two-component signal transduction system was identified in Deinococcus radiodurans. DR1558 is reported to confer cellular robustness to cells by binding the promoter regions of genes via DNA-binding domains or by binding to the effector molecules, which enable the microorganisms to survive in various environmental stress conditions, such as oxidative stress, high osmotic shock, and low pH. Results: In this study, the effect of DR1558 in enhancing GABA production was examined using two different strategies: whole-cell bioconversion of GABA from MSG and direct fermentative production of GABA from glucose under acidic culture conditions. In the whole-cell bioconversion, GABA produced by E. coli expressing GadBC and DR1558 (6.52 g/L GABA from 13 g/L MSG•H 2 O) in shake flask culture at pH 4.5 was 2.2-fold higher than that by E. coli expressing only GadBC (2.97 g/L of GABA from 13 g/L MSG•H 2 O). In direct fermentative production of GABA from glucose, E. coli ∆gabT expressing isocitrate dehydrogenase (IcdA), glutamate dehydrogenase (GdhA), GadBC, and DR1558 produced 1.7-fold higher GABA (2.8 g/L of GABA from 30 g/L glucose) than E. coli ∆gabT expressing IcdA, GdhA, and GadBC (1.6 g/L of GABA from 30 g/L glucose) in shake flask culture at an initial pH 7.0. The transcriptional analysis of E. coli revealed that DR1558 conferred acid resistance to E. coli during GABA production. The fed-batch fermentation of E. coli expressing IcdA, GdhA, GadBC, and DR1558 performed at pH 5.0 resulted in the final GABA titer of 6.16 g/L by consuming 116.82 g/L of glucose in 38 h. Conclusion: This is the first report to demonstrate GABA production by acidic fermentation and to provide an engineering strategy for conferring acid resistance to the recombinant E. coli for GABA production.

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“…Due to the collinear and modular biosynthetic logic, the structural diversity of the products of modular PKS and NRPS could be largely attributed to a few variables (Kornfuehrer and Eustáquio, 2019). The modules of PKS and NRPS are suitable devices for retro-biosynthesis, which starts from the target product and proceeds backward to precursors by stepwise combination of the independent module reactions (Pang et al, 2019).…”

Section: Modular Pks and Nrps Architecture And Mechanismmentioning

confidence: 99%

“…Most recently, an in silico toolkit called ClusterCAD, a computational platform for designing novel multi-modular type I PKS, has been developed and applied to several PKS repurposing studies (Eng et al, 2018). However, previous studies indicated that constructing multimodular PKSs to produce novel chemical is still challenging (Weissman, 2016;Pang et al, 2019). The relationship between PKS module structure and acyl chain passage from one module to the next is not well understood thus, when testing the multimodular assembly line, the acyl chain extension was frequently stalled at the middle of the synthesis process.…”

Section: Redesigning Modular Pkss For Retro-biosynthesismentioning

confidence: 99%

“…As the organization and the order of these modules are co-linearly correlated with each unit of the final polyketide and polypeptide products, the target modules of rational engineering could be predicted for the production of novel derivatives having the modified unit at a specific position (Alanjary et al, 2019). Using this modular biosynthetic logic of type I modular PKS and NRPS, each reaction of a module was capable of being separated from the original assembly reactions and repurposed to construct de novo biosynthetic pathway for other chemicals (Pang et al, 2019). This approach is favorable in terms of (i) the potential diversity of available synthetic parts governing unique chemical reactions, (ii) enabling retro-biosynthesis by combinatorial assembly of domains and modules, and (iii) the relative ease of engineering, owing to avoidance of the structural perturbation compared to the engineering within the multi-enzyme complex.…”

Section: Introductionmentioning

confidence: 99%

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Repurposing Modular Polyketide Synthases and Non-ribosomal Peptide Synthetases for Novel Chemical Biosynthesis

Hwang

Lee

Cho

et al. 2020

Front. Mol. Biosci.

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In nature, various enzymes govern diverse biochemical reactions through their specific three-dimensional structures, which have been harnessed to produce many useful bioactive compounds including clinical agents and commodity chemicals. Polyketide synthases (PKSs) and non-ribosomal peptide synthetases (NRPSs) are particularly unique multifunctional enzymes that display modular organization. Individual modules incorporate their own specific substrates and collaborate to assemble complex polyketides or non-ribosomal polypeptides in a linear fashion. Due to the modular properties of PKSs and NRPSs, they have been attractive rational engineering targets for novel chemical production through the predictable modification of each moiety of the complex chemical through engineering of the cognate module. Thus, individual reactions of each module could be separated as a retro-biosynthetic biopart and repurposed to new biosynthetic pathways for the production of biofuels or commodity chemicals. Despite these potentials, repurposing attempts have often failed owing to impaired catalytic activity or the production of unintended products due to incompatible protein-protein interactions between the modules and structural perturbation of the enzyme. Recent advances in the structural, computational, and synthetic tools provide more opportunities for successful repurposing. In this review, we focused on the representative strategies and examples for the repurposing of modular PKSs and NRPSs, along with their advantages and current limitations. Thereafter, synthetic biology tools and perspectives were suggested for potential further advancement, including the rational and large-scale high-throughput approaches. Ultimately, the potential diverse reactions from modular PKSs and NRPSs would be leveraged to expand the reservoir of useful chemicals.

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Technical Advances to Accelerate Modular Type I Polyketide Synthase Engineering towards a Retro-biosynthetic Platform

Cited by 18 publications

References 97 publications

Recent Advances in Sustainable Plastic Upcycling and Biopolymers

Recent Advances in Sustainable Plastic Upcycling and Biopolymers

Effect of DR1558, a Deinococcus radiodurans response regulator, on the production of GABA in the recombinant Escherichia coli under low pH conditions

Repurposing Modular Polyketide Synthases and Non-ribosomal Peptide Synthetases for Novel Chemical Biosynthesis

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