Industrial biotechnology : products and processes / edited by Christoph Wittmann and James C. Liao.

Includes bibliographical references.

TABLE OF CONTENTS
List of Contributors XXI

About the Series Editors XXXI

Preface XXXIII

Part I Enabling and Improving Large-Scale Bio-production 1

1 Industrial-Scale Fermentation 3
Hans-Peter Meyer, Wolfgang Minas, and Diego Schmidhalter

1.1 Introduction 3

1.2 Industrial-Scale Fermentation Today 5

1.3 Engineering and Design Aspects 18

1.4 Industrial Design Examples 36

1.5 Cost Analysis for the Manufacture of Biotechnological Products 42

1.6 Influence of Process- and Facility-Related Aspects on Cost Structure 47

Acknowledgments 51

References 52

2 Scale-Down: Simulating Large-Scale Cultures in the Laboratory 55
Alvaro R. Lara, Laura A. Palomares, and Octavio T. Ramírez

2.1 Introduction 55

2.2 Heterogeneities at Large Scale and the Need for Scaling Down 56

2.3 Bioreactor Scale-Down 58

2.4 Tools to Study Cell Responses to Environmental Heterogeneities 62

2.5 Physiological Effects of Environmental Heterogeneities 68

2.6 Improvements Based on Scale-Down Studies: Bioreactor Design and Cell Engineering 72

2.7 Perspectives 73

Acknowledgment 74

References 74

3 Bioreactor Modeling 81
Rob Mudde, Henk Noorman, and Matthias Reuss

3.1 Large-Scale Industrial Fermentations: Challenges for Bioreactor Modeling 81

3.2 Bioreactors 83

3.3 Compartment and Hybrid Multizonal/Computational Fluid Dynamics Approaches for the Description of Large-Scale Bioreactor Phenomena 89

3.4 Computational Fluid Dynamics Modeling: Unstructured Continuum Approach (Euler–Euler) 92

3.5 Computational Fluid Dynamics Modeling: Structured Segregated Approach (Euler–Lagrange) 114

3.6 Conclusion 122

3.7 Outlook 122

References 124

4 Cell Culture Technology 129
Ralf Pörtner, Uwe Jandt, and An-Ping Zeng

4.1 Introduction 129

4.2 Overview of Applications for Cell Culture Products and Tissue Engineering 129

4.3 Fundamentals 131

4.4 Bioreactors for Cell Culture 140

4.5 Downstream 146

4.6 Regulatory and Safety Issues 150

4.7 Conclusions and Outlook 152

References 152

Part II Getting Out More: Strategies for Enhanced Bioprocessing 159

5 Production of Fuels and Chemicals from Biomass by Integrated Bioprocesses 161
Tomohisa Hasunuma and Akihiko Kondo

5.1 Introduction 161

5.2 Utilization of Starchy Biomass 163

5.3 Utilization of Lignocellulosic Biomass 166

5.4 Conclusions and Perspectives 177

Acknowledgment 177

References 178

6 Solid-State Fermentation 187
Reeta Rani Singhania, Anil Kumar Patel, Leya Thomas, and Ashok Pandey

6.1 Introduction 187

6.2 Fundamentals Aspects of SSF 188

6.3 Factors Affecting Solid-State Fermentation 193

6.4 Scale-Up 196

6.5 Product Recovery 198

6.6 Bioreactor Designing 198

6.7 Kinetics and Modeling 200

6.8 Applications 201

6.9 Challenges in SSF 202

6.10 Summary 203

References 203

7 Cell Immobilization: Fundamentals, Technologies, and Applications 205
Xumeng Ge, Liangcheng Yang, and Jianfeng Xu

7.1 Introduction 205

7.2 Fundamentals of Cell Immobilization 206

7.3 Immobilization with Support Materials 207

7.4 Self-Immobilization 212

7.5 Immobilized Cells and their Applications 218

7.6 Bioreactors for Cell Immobilization 225

7.7 Challenges and Recommendations for Future Research 229

7.8 Conclusions 230

References 231

Part III Molecules for Human Use: High-Value Drugs, Flavors, and Nutraceuticals 237

8 Anticancer Drugs 239
Le Zhao, Zengyi Shao, and Jacqueline V Shanks

8.1 Natural Products as Anticancer Drugs 239

8.2 Anticancer Drug Production 239

8.3 Important Anticancer Natural Products 243

8.4 Prospects 261

References 263

9 Biotechnological Production of Flavors 271
Maria Elisabetta Brenna and Fabio Parmeggiani

9.1 History 271

9.2 Survey on Today’s Industry 272

9.3 Regulations 273

9.4 Flavor Production 274

9.5 Biotechnological Production of Flavors 275

9.6 Vanillin 277

9.7 2-Phenylethanol 281

9.8 Benzaldehyde 283

9.9 Lactones 285

9.10 Raspberry Ketone 289

9.11 Green Notes 291

9.12 Nootkatone 293

9.13 Future Perspectives 296

References 297

10 Nutraceuticals (Vitamin C, Carotenoids, Resveratrol) 309
Sanjay Guleria, Jingwen Zhou, and Mattheos A.G. Koffas

10.1 Introduction 309

10.2 Vitamin C 310

10.3 Carotenoids 317

10.4 Resveratrol 323

10.5 Future Perspectives 329

References 330

Part IV Industrial Amino Acids 337

11 Glutamic Acid Fermentation: Discovery of Glutamic Acid-Producing Microorganisms, Analysis of the Production Mechanism, Metabolic Engineering, and Industrial Production Process 339
Takashi Hirasawa and Hiroshi Shimizu

11.1 Introduction 339

11.2 Discovery of the Glutamic Acid-Producing Bacterium C.glutamicum 340

11.3 Analysis of the Mechanism of Glutamic Acid Production by C. glutamicum 342

11.4 Metabolic Engineering of C. glutamicum for Glutamic Acid Production 350

11.5 Glutamic Acid Fermentation by Other Microorganisms 352

11.6 Industrial Process of Glutamic Acid Production 353

11.7 Future Perspectives 354

References 355

12 L-Lysine 361
Volker F.Wendisch

12.1 Uses of L-Lysine 361

12.2 Biosynthesis and Production of L-Lysine 363

12.3 The Chassis Concept: Biotin Prototrophy and Genome Reduction 374

12.4 L-Lysine Biosensors for Strain Selection and on-Demand Flux Control 377

12.5 Perspective 380

References 380

Part V Bio-Based Monomers and Polymers 391

13 Diamines for Bio-Based Materials 393
Judith Becker and Christoph Wittmann

13.1 Introduction 393

13.2 Diamine Metabolism in Bacteria 395

13.3 Putrescine – 1,4-Diaminobutane 395

13.4 Cadaverine – 1,5-Diaminopentane 399

13.5 Conclusions and Perspectives 403

References 404

14 Microbial Production of 3-Hydroxypropionic Acid 411
Yokimiko David, Young Hoon Oh, Mary Grace Baylon, Kei-Anne Baritugo, Jeong Chan Joo, Cheol Gi Chae, You Jin Kim, and Si Jae Park

14.1 Introduction 411

14.2 3-HP Obtained from Native Producers 413

14.3 Synthesis of 3-HP from Glucose 417

14.4 Synthesis of 3-HP from Glycerol 421

14.5 Bridging the Gap Between Glucose and Glycerol in 3-HP Production 437

14.6 Other Strains for 3-HP Production from Glycerol 438

14.7 Limitations of 3-HP Synthesis 440

14.8 Conclusions and Future Prospects 442

Acknowledgments 443

References 444

15 Itaconic Acid – An Emerging Building Block 453
Matthias G. Steiger, Nick Wierckx, Lars M. Blank, Diethard Mattanovich, and Michael Sauer

15.1 Background, History, and Economy 453

15.2 Biosynthesis of Itaconic Acid 455

15.3 Production Conditions for Itaconic Acid 459

15.4 Physiological Effects and Metabolism of Itaconic acid 461

15.5 Metabolic Engineering for Itaconic Acid Production 462

15.6 Outlook 467

Acknowledgments 468

References 469

Part VI Top-Value Platform Chemicals 473

16 Microbial Production of Isoprene: Opportunities and Challenges 475
Huibin Zou, Hui Liu, Elhussiny Aboulnaga, Huizhou Liu, Tao Cheng, and Mo Xian

16.1 Introduction 475

16.2 The Milestones of Isoprene Production 476

16.3 Microbial Production of Isoprene: Out of the Laboratory 477

16.4 Main Challenges for Bioisoprene Production 489

16.5 Future Prospects 491

Acknowledgments 498

References 498

17 Succinic Acid 505
Jung Ho Ahn, Yu-Sin Jang, and Sang Yup Lee

17.1 Introduction 505

17.2 Development of Succinic Acid Producers and Fermentation Strategies 506

17.3 Succinic Acid Recovery and Purification 533

17.4 Summary 536

Acknowledgments 537

References 537

Part VII Biorenewable Fuels 545

18 Ethanol: A Model Biorenewable Fuel 547
Tao Jin, Jieni Lian, and Laura R. Jarboe

18.1 Introduction 547

18.2 Metabolic Engineering: Design, Build, Test, Learn 549

18.3 Biomass Deconstruction 563

18.4 Closing Remarks 564

Acknowledgments 564

References 564

19 Microbial Production of Butanols 573
Sio Si Wong, Luo Mi, and James C. Liao

19.1 Introduction 573

19.2 A Historical Perspective of n-Butanol Production 574

19.3 ABE Fermentation 575

19.4 n-Butanol Production in Non-native Producers 580

19.5 Isobutanol Production 583

19.6 Summary and Outlook 589

Acknowledgments 589

References 589

Index 597

The latest volume in the Advanced Biotechnology series provides an overview of the main product classes and platform chemicals produced by biotechnological processes today, with applications in the food, healthcare and fine chemical industries. Alongside the production of drugs and flavors as well as amino acids, bio-based monomers and polymers and biofuels, basic insights are also given as to the biotechnological processes yielding such products and how large-scale production may be enabled and improved.
Of interest to biotechnologists, bio and chemical engineers, as well as those working in the biotechnological, chemical, and food industries.

ABOUT THE AUTHOR
Christoph Wittmann is Director of the Institute of Systems Biotechnology at Saarland University, Saarbrücken, Germany. Having obtained his academic degrees from Braunschweig Technical University, Germany, he was postdoc at Helsinki University, Finland, held chairs for Biotechnology at Münster University, Germany, and for Biochemical Engineering at Braunschweig Technical University and was invited guest professor at Université Rangueil de Toulouse, France, before taking up his present position. He has authored more than 150 scientific publications, more than 20 books and book chapters, holds more than 20 patents and has received several scientific awards, including the Young Scientist Award of the European Federation of Biotechnology, and is board member of various scientific journals.

James Liao is the Department Chair of Chemical and Biomolecular Engineering at University of California, in Los Angeles (UCLA), USA. Having obtained his PhD degree from University of Wisconsin, Madison, USA, he started his career at Eastman Kodak Company, before moving to Texas A&M, USA, and then UCLA for his academic career. Professor Liao has received numerous scientific awards, including the Presidential Green Chemistry Challenge Award and the ENI award in renewable energy. He is also a member of the US National Academy of Sciences, National Academy of Engineering, and Academia Sinica in Taiwan.

Sang Yup Lee is Distinguished Professor at the Department of Chemical and Biomolecular Engineering at the Korea Advanced Institute of Science and Technology (KAIST). He is currently the Director of the Center for Systems and Synthetic Biotechnology, Director of the BioProcess Engineering Research Center, and Director of the Bioinformatics Research Center. He has published more than 500 journal papers, 64 books and book chapters, and more than 580 patents (either registered or applied). He received numerous awards, including the National Order of Merit, the Merck Metabolic Engineering Award, the ACS Marvin Johnson Award, Charles Thom Award, Amgen Biochemical Engineering Award, Elmer Gaden Award, POSCO TJ Park Prize, and HoAm Prize. He currently is Fellow of American Association for the Advancement of Science, the American Academy of Microbiology, American Institute of Chemical Engineers, Society for Industrial Microbiology and Biotechnology, American Institute of Medical and Biological Engineering, the World Academy of Science, the Korean Academy of Science and Technology, and the National Academy of Engineering of Korea. He is also Foreign Member of National Academy of Engineering USA. He is currently honorary professor of the University of Queensland (Australia), honorary professor of the Chinese Academy of Sciences, honorary professor of Wuhan University (China), honorary professor of Hubei University of Technology (China), honorary professor of Beijing University of Chemical Technology (China), and advisory professor of the Shanghai Jiaotong University (China). Lee is the Editor-in-Chief of the Biotechnology Journal and Associate Editor and board member of numerous other journals. Lee is currently serving as a member of Presidential Advisory Committee on Science and Technology (Korea).

Jens Nielsen is Professor and Director to Chalmers University of Technology (Sweden) since 2008. He obtained an MSc degree in Chemical Engineering and a PhD degree (1989) in Biochemical Engineering from the Technical University of Denmark (DTU) and after that established his independent research group and was appointed full Professor there in 1998. He was Fulbright visiting professor at MIT in 1995-1996. At DTU, he founded and directed the Center for Microbial Biotechnology. Jens Nielsen has published more than 350 research papers, co-authored more than 40 books and he is inventor of more than 50 patents. He has founded several companies that have raised more than 20 million in venture capital. He has received numerous Danish and international awards and is member of the Academy of Technical Sciences (Denmark), the National Academy of Engineering (USA), the Royal Danish Academy of Science and Letters, the American Institute for Medical and Biological Engineering and the Royal Swedish Academy of Engineering Sciences.

Professor Gregory Stephanopoulos is the W. H. Dow Professor of Chemical Engineering at the Massachusetts Institute of Technology (MIT, USA) and Director of the MIT Metabolic Engineering Laboratory. He is also Instructor of Bioengineering at Harvard Medical School (since 1997). He received his BS degree from the National Technical University of Athens and his PhD from the University of Minnesota (USA). He has co-authored approximately 400 research papers and 50 patents, along with the first textbook on Metabolic Engineering. He has been recognized by numerous awards from the American Institute of Chemical Engineers (AIChE) (Wilhelm, Walker and Founders awards), American Chemical Society (ACS), Society of industrial Microbiology (SIM), BIO (Washington Carver Award), the John Fritz Medal of the American Association of Engineering Societies, and others. In 2003 he was elected member of the National Academy of Engineering (USA) and in 2014 President of AIChE.