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Industrial Biotechnology of Vitamins, Biopigments, and Antioxidants

Industrial Biotechnology of Vitamins, Biopigments, and Antioxidants

Erick J. Vandamme, José Luis Revuelta

ISBN: 978-3-527-68177-8

Jul 2016

578 pages

$196.99

Description

Vitamins are a group of physiologically very important, chemically quite complex organic compounds, that are essential for humans and animals. Some vitamins and other growth factors behave as antioxidants, while some can be considered as biopigments. As their chemical synthesis is laborious, their biotechnology-based synthesis and production via microbial fermentation has gained substantial interest within the last decades. Recent progress in microbial genetics and in metabolic engineering and implementation of innovative bioprocess technology has led to a biotechnology-based industrial production of many vitamins and related compounds. Divided into three sections, this volume covers:

1. water-soluble vitamins
2. fat-soluble vitamin compounds and
3. other growth factors, biopigments, and antioxidants.

They are all reviewed systematically: from natural occurrence and assays, via biosynthesis, strain development, to industrially-employed biotechnological syntheses and applications.

List of Contributors XIX

Preface XXVII

1 Vitamins, Biopigments, Antioxidants and Related Compounds: A Historical, Physiological and (Bio)technological Perspective 1
Erick J. Vandamme and José L. Revuelta

1.1 Historical Aspects of the Search for Vitamins 1

1.2 Vitamins: What’s in a Name 3

1.3 Physiological Functions of Vitamins and Related Compounds 6

1.4 Technical Functions of Vitamins and Related Compounds 8

1.5 Production and Application of Vitamins and Related Factors 8

1.6 Outlook 13

References 13

Part I Water-Soluble Vitamins 15

2 Industrial Production of Vitamin B2 by Microbial Fermentation 17
José L. Revuelta, Rodrigo Ledesma-Amaro, and Alberto Jiménez

2.1 Introduction and Historical Outline 17

2.2 Occurrence in Natural/Food Sources 17

2.3 Chemical and Physical Properties; Technical Functions 18

2.4 Assay Methods and Units 18

2.5 Biological Role of Flavins and Flavoproteins 19

2.6 Biotechnological Synthesis of Riboflavin 21

2.6.1 Riboflavin-Producing Microorganisms 21

2.6.2 Biosynthesis of Riboflavin 22

2.6.3 Regulation of the Biosynthesis of Riboflavin 25

2.7 Strain Development: Genetic Modifications, Molecular Genetics and Metabolic Engineering 26

2.8 Fermentation Process 31

2.9 Downstream Processing 32

2.10 Chemical Synthesis 33

2.11 Application and Economics 33

References 33

3 Vitamin B3, Niacin 41
Tek Chand Bhalla and Savitri

3.1 Introduction 41

3.2 History 42

3.3 Occurrence in Nature/Food Sources 43

3.4 Chemical and Physical Properties 44

3.4.1 Chemical Properties 44

3.4.2 Physical Properties 44

3.5 Vitamin B3 Deficiency Disease (Pellagra) 45

3.6 Methods Used for Determination of Vitamin B3 46

3.6.1 Microbiological Methods 46

3.6.2 Chemical Methods 46

3.7 Synthesis 47

3.7.1 Chemical Process Used for Nicotinic Acid Production 47

3.7.2 Biosynthesis 49

3.7.2.1 Biological Processes Used for Nicotinic Acid Production 49

3.8 Downstream Processing of Nicotinic Acid 52

3.9 Reactive Extraction 53

3.10 Physiological Role of Vitamin B3 (Niacin) 53

3.10.1 Coenzyme in Metabolic Reactions 53

3.10.2 Therapeutic Molecule 56

3.10.2.1 Treatment of Pellagra 56

3.10.2.2 Treatment of Cardiovascular Diseases 57

3.10.2.3 Antihyperlipidemic Effect 57

3.10.2.4 Treatment of Hypercholesterolemia 57

3.10.2.5 Diabetes 58

3.10.2.6 Fibrinolysis 58

3.10.2.7 Treatment of Neurodegenerative Disorders 58

3.11 Safety of Niacin 59

3.12 Toxicity of Niacin 59

3.12.1 Hepatotoxicity 59

3.12.2 Vasodilation/Niacin Flush 59

3.12.3 Glucose Intolerance 60

3.13 Derivatives of Niacin 60

3.14 Application in Cosmetics, Food and Feed 61

3.15 Future Prospects 61

References 61

4 Pantothenic Acid 67
Jesus Gonzalez-Lopez, Luis Aliaga, Alejandro Gonzalez-Martinez, and Maria V. Martinez-Toledo

4.1 Introduction and Historical Outline 67

4.2 Occurrence in Natural Food Sources and Requirements 71

4.3 Physiological Role as Vitamin or as Coenzyme 74

4.4 Chemical and Physical Properties 77

4.5 Assay Methods 79

4.6 Chemical and Biotechnological Synthesis 81

4.7 Application and Economics 92

References 98

5 Folate: Relevance of Chemical and Microbial Production 103
Maddalena Rossi, Stefano Raimondi, Luca Costantino, and Alberto Amaretti

5.1 Introduction 103

5.2 Folates: Chemical Properties and Occurrence in Food 103

5.3 Biosynthesis 105

5.4 Physiological Role 106

5.5 Bioavailability and Dietary Supplements 109

5.6 Chemical and Chemoenzymatic Synthesis of Folic Acid and Derivatives 110

5.7 Intestinal Microbiota, Probiotics and Vitamins 114

5.8 Folate Production by Lactic acid Bacteria 115

5.9 Folate Production by Bifidobacteria 117

5.10 Conclusions 120

References 124

6 Vitamin B12 – Physiology, Production and Application 129
Janice Marie Sych, Christophe Lacroix, and Marc J.A. Stevens

6.1 Introduction and Historical Outline 129

6.2 Occurrence in Food and Other Natural Sources 130

6.3 Physiological Role as a Vitamin or Coenzyme 131

6.3.1 Absorption and Transport 131

6.3.2 Metabolic Functions 132

6.3.3 Main Causes and Prevalence of Deficiencies 133

6.3.4 Diagnosis of Deficiencies 134

6.4 Chemical and Physical Properties 134

6.5 Assay Methods 137

6.6 Biotechnological Synthesis 140

6.6.1 Producing Microorganisms 140

6.6.1.1 Propionibacteria (PAB) 142

6.6.1.2 Pseudomonades 143

6.6.2 Biosynthesis and Metabolic Regulation 144

6.6.3 Engineering of B12 Production 145

6.6.3.1 Propionibacteria 145

6.6.3.2 Pseudomonades 146

6.6.4 Fermentation Process 146

6.6.4.1 Propionibacteria 146

6.6.4.2 Pseudomonades 148

6.7 Downstream Processing; Purification and Formulation 149

6.8 Application and Economics 150

6.9 Conclusions and Outlook 151

References 151

7 Industrial Fermentation of Vitamin C 161
Weichao Yang and Hui Xu

7.1 Introduction and Historical Outline 161

7.2 Occurrence in Natural/Food Sources 162

7.2.1 Occurrence of Asc in Foods 162

7.2.2 Biosynthesis of Asc in Plants and Mammals 164

7.3 Physiological Role of Asc 164

7.4 Chemical and Physical Properties 165

7.5 Assay Methods 165

7.6 Industrial Fermentation of Asc 166

7.6.1 The Reichstein Process:The Major Industrial Asc Process until the Late 1990s 167

7.6.1.1 The Establishment of the Reichstein Process 167

7.6.1.2 Bioconversion of D-Sorbitol to L-Sorbose by Gluconobacter 167

7.6.1.3 The Key Enzyme of Gluconobacter for L-Sorbose Production 168

7.6.1.4 Oxidation of L-Sorbose to 2-KLG and Rearrangement to Asc 168

7.6.2 The Two-Step Fermentation Process for Asc Production 168

7.6.2.1 The First Step of Fermentation: Conversion of D-Sorbitol to L-Sorbose 169

7.6.2.2 The Second Step of Fermentation: Conversion of L-Sorbose to 2-Keto-L-Gulonic acid 170

7.6.2.3 Strain Development: Genetic Modification, Molecular Genetics and Metabolic Engineering 175

7.6.2.4 Fermentation Process 177

7.6.2.5 Upstream and Downstream Processing 181

7.7 Application and Economics 182

7.8 Outlook 183

References 185

8 Direct Microbial Routes to Vitamin C Production 193
Günter Pappenberger and Hans-Peter Hohmann

8.1 Introduction and Scope 193

8.2 Principles of Direct L-Ascorbic Acid Formation:The Major Challenges 195

8.2.1 Stereochemistry of L-Ascorbic Acid 195

8.2.2 Enzymes Producing L-Ascorbic Acid and Their By-Product Spectrum 196

8.3 Direct L-Ascorbic Acid Formation via 1,4-Lactones 197

8.3.1 L-Ascorbic Acid Forming Enzymes: 1,4-Lactone Oxidoreductases 198

8.3.2 Direct L-Ascorbic Acid Formation in HeterotrophicMicroalgae 200

8.3.3 Direct L-Ascorbic Acid Formation in Recombinant Yeast 201

8.3.4 Direct L-Ascorbic Acid Formation from Orange Processing Waste in Recombinant Aspergillus niger 203

8.3.5 Overall Conclusion on 1,4-Lactone Routes 204

8.4 Direct L-Ascorbic Acid Formation via 2-Keto Aldoses 206

8.4.1 L-Ascorbic Acid Forming Enzymes: L-Sorbosone Dehydrogenases 208

8.4.1.1 Sndhak 208

8.4.1.2 Sndhai 211

8.4.1.3 Prevalence of L-Asc Forming Sorbosone Dehydrogenases in Nature 211

8.4.2 L-Asc or 2-KGA from L-Sorbosone: One Substrate, Several Isomers, Two Products 212

8.4.3 L-Sorbose Dehydrogenase, Accumulating L-Sorbosone 215

8.4.3.1 Ssdh from K. vulgare 215

8.4.3.2 Sorbose Dehydrogenase Sdh from G. oxydans 217

8.4.4 Gluconobacter as Host for Direct L-Ascorbic Acid Formation 217

8.5 Outlook 219

Acknowledgement 220

References 220

Part II Fat Soluble Vitamins 227

9 Synthesis of ��-Carotene and Other Important Carotenoids with Bacteria 229
Christoph Albermann and Holger Beuttler

9.1 Introduction 229

9.2 Carotenoids: Chemical Properties, Nomenclature and Analytics 230

9.2.1 Nomenclature 231

9.2.2 Analysis of Carotenoids 231

9.2.2.1 Handling Precautions 231

9.2.2.2 Extraction 232

9.2.2.3 Chromatography Methods for Analysis of Carotenoids 233

9.3 Natural Occurrence in Bacteria 234

9.4 Biosynthesis of Carotenoids in Bacteria 236

9.5 Biotechnological Synthesis of Carotenoids by Carotenogenic and Non-Carotenogenic Bacteria 239

9.5.1 Heterologous Expression of Carotenoid Biosynthesis Genes 240

9.5.2 Increased Isoprenoid Precursor Supply 243

9.5.3 Genome-Wide Modification of E. coli to Increase Carotenoid Formation 244

9.5.4 Balancing Recombinant Enzyme Activities for an Improved Synthesis of Carotenoids by E. coli 249

9.5.5 Production of Industrially Important Carotenoids by Other Recombinant Bacteria 252

9.5.6 Culture Conditions of Improved Formation of Carotenoids by Recombinant Bacteria 252

9.6 Conclusion 253

References 254

10 ��-Carotene and Other Carotenoids and Pigments from Microalgae 265
Borhane Samir Grama, Antoine Delhaye, Spiros N. Agathos, and Clayton Jeffryes

10.1 Introduction and Historical Outline 265

10.2 Occurrence in Nature and Food Sources 266

10.3 Physiological Role as a Vitamin or as a Coenzyme 267

10.4 Chemical and Physical Properties; Technical Functions 268

10.5 Assay Methods and Units 270

10.6 Biotechnological Synthesis 270

10.6.1 Producing Organisms 270

10.6.2 Biosynthesis and Metabolic Regulation 273

10.6.3 Strain Development: Genetic Modification, Molecular Genetics and Metabolic Engineering 276

10.6.4 Downstream Processing, Purification and Formulation 276

10.7 Chemical Synthesis or Extraction 279

10.8 Process Economics 279

References 280

11 Microbial Production of Vitamin F and Other Polyunsaturated Fatty Acids 287
Colin Ratledge

Lipid Nomenclature 287

11.1 Introduction: Essential Fatty Acids 288

11.2 General Principles for the Accumulation of Oils and Fats in Microorganisms 294

11.3 Production of Microbial Oils 297

11.3.1 Production of Gamma-Linolenic Acid (GLA; 18 : 3 n-6) 297

11.3.2 Productions of Docosahexaenoic Acid (DHA) and Arachidonic Acid (ARA) 300

11.3.3 Alternative Sources of DHA 302

11.3.4 Production of Eicosapentaenoic Acid (EPA n-3) 305

11.3.5 Prospects of Photosynthetic Microalgae for Production of PUFAs 307

11.4 Safety Issues 310

11.5 Future Prospects 312

Acknowledgements 315

References 316

12 Vitamin Q10: Property, Production and Application 321
Joong K. Kim, Eun J. Kim, and Hyun Y. Jung

12.1 Background of Vitamin Q10 321

12.1.1 Historical Aspects 321

12.1.2 Definition 321

12.1.3 Occurrence 322

12.1.3.1 In Nature 322

12.1.3.2 In Food Sources 322

12.1.3.3 In Microorganisms 326

12.1.4 Functions 326

12.2 Chemical and Physical Properties of CoQ10 326

12.2.1 Chemical Properties 326

12.2.2 Physical Properties 327

12.3 Biosynthesis and Metabolic Regulation of CoQ10 327

12.3.1 Biosynthesis of CoQ10 327

12.3.1.1 Microorganisms 327

12.3.1.2 Biosynthetic Pathways 329

12.3.2 Metabolic Regulation 334

12.3.3 Strain Development 335

12.3.3.1 Mutagenesis 335

12.3.3.2 Genetic Modification 335

12.3.3.3 Metabolic Engineering 337

12.3.4 Fermentation Process 339

12.3.5 Upstream and Downstream Processing 340

12.3.5.1 Upstream Processing 340

12.3.5.2 Downstream Processing 343

12.4 Chemical Synthesis and Separation of CoQ10 345

12.4.1 Chemical Synthesis 345

12.4.2 Solvent Extraction 346

12.4.3 Purification 350

12.5 Applications and Economics of CoQ10 351

12.5.1 Applications 351

12.5.1.1 In Diseases 351

12.5.1.2 In Cosmetics 352

12.5.1.3 In Foods and Others 353

12.5.2 Economics 354

References 355

13 Pyrroloquinoline Quinone (PQQ) 367
Hirohide Toyama

13.1 Introduction and Historical Outline 367

13.2 Occurrence in Natural/Food Sources 367

13.3 Physiological Role as Vitamin or as Bioactive Substance 368

13.4 Physiological Role as a Cofactor 373

13.5 Chemical and Physical Properties; Technical Functions 376

13.6 Assay Methods 377

13.7 Biotechnological Synthesis 377

13.7.1 Producing Microorganisms 377

13.7.2 Biosynthesis and Metabolic Regulation 378

13.8 Strain Development: Genetic Modification, Molecular Genetics and Metabolic Engineering 378

13.9 Up- and Down-stream Processing; Purification and Formulation 380

13.10 Chemical Synthesis or Extraction Technology 380

13.11 Application and Economics 380

References 381

Part III Other Growth Factors, Biopigments and Antioxidants 389

14 L-Carnitine, the Vitamin BT: Uses and Production by the Secondary Metabolism of Bacteria 391
Vicente Bernal, Paula Arense, and Manuel Cánovas

14.1 Introduction and Historical Outline 391

14.2 Occurrence in Natural/Food Sources 392

14.3 Physiological Role as Vitamin or as Coenzyme 393

14.3.1 Physiological Role of Carnitine in the Mitochondria 393

14.3.2 Physiological Role of Carnitine in the Peroxisomes 394

14.3.3 Other Functions of Carnitine 394

14.4 Chemical and Physical Properties 394

14.5 Assay Methods and Units 395

14.5.1 Chromatographic Methods 395

14.5.2 MS-Based Methods 395

14.5.3 Enzymatic Methods 398

14.5.4 Automated Methods 399

14.6 Biotechnological Synthesis of L-Carnitine Microbial Metabolism of L-Carnitine and Its Regulation 399

14.6.1 Biotechnological Methods for L-Carnitine Production 399

14.6.1.1 De novo Biosynthesis of L-Carnitine 399

14.6.1.2 Biological Resolution of Racemic Mixtures 399

14.6.1.3 Biotransformation from Non-Chiral Substrates 400

14.6.2 Roles of L-Carnitine in Microorganisms 401

14.6.2.1 Protectant Agent 401

14.6.2.2 Carbon and Nitrogen Source 401

14.6.2.3 Electron Acceptor: Carnitine Respiration 402

14.6.3 L-Carnitine Metabolism in Enterobacteria and Its Regulation 403

14.6.3.1 Metabolism of L-Carnitine in E. coli 403

14.6.3.2 Metabolism of L-Carnitine in Proteus sp. 405

14.6.4 Expression of Metabolising Activities: Effect of Inducers, Oxygen and Substrates 406

14.6.5 Biotransformation with D-Carnitine or Crotonobetaine as Substrates 406

14.6.6 Transport Phenomena for L-Carnitine Production 407

14.6.6.1 Membrane Permeabilisation 407

14.6.6.2 Osmotic Stress Induction of Transporters 408

14.6.6.3 Overexpression of the Transporter caiT 408

14.6.7 Metabolic Engineering for High-Yielding L-Carnitine Producing Strains 408

14.6.7.1 Link between Central and Secondary Metabolism during Biotransformation 408

14.6.7.2 Metabolic Engineering for Strain Engineering: Feedback between Modelling and Experimental Analysis of Cell Metabolism 409

14.7 Other Methods for L-Carnitine Production: Extraction from Natural Sources and Chemical Synthesis 411

14.7.1 Isolation of L-Carnitine from Natural Sources 411

14.7.2 Chemical Synthesis 411

Acknowledgement 412

References 412

15 Application of Carnosine and Its Functionalised Derivatives 421
Isabelle Chevalot, Elmira Arab-Tehrany, Eric Husson, and Christine Gerardin

15.1 Introduction and Historical Outline 421

15.2 Sources and Synthesis 422

15.2.1 Occurrence in Natural/Food Sources 422

15.2.2 Chemical Synthesis of Carnosine 422

15.2.3 Enzymatic Synthesis of Carnosine 423

15.3 Physico-Chemical and Biological Properties of Carnosine 425

15.3.1 Physico-Chemical Properties 425

15.3.2 Physiological Properties 426

15.4 Biotechnological Synthesis of Carnosine Derivatives: Modification, Vectorisation and Functionalisation 427

15.4.1 Chemical Functionalisation 427

15.4.2 Enzymatic Functionalisation: Enzymatic N-Acylation of Carnosine 430

15.4.2.1 Lipase-Catalysed N-Acylation of Carnosine in Non-Aqueous Medium 431

15.4.2.2 Acyltransferase-Catalysed N-Acylation of Carnosine in Aqueous Medium 432

15.4.2.3 Impact of Enzymatic Oleylation of Carnosine on Some Biological Properties 434

15.4.3 Vectorisation 434

15.5 Applications of Carnosine and Its Derivatives 435

15.5.1 Nutraceutics and Food Supplementation 435

15.5.2 Cosmetics 436

15.5.3 Pharmaceuticals 436

References 438

16 Metabolism and Biotechnological Production of Gamma-Aminobutyric Acid (GABA) 445
Feng Shi, Yalan Ni, and Nannan Wang

16.1 Introduction 445

16.2 Properties and Occurrence of GABA in Natural Sources 446

16.3 Metabolism of GABA 447

16.3.1 Biosynthesis and Export of GABA 450

16.3.1.1 Biosynthesis of GABA 450

16.3.1.2 Essential Enzyme for GABA Biosynthesis – GAD 451

16.3.1.3 Export of GABA 452

16.3.2 Uptake and Catabolism of GABA 454

16.3.2.1 The Uptake System of GABA 454

16.3.2.2 The Catabolism of GABA 455

16.4 Regulation of GABA Biosynthesis 456

16.5 Biotechnological Production of GABA 457

16.5.1 Fermentative Production of GABA by LAB 458

16.5.2 Production of GABA by Enzymatic Conversion 459

16.5.2.1 Production of GABA by Immobilised GAD 459

16.5.2.2 Improving GAD Activity by Rational and Irrational Designs 459

16.5.3 Fermentation of GABA by Recombinant C. glutamicum 460

16.6 Physiological Functions and Applications of GABA 461

16.6.1 Physiological Functions of GABA 461

16.6.2 Applications of GABA 462

16.7 Conclusion 462

Acknowledgement 462

References 463

17 Flavonoids: Functions,Metabolism and Biotechnology 469
Celestino Santos-Buelga and Ana M. González-Paramás

17.1 Introduction 469

17.2 Structure and Occurrence in Food 471

17.3 Activity and Metabolism 476

17.4 Biosynthesis of Flavonoids in Plants 481

17.5 Biotechnological Production 484

17.5.1 Reconstruction of Flavonoid Pathways in Plant Systems 485

17.5.2 Reconstruction of Flavonoid Pathways in Microbial Systems 487

17.5.2.1 E. coli Platform 487

17.5.2.2 Saccharomyces cerevisiae Platform 489

17.6 Concluding Remarks 489

References 490

18 Monascus Pigments 497
Yanli Feng, Yanchun Shao, Youxiang Zhou,Wanping Chen, and Fusheng Chen

18.1 Introduction and History of Monascus Pigments 497

18.2 Categories of MPs 497

18.3 Physiological Functions of MPs 498

18.3.1 Anti-Cancer Activities 498

18.3.2 Antimicrobial Activities 508

18.3.3 Anti-Obesity Activities 509

18.3.4 Anti-Inflammation Activities 510

18.3.5 Regulation of Cholesterol Levels 510

18.3.6 Anti-Diabetes Activities 511

18.4 Chemical and Physical Properties of MPs 511

18.4.1 Solubility 511

18.4.2 Stability 511

18.4.2.1 Effects of Temperature, pH and Solvent on Stability of MPs 511

18.4.2.2 Effect of Light on Stability of MPs 512

18.4.2.3 Effect of Metal Ion on Stability of MPs 513

18.4.3 Safety 513

18.5 Assay Methods and Units of MPs 513

18.5.1 Extraction and Detection of MPs 513

18.5.2 Isolation and Purification of MPs Components 514

18.5.2.1 CC and TLC 514

18.5.2.2 HPLC 515

18.5.2.3 CE and the Others 515

18.5.3 Identification of MPs Components 515

18.6 MPs Producer – Monascus spp. 520

18.6.1 Brief Introduction of Monascus Species and Their Applications 520

18.6.2 Producing Methods of MPs 520

18.6.3 Progress of Monascus spp. at the Genetic Level 521

18.6.3.1 DNA Transformation 521

18.6.3.2 Citrinin Synthesis and Its Regulations 521

18.6.3.3 MK Synthesis and Its Regulations 522

18.6.3.4 MPs Synthesis and Its Regulation 522

18.6.3.5 The Regulation of Secondary Metabolism in Monascus spp. 523

18.6.4 Monascus Genomics 524

18.7 Application and Economics of MPs 524

Acknowledgements 524

References 526

Index 537