Pathway analysis and optimization in metabolic engineering /

Cover 1
Half-title 3
Title 5
Copyright 6
Dedication 7
Contents 9
Preface 11
CHAPTER ONE Target: A Useful Model 17
CRITERIA FOR MODEL SELECTION 17
MODELS OF BIOCHEMICAL PROCESSES 22
Thermodynamics 22
Kinetics 26
The Michaelis\u2013Menten Rate Law 29
Validity 31
Mathematical Convenience 33
Stoichiometric Systems 35
Simplified Representations 38
Bode Analysis 39
Power-Law Approximation 40
S-Systems 45
Generalized Mass Action (GMA) Systems 46
Metabolic Control Analysis (MCA) 47
Richness of Structure 50
SUMMARY 51
REFERENCES 52
CHAPTER TWO Methods of Biochemical Systems Theory 58
MODEL DESIGN 59
DESIGN OF EQUATIONS IN BST 62
PARAMETER ESTIMATION 64
Estimation Based on Fluxes 64
Estimation from Dynamical Data 69
DYNAMIC ANALYSIS 72
Alterations in System Characteristics 72
Monte-Carlo Simulation 74
STEADY-STATE ANALYSIS 76
STABILITY ANALYSIS 80
EVALUATION AND INTERPRETATION 83
REFERENCES 87
CHAPTER THREE A Model of Citric Acid Production in the Mold Aspergillus niger 91
INTRODUCTION 91
BASIC CHEMISTRY AND BIOCHEMISTRY OF CITRIC ACID 92
A FIRST MATHEMATICAL MODEL 95
Mass Balance and S-System Equations 95
Parameter Estimation and S-System Representation 99
Kinetic Orders and Rate Constants 99
Constraints 103
Steady State 107
Local Stability 107
Robustness 109
Sensitivities 109
Logarithmic Gains 113
Dynamic Behavior 117
Limitations and Shortcomings of the Original Model 117
REVISED MODEL 121
New Processes and Biochemical Data 121
Mass Balance and S-System Equations 123
Local Stability and Characterization of the Steady State 129
Robustness 129
Rate Constant Sensitivities 129
Kinetic Order Sensitivities 133
Logarithmic Gains 135
Dynamic Behavior 141
QUALITY ASSESSMENT OF THE REVISED MODEL 142
APPENDIX: MATHEMATICAL FORMULATION OF CONSTRAINTS IN THE REVISED MODEL 143
REFERENCES 145
CHAPTER FOUR Optimization Methods 150
ANALYTICAL METHODS 151
Extrema of Functions of One Variable 151
Analytical Computation of Extrema of Nonlinear Functions in One Variable 154
Analytical Computation of Extrema of Nonlinear Functions in Several Variables 157
Optimization of Nonlinear Functions with Constraints 167
SEARCH ALGORITHMS 173
Functions of One Variable 173
Searching Nonlinear Functions of Several Variables 176
Genetic Algorithms 179
REFERENCES 180
CHAPTER FIVE Optimization of Biochemical Systems 182
INTRODUCTION 182
ARE NONLINEARITIES REALLY NECESSARY? 186
SEARCHING FOR EXTREMA OF LINEAR FUNCTIONS WITH MANY VARIABLES 189
OPTIMIZATION OF STOICHIOMETRIC NETWORKS 195
OPTIMIZATION OF S-SYSTEMS 197
OPTIMIZATION OF GMA SYSTEMS 200
MULTIPLE CRITERIA OPTIMIZATION 202
Vector Optimization 207
Goal Programming 208
OPTIMIZATION OF STRUCTURE 209
REFERENCES 211
CHAPTER SIX Optimization of Citric Acid Production in Aspergillus niger 217
INTRODUCTION 217
A LINEAR PROGRAM FOR OPTIMIZED CITRIC ACID PRODUCTION IN ASPERGILLUS NIGER 219
Objective Function 221
Constraints 221
OPTIMAL SOLUTIONS 227
SYSTEMATIC SEARCH FOR THE BEST SEQUENCE OF STEPS TOWARD THE OPTIMAL SOLUTION 230
ANALYSIS OF THE EFFECTS OF IMPRECISION DURING IMPLEMENTATION 234
Shapes of Output Distributions 236
Citrate Production 236
Constraint Violations 238
CONCLUSIONS 242
REFERENCES 244
CHAPTER SEVEN Maximization of Ethanol Production in Saccharomyces cerevisiae 247
INTRODUCTION 247
BACKGROUND 249
GALAZZO AND BAILEY\u2019S MODEL 251
Mass Balance Equations 251
KINETIC MODEL 251
S-SYSTEM MODEL 254
QUALITY ASSESSMENT OF THE MODEL 255
Local Stability of the Steady State 256
Robustness of the Model 256
Dynamic Behavior 258
OPTIMIZATION: THE INDIRECT OPTIMIZATION METHOD (IOM) 258
Direct S-System Optimization 259
Objective Functions 260
Constraints 261
RESULTS 264
Maximization of Ethanol Production 264
Maximization of Glycerol and Carbohydrate Production 267
QUALITY ASSESSMENT OF THE INDIRECT OPTIMIZATION METHOD 272
Formulation of the Direct Optimization Approach (DOA) 273
Implementation of DOA for Ethanol Production 275
Optimal IOM and DOA Solutions for Ethanol Production 275
MULTI-OBJECTIVE OPTIMIZATION 278
The Indirect Multi-Objective Optimization Method (IMOOM) 280
Mono-Objective Optimization 281
Multi-Objective Optimization 283
Comparison with Observations on Simultaneous Overexpression of Glycolytic Enzymes 285
DISCUSSION 287
REFERENCES 289
CHAPTER EIGHT Conclusions 293
L-CARNITINE PRODUCTION IN HIGH-DENSITY CULTURES OF ESCHERICHIA COLI 294
TRYPTOPHAN BIOSYNTHESIS IN ESCHERICHIA COLI 297
TRENDS IN PATHWAY ANALYSIS AND THE ROLE OF GENE TECHNOLOGY AND GENOMICS 299
Metabolic Flux Analysis 301
Genome Information and Biochemical Systems Theory 302
THE FUTURE HAS BEGUN 306
REFERENCES 307
Author Index 311
Subject Index 319