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Mahadevan, Radhakrishnan,Burgard, Anthony P.,Famili, Iman,Dien, Steve Van,Schilling, Christophe H. The Korean Society for Biotechnology and Bioengine 2005 Biotechnology and Bioprocess Engineering Vol.10 No.5
Increasing numbers of value added chemicals are being produced using microbial fermentation strategies. Computational modeling and simulation of microbial metabolism is rapidly becoming an enabling technology that is driving a new paradigm to accelerate the bioprocess development cycle. In particular, constraint-based modeling and the development of genome-scale models of industrial microbes are finding increasing utility across many phases of the bioprocess development workflow. Herein, we review and discuss the requirements and trends in the industrial application of this technology as we build toward integrated computational/experimental platforms for bioprocess engineering. Specifically we cover the following topics: (1) genome-scale models as genetically and biochemically consistent representations of metabolic networks; (2) the ability of these models to predict, assess, and interpret metabolic physiology and flux states of metabolism; (3) the model-guided integrative analysis of high throughput 'omics' data; (4) the reconciliation and analysis of on- and off-line fermentation data as well as flux tracing data; (5) model-aided strain design strategies and the integration of calculated biotransformation routes; and (6) control and optimization of the fermentation processes. Collectively, constraint-based modeling strategies are impacting the iterative characterization of metabolic flux states throughout the bioprocess development cycle, while also driving metabolic engineering strategies and fermentation optimization.
Christophe H. Schilling,Radhakrishnan Mahadevan,Anthony P. Burgard,Iman Famili,Steve Van Dien 한국생물공학회 2005 Biotechnology and Bioprocess Engineering Vol.10 No.5
Increasing numbers of value added chemicals are being produced using microbial fermentation strategies. Computational modeling and simulation of microbial metabolism is rapidly becoming an enabling technology that is driving a new paradigm to accelerate the bioprocess development cycle. In particular, constraint-based modeling and the development of genome-scale models of industrial microbes are finding increasing utility across many phases of the bioprocess development workflow. Herein, we review and discuss the requirements and trends in the industrial application of this technology as we build toward integrated computational/experimental platforms for bioprocess engineering. Specifically we cover the following topics: (1) genome-scale models as genetically and biochemically consistent representations of metabolic networks; (2) the ability of these models to predict, assess, and interpret metabolic physiology and flux states of metabolism; (3) the model-guided integrative analysis of high throughput ‘omics’ data; (4) the reconciliation and analysis of on- and off-line fermentation data as well as flux tracing data; (5) model-aided strain design strategies and the integration of calculated biotransformation routes; and (6) control and optimization of the fermentation processes. Collectively, constraint-based modeling strategies are impacting the iterative characterization of metabolic flux states throughout the bioprocess development cycle, while also driving metabolic engineering strategies and fermentation optimization.
Exploring Bacterial Carboxylate Reductases for the Reduction of Bifunctional Carboxylic Acids
Khusnutdinova, Anna N.,Flick, Robert,Popovic, Ana,Brown, Greg,Tchigvintsev, Anatoli,Nocek, Boguslaw,Correia, Kevin,Joo, Jeong C.,Mahadevan, Radhakrishnan,Yakunin, Alexander F. Wiley Blackwell (John Wiley Sons) 2017 BIOTECHNOLOGY JOURNAL Vol.12 No.11
Nemr, Kayla,Mü,ller, Jonas E.N.,Joo, Jeong Chan,Gawand, Pratish,Choudhary, Ruhi,Mendonca, Burton,Lu, Shuyi,Yu, Xiuyan,Yakunin, Alexander F.,Mahadevan, Radhakrishnan Elsevier 2018 Metabolic engineering Vol.48 No.-
<P><B>Abstract</B></P> <P>Microbial processes can produce a wide range of compounds; however, producing complex and long chain hydrocarbons remains a challenge. Aldol condensation offers a direct route to synthesize these challenging chemistries and can be catalyzed by microbes using aldolases. Deoxyribose-5-phosphate aldolase (DERA) condenses aldehydes and/or ketones to β -hydroxyaldehydes, which can be further converted to value-added chemicals such as a precursor to cholesterol-lowering drugs. Here, we implement a short, aldolase-based pathway in <I>Escherichia coli</I> to produce (<I>R</I>)-1,3-BDO from glucose, an essential component of pharmaceutical products and cosmetics. First, we expressed a three step heterologous pathway from pyruvate to produce 0.3 g/L of (<I>R</I>)-1,3-BDO with a yield of 11.2 mg/g of glucose in wild-type <I>E. coli</I> K12 MG1655. We used a systems metabolic engineering approach to improve (<I>R</I>)-1,3-BDO titer and yield by: 1) identifying and reducing major by-products: ethanol, acetoin, and 2,3-butanediol; 2) increasing pathway flux through DERA to reduce accumulation of toxic acetaldehyde. We then implemented a two-stage fermentation process to improve (<I>R</I>)-1,3-BDO titer by 8-fold to 2.4 g/L and yield by 5-fold to 56 mg/g of glucose ( 11 % of maximum theoretical yield) in strain BD24, by controlling pH to 7 and higher dissolved oxygen level. Furthermore, this study highlights the potential of the aldolase chemistry to synthesize diverse products directly from renewable resources in microbes.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Platform for non-natural chemicals developed using aldol condensation. </LI> <LI> Modular pathway design demonstrated in E. coli for (R)-1,3-BDO production. </LI> <LI> Carbon flux optimized by blocking pyruvate and acetaldehyde-consuming pathways. </LI> <LI> Final (R)-1,3-BDO production: 2.4 g/L and 11% of maximum theoretical yield. </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>