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Open Thesispriti.Pdf The Pennsylvania State University The Graduate School Department of Chemical Engineering OPTIMIZATION BASED REDESIGN OF MICROBIAL PRODUCTION SYSTEMS A Thesis in Chemical Engineering by Priti Pharkya 2005 Priti Pharkya Submitted in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy December 2005 The thesis of Priti Pharkya was reviewed and approved* by the following: Costas D. Maranas Donald B. Broughton Professor of Chemical Engineering Thesis Advisor Chair of Committee Patrick C. Cirino Assistant Professor of Chemical Engineering John M. Regan Assistant Professor of Environmental Engineering Andrew L. Zydney Walter L. Robb Chair and Professor of Chemical Engineering Head of the Department of Chemical Engineering *Signatures are on file in the Graduate School iii ABSTRACT The primary objective of this research is to develop computational tools for guiding experimental strain engineering strategies. The key questions addressed in this work are (i) how can optimal gene deletions be selected so that biochemical production in a stoichiometric network is coupled to biomass formation?, (ii) alternatively, how can one select the recombination candidates from a database of biotransformations to confer the ability to produce a specific chemical from an optimal substrate in a host organism?, (iii) what are the best reaction candidates for modulation to enhance the yields of biochemicals in a microbial network, and (iv) finally, what are the smallest enzyme sets that can be modulated to achieve the maximum possible enhancement of a specific reaction flux if a detailed kinetic model is used to describe metabolism? This thesis begins with the description of a bilevel framework introduced to identify not only optimal reaction deletions but also the optimal transport rates of key metabolites so that complex compounds can be produced as an obligatory byproduct of growth. Case studies involve prediction of deletion strategies for different amino acids in Escherichia coli. Next, an integrated framework, OptStrain is presented to uncover and investigate different alternative pathways in conjunction with the examination of multiple organisms and substrates for selecting the best strategy for producing a target metabolite. These alternative pathways are identified from a database of reactions compiled from publicly available biopathway databases and stoichiometric models of metabolism. Results include manipulation strategies for overproducing hydrogen in networks of vastly different microbial organisms such as E. coli, Clostridium acetobutylicum and iv Methylobacterium extorquens, and for vanillin production in E. coli. The array of in silico genetic manipulations that can be predicted by using optimization frameworks is completed by the OptReg framework which can predict inhibition, up regulation and deletion of reactions for strain redesign. The applicability of this tool is demonstrated for ethanol overproduction in Escherichia coli. Finally, a kinetic model of the central metabolism of E. coli is examined for elucidating the enzyme sets that can favorably influence the flux towards serine synthesis and through the phosphotransferase uptake system in the network. The broad array of genetic manipulation strategies identifiable though the proposed frameworks highlights their utility as efficient strain design tools. v TABLE OF CONTENTS LIST OF FIGURES .....................................................................................................vii LIST OF TABLES.......................................................................................................x ACKNOWLEDGEMENTS.........................................................................................xi Chapter 1 Introduction ................................................................................................1 1.1 Motivation and objective ................................................................................1 1.2 Background.....................................................................................................2 1.2.1 Kinetic models of metabolism..............................................................2 1.2.2 Constraint-based modeling...................................................................4 1.2.2.1 Flux balance analysis .................................................................5 1.3 Thesis overview..............................................................................................7 Chapter 2 Reaction deletions for complex compound overproduction ......................11 2.1 Background.....................................................................................................11 2.2 Modifications to the OptKnock framework....................................................12 2.2.1 Modified OptKnock procedure.............................................................14 2.3 Computational protocol ..................................................................................14 2.4 Results.............................................................................................................18 2.4.1 Chorismate formation (Precursor to aromatic amino acids).................19 2.4.2 Alanine overproduction (Pyruvate family)...........................................22 2.4.3 Serine overproduction (3-phosphoglycerate family)............................24 2.4.4 Aspartate overproduction (Aspartate family).......................................25 2.4.5 Glutamate overproduction (α-ketoglutarate family).............................27 2.5 Conclusion ......................................................................................................29 Chapter 3 Redesigning strains by reaction additions and deletions............................47 3.1 Background.....................................................................................................47 3.2 The OptStrain Procedure ................................................................................50 3.2.1 Curation of the database .......................................................................52 3.2.2 Determination of the maximum yield...................................................52 3.2.3 Identification of the minimum number of non-native reactions...........53 3.2.4 Incorporating the non-native reactions into host organism’s stoichiometric model ..............................................................................54 3.3 Mathematical formulation ..............................................................................54 3.4 Results.............................................................................................................57 3.4.1 Hydrogen production case study ..........................................................58 3.4.1.1 Escherichia coli ..........................................................................59 vi 3.4.1.2 Clostridium acetobutylicum .......................................................61 3.4.1.3 Methylobacterium extorquens AM1 ..........................................62 3.4.2 Vanillin production case study .............................................................63 3.5 Conclusion ......................................................................................................67 Chapter 4 Identifying Reaction Activation/Inhibition Candidates for Overproduction in Microbial Systems..................................................................78 4.1 Background.....................................................................................................78 4.2 Modeling and computational protocol............................................................81 4.2.1 Steady-state flux determination............................................................81 4.2.2 Modeling of genetic manipulations......................................................83 4.2.3 OptReg framework ...............................................................................85 4.3 Strategies for overproducing ethanol..............................................................90 4.3.1 Two reaction modification strategies ...................................................90 4.3.2 Three reaction modification strategies .................................................94 4.3.3 Evaluating the mutant networks using an alternate objective: MOMA...................................................................................................96 4.3.4 Effect of the value of the regulation strength parameter, C..................97 4.4 Conclusion ......................................................................................................99 4.5 Appendix 4.1...................................................................................................101 4.6 Appendix 4.2...................................................................................................103 Stoichiometry of selected reactions...............................................................103 Chapter 5 Optimal enzyme selection using kinetic models........................................113 5.1 Introduction.....................................................................................................113 5.2 Modeling cellular kinetics and cellular machinery.........................................114 5.3 Solution Method .............................................................................................117 5.3.1 Mixed Integer Non-linear Programming Problem (MINLP) ...............117 5.3.2 Search for optimal enzyme sets and levels...........................................117
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