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Cascade Biocatalysis Integrating Stereoselective and Environmentally Friendly Reactions

Sergio Riva (Editor), Wolf-Dieter Fessner (Editor)
ISBN: 978-3-527-33522-0
488 pages
September 2014
Cascade Biocatalysis Integrating Stereoselective and Environmentally Friendly Reactions (3527335226) cover image
This ready reference presents environmentally friendly and stereoselective methods of modern biocatalysis.
The experienced and renowned team of editor have gathered top international authors for this book. They cover such emerging topics as chemoenzymatic methods and multi-step enzymatic reactions, while showing how these novel methods and concepts can be used for practical applications. Multidisciplinary topics, including directed evolution, dynamic kinetic resolution, and continuous-flow methodology are also discussed.

From the contents:
- Directed evolution of ligninolytic oxidoreductases: from functional expression to stabilization
- New trends in the in situ enzymatic recycling of NAD(P)(H) cofactor
- Redox Cascade Biotransformations
- Chemistry and Biochemistry synergies for ß-amino acids production
- Dynamic kinetic resolution of amino acid thioesters
- Stereoselective hydrolase-catalyzed processes in continuous-flow mode
- Perspectives on multi-enzyme processes
- Nitrile converting enzymes involved in natural and synthetic cascade reactions
- Mining genomes for nitrilases
- Kinetic aspects of the in-situ NHase/AMase cascade system of M. imperiale resting cells for nitrile bioconversion
- Stereoselective hydrolysis of beta substituted nitriles
- New applications of Transketolase
- Enzymatic generation of sialoconjugate diversity
- Methyltransferases in biocatalysis
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List of Contributors XIII

Preface XXI

1 Directed Evolution of Ligninolytic Oxidoreductases: from Functional Expression to Stabilization and Beyond 1
Eva Garcia-Ruiz, Diana M. Mate, David Gonzalez-Perez, Patricia Molina-Espeja, Susana Camarero, Angel T. Martínez, Antonio O. Ballesteros, and Miguel Alcalde

1.1 Introduction 1

1.2 Directed Molecular Evolution 1

1.3 The Ligninolytic Enzymatic Consortium 3

1.4 Directed Evolution of Laccases 6

1.4.1 Directed Evolution of Low-Redox Potential Laccases 7

1.4.2 Directed Evolution of Medium-Redox Potential Laccases 7

1.4.3 Directed Evolution of Ligninolytic High-Redox Potential Laccases (HRPLs) 8

1.5 Directed Evolution of Peroxidases and Peroxygenases 11

1.6 Saccharomyces cerevisiae Biomolecular Tool Box 15

1.7 Conclusions and Outlook 16

Acknowledgments 17

Abbreviations 17

References 18

2 New Trends in the In Situ Enzymatic Recycling of NAD(P)(H) Cofactors 23
Erica Elisa Ferrandi, Daniela Monti, and Sergio Riva

2.1 Introduction 23

2.2 Recent Advancements in the Enzymatic Methods for the Recycling of NAD(P)(H) Coenzymes and Novel Regeneration Systems 24

2.2.1 In Situ Regeneration of Reduced NAD(P)H Cofactors 24

2.2.1.1 Formate Dehydrogenase and Glucose Dehydrogenase 24

2.2.1.2 Phosphite Dehydrogenase 26

2.2.1.3 Hydrogenase 27

2.2.1.4 Glucose 6-Phosphate Dehydrogenase 29

2.2.1.5 Alcohol Dehydrogenase 29

2.2.2 In Situ Regeneration of Oxidized NAD(P)+ Cofactors 31

2.2.2.1 Lactate Dehydrogenase 31

2.2.2.2 NAD(P)H Oxidase 32

2.2.2.3 Alcohol Dehydrogenase 34

2.2.2.4 Mediator-Coupled Enzyme Systems 35

2.3 Conclusions 37

Acknowledgments 38

References 38

3 Monooxygenase-Catalyzed Redox Cascade Biotransformations 43
Florian Rudroff and Marko D. Mihovilovic

3.1 Introduction 43

3.1.1 Scope of this Chapter 43

3.1.2 Enzymatic Oxygenation 43

3.1.3 Effective Cofactor Recycling 44

3.1.4 In Vitro Multistep Biocatalysis 46

3.1.5 Combined In Vitro and In Vivo Multistep Biocatalysis 48

3.1.6 In Vivo Multistep Biocatalysis 51

3.1.7 Chemo-Enzymatic Cascade Reactions 56

3.1.8 Conclusion and Outlook 60

References 61

4 Biocatalytic Redox Cascades Involving ��-Transaminases 65
Robert C. Simon, Nina Richter, and Wolfgang Kroutil

4.1 Introduction 65

4.2 General Features of ω-Transaminases 66

4.2.1 Cascades to Shift the Equilibrium for Amination 67

4.3 Linear Cascade Reactions Involving ω-Transaminases 69

4.3.1 Redox and Redox-Neutral Cascade Reactions 70

4.3.2 Carbonyl Amination Followed by Spontaneous Ring Closure 75

4.3.3 Deracemization of Racemic Amines Employing Two ω-Transaminases 78

4.3.4 Cascade Reactions of ω-TAs with Lyases and C–C Hydrolases/Lipases 80

4.4 Concluding Remarks 82

References 83

5 Multi-Enzyme Systems and Cascade Reactions Involving Cytochrome P450 Monooxygenases 87
Vlada B. Urlacher and Sebastian Schulz

5.1 Introduction 87

5.1.1 Multistep Cascade Reactions 87

5.1.2 Cytochrome P450 Monooxygenases 88

5.1.3 General Overview of presented cascade types 91

5.2 Physiological Cascade Reactions Involving P450s 92

5.2.1 Multistep Oxidations Catalyzed by a Single P450 92

5.2.2 Multistep Oxidations Catalyzed by Multiple P450s 102

5.3 Artificial Cascade Reactions Involving P450s 108

5.3.1 Cascade Reactions Involving P450s and Cofactor Regenerating Enzymes 108

5.3.1.1 Cofactor Regeneration in Cell-Free Systems (In Vitro) 108

5.3.2 Cofactor Regeneration in Whole-Cell Biocatalysts 114

5.3.3 Artificial Enzyme Cascades Involving P450s and Other Enzymes 115

5.3.3.1 Artificial Multi-Enzyme Cascades with Isolated Enzymes 116

5.3.3.2 Artificial Multi-Enzyme Cascades In Vivo 120

5.4 Conclusions and Outlook 124

References 125

6 Chemo-Enzymatic Cascade Reactions for the Synthesis of Glycoconjugates 133
Ruben R. Rosencrantz, Bastian Lange, and Lothar Elling

6.1 Introduction 133

6.1.1 Impact of Glycoconjugates and Their Synthesis 133

6.1.2 Biocatalysts for the Synthesis of Glycoconjugates 134

6.1.2.1 Glycosyltransferases 134

6.1.2.2 Glycosidases and Glycosynthases 136

6.1.3 Definition of Cascade Reactions 137

6.2 Sequential Syntheses 139

6.2.1 Nucleotide Sugars 139

6.2.2 Glycoconjugates 141

6.3 One-Pot Syntheses 146

6.3.1 Nucleotide Sugars 146

6.3.2 Glycan Structures 148

6.4 Convergent Syntheses 151

6.5 Conclusion 153

Acknowledgment 153

References 153

7 Synergies of Chemistry and Biochemistry for the Production of ��-Amino Acids 161
Josefa María Clemente-Jiménez, Sergio Martínez-Rodríguez, Felipe Rodríguez-Vico, and Francisco Javier Las Heras-Vázquez

7.1 Introduction 161

7.2 Dihydropyrimidinase 163

7.3 N-Carbamoyl-β-Alanine Amidohydrolase 166

7.4 Bienzymatic System for β-Amino Acid Production 173

7.5 Conclusions and Outlook 174

Acknowledgments 174

References 174

8 Racemizable Acyl Donors for Enzymatic Dynamic Kinetic Resolution 179
Davide Tessaro

8.1 Introduction 179

8.2 The Tools 180

8.2.1 The Enzymes 180

8.2.2 The Racemization of Acyl Compounds 182

8.3 Applications of DKR to Acyl Compounds 183

8.3.1 Base-Catalyzed Racemization 183

8.3.2 DKR of Oxoesters 185

8.3.3 DKR of Thioesters 188

8.4 Conclusions 193

Acknowledgments 194

References 194

9 Stereoselective Hydrolase-Catalyzed Processes in Continuous-Flow Mode 199
Zoltán Boros, Gábor Hornyánszky, József Nagy, and László Poppe

9.1 Introduction 199

9.1.1 General Remarks on Reactions in Continuous-Flow Systems 199

9.1.1.1 Stereoselective Reactions in Continuous Flow Systems 202

9.1.1.2 Analytical Applications 203

9.1.2 Nonstereoselective Enzymatic Processes 204

9.2 Enzyme-Catalyzed Stereoselective Reactions in Continuous-Flow Systems 204

9.2.1 Stereoselective Processes Catalyzed by Nonhydrolytic Enzymes 204

9.2.2 Stereoselective Processes Catalyzed by Hydrolases 207

9.2.2.1 Applicable Types of Selectivities 207

9.2.2.2 Stereoselective Hydrolytic Reactions 207

9.2.2.3 Stereoselective Acylations 211

9.2.2.4 Effects of the Operation Conditions and the Mode of Enzyme Immobilization 220

9.3 Outlook and Perspectives 222

References 222

10 Perspectives on Multienzyme Process Technology 231
Paloma A. Santacoloma and John M. Woodley

10.1 Introduction 231

10.2 Multienzyme System Classification 233

10.3 Biocatalyst Options 233

10.3.1 Transport Limitations 235

10.3.2 Compartmentalization 237

10.4 Reactor Options 237

10.5 Process Development 239

10.5.1 Recombinant DNA Technology 240

10.5.2 Process Engineering 241

10.6 Process Modeling 241

10.7 Future 244

10.8 Concluding Remarks 245

References 245

11 Nitrile Converting Enzymes Involved in Natural and Synthetic Cascade Reactions 249
Ludmila Martínková, Andreas Stolz, Fred van Rantwijk, Nicola D’Antona, Dean Brady, and Linda G. Otten

11.1 Introduction 249

11.2 Natural Cascades 250

11.2.1 Nitrile Hydratase – Amidase 250

11.2.2 Aldoxime Dehydratase–Nitrile Hydratase–Amidase 255

11.2.3 Other Natural Cascades 256

11.3 Artificial Cascades 257

11.3.1 Nitrile Hydratase–Amidase 257

11.3.2 Nitrilase–Amidase 258

11.3.3 Hydroxynitrile Lyase–Nitrilase 259

11.3.4 Hydroxynitrile Lyase–Nitrilase–Amidase 261

11.3.5 Hydroxynitrile Lyase–Nitrile Hydratase 261

11.3.6 Oxygenase–Nitrilase 262

11.3.7 Lipase–Nitrile Hydratase–Amidase 263

11.4 Conclusions and Future Use of These Enzymes 264

Acknowledgments 265

References 265

12 Mining Genomes for Nitrilases 271
Ludmila Martnková

12.1 Strategies in Nitrilase Search 271

12.2 Diversity of Nitrilase Sequences 272

12.2.1 Nitrilases in Bacteria 274

12.2.2 Nitrilases in Fungi 274

12.2.3 Nitrilases in Plants 275

12.3 Structure–Function Relationships 275

12.3.1 Sequence Clustering 275

12.3.2 Analysis of Specific Regions 276

12.3.3 Analysis of Enzyme Mutants 276

12.4 Enzyme Properties and Applications 277

12.4.1 Arylacetonitrilases 277

12.4.2 Aromatic Nitrilases 278

12.4.3 Aliphatic Nitrilases 278

12.4.4 Cyanide-Transforming Enzymes 279

12.5 Conclusions 279

Acknowledgment 279

References 280

13 Key-Study on the Kinetic Aspects of the In Situ NHase/AMase Cascade System of M. imperiale Resting Cells for Nitrile Bioconversion 283
Laura Cantarella, Fabrizia Pasquarelli, Agata Spera, Ludmila Martínková, and Maria Cantarella

13.1 Introduction 283

13.2 The Temperature Effect on the NHase–Amidase Bi-Enzymatic Cascade System 284

13.3 Effect of Nitrile Concentration on NHase Activity and Stability 287

13.4 Effect of Nitrile on the AMase Activity and Stability 289

13.5 Concluding Remarks 293

Acknowledgments 293

References 293

14 Enzymatic Stereoselective Synthesis of ��-Amino Acids 297
Varsha Chhiba, Moira Bode, Kgama Mathiba, and Dean Brady

14.1 Introduction 297

14.2 Preparation of β-Amino Acids 298

14.2.1 Chemical Methods for Generating β-Amino Acids 298

14.2.2 Biocatalytic Preparation of Enantiopure β-Amino Acids 299

14.2.2.1 Lipases and Aminoacylases 299

14.2.2.2 Transaminases 300

14.2.2.3 Nitrile Converting Biocatalysts 300

14.3 Nitrile Hydrolysis Enzymes 301

14.3.1 Nitrilase 301

14.3.1.1 Nitrilase Structure and Mechanism 301

14.3.1.2 Nitrilase Substrate Selectivity 302

14.3.2 Nitrile Hydratase 302

14.3.2.1 Nitrile Hydratase Structure and Mechanism 303

14.3.3 Amidases 304

14.3.3.1 Amidase Structure and Mechanism 304

14.3.4 Nitrile Hydratase and Amidase Cascade Substrate Selectivity 304

14.4 Conclusion 308

Acknowledgments 309

References 309

15 New Applications of Transketolase: Cascade Reactions for Assay Development 315
Laurence Hecquet, Wolf-Dieter Fessner, Virgil Hélaine, and Franck Charmantray

15.1 Introduction 315

15.2 Cascade Reactions for Assaying Transketolase Activity In Vitro 317

15.2.1 Coupling with Other Enzymes as Auxiliary Agents 317

15.2.1.1 Coupling with NAD(H)-Dependent Dehydrogenases 317

15.2.1.2 Coupling with Bovine Serum Albumin 319

15.2.1.3 Coupling with BSA and Polyphenol Oxidase 321

15.2.2 Coupling with a Nonprotein Auxiliary Agent 325

15.2.2.1 Chemoenzymatic Cascade Reaction Based on Redox Chromophore 325

15.2.2.2 Phenol Red as pH Indicator 326

15.3 Cascade Reactions for Assaying Transketolase Activity by In Vivo Selection 329

15.3.1 Biocatalyzed Synthesis of Probes 16a,b 330

15.3.2 In Vitro Studies with Wild-Type TK and Probes 16a,b by LC/MS 330

15.3.3 Detection of TK Activity in E. coli Auxotrophs from Amino Acid Precursors 331

15.4 Conclusion 334

References 335

16 Aldolases as Catalyst for the Synthesis of Carbohydrates and Analogs 339
Pere Clapés, Jesús Joglar, and Jordi Bujons

16.1 Introduction 339

16.2 Iminocyclitol and Aminocyclitol Synthesis 340

16.3 Carbohydrates and Other Polyhydroxylated Compounds 351

16.4 Conclusions 355

Acknowledgments 356

References 356

17 Enzymatic Generation of Sialoconjugate Diversity 361
Wolf-Dieter Fessner, Ning He, Dong Yi, Peter Unruh, and Marion Knorst

17.1 Introduction 361

17.2 A Generic Strategy for the Synthesis of Sialoconjugate Libraries 363

17.2.1 Synthesis of Sialic Acid Diversity 368

17.2.1.1 Neuraminic Acid Aldolase 368

17.2.1.2 Neuraminic Acid Synthase 371

17.2.2 Nucleotide Activation of Sialic Acids 372

17.2.2.1 Kinetics of Sialic Acid Activation 373

17.2.2.2 Substrate Binding Model 373

17.2.2.3 Engineering of Promiscuous CSS Variants 376

17.2.3 Sialic Acid Transfer 377

17.3 Cascade Synthesis of neo-Sialoconjugates 378

17.3.1 Choice of Sialyl Acceptor 378

17.3.2 One-Pot Two-Step Cascade Reactions 379

17.3.3 One-Pot Three-Step Cascade Reactions 383

17.3.4 Metabolic Diversification 385

17.3.5 Post-Synthetic Diversification 386

17.3.6 Biomedical Applications of Sialoconjugate Arrays 388

17.4 Conclusions 388

Acknowledgments 389

References 389

18 Methyltransferases in Biocatalysis 393
Ludger Wessjohann, Martin Dippe, Martin Tengg, and Mandana Gruber-Khadjawi

18.1 Introduction 393

18.2 SAM-Dependent Methyltransferases 395

18.2.1 Substrates 396

18.2.2 Cofactors 400

18.2.3 Higher Homologs and Derivatives of SAM 403

18.2.4 Cofactor (Re)Generation 406

18.2.5 Cascade Applications 410

18.3 Conclusion and Outlook 415

Abbreviations 417

Acknowledgement 417

References 418

19 Chemoenzymatic Multistep One-Pot Processes 427
Harald Gröger and Werner Hummel

19.1 Introduction: Why Chemoenzymatic Cascades and Why One-Pot Processes? 427

19.2 Concepts of Chemoenzymatic Processes 427

19.3 Combination of Substrate Isomerization and their Derivatization with Chemo- and Biocatalysts Resulting in Dynamic Kinetic Resolutions and Related Processes 429

19.4 Combination of Substrate Synthesis (Without Isomerization) and Derivatization Step(s) 438

19.4.1 One-Pot Processes with an Initial Biocatalytic Step, Followed by Chemocatalysis or a Noncatalyzed Chemical Process 439

19.4.2 One-Pot Process with an Initial Chemo Process, Followed by Biocatalysis 443

19.4.2.1 Combination of Noncatalyzed Organic Reactions and Biocatalysis 443

19.4.2.2 Combination of Metal Catalysis and Biocatalysis 445

19.4.2.3 Combination of Organocatalysis and Biocatalysis 449

19.5 Conclusion and Outlook 453

References 453

Index 457

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Dr. Sergio Riva is the Director of the Institute of the Chemistry of Molecular Recognition (ICRM) of the Italian National Council of Research (C.N.R.), where he has been working since 1984, and "Professore a Contratto" at the University of Modena and Reggio Emilia since 2000.
He took his Laurea in Chemistry at Milano University in 1983 and his Diploma di Specialità in Organic Synthesis at Milano Politecnico in 1989.
He spent one year (1987) at M.I.T. (Cambridge, USA) working with Prof. A. Klibanov.
In 1993 he was awarded the Ciamician medal by the Organic Chemical Division of the Italian Chemical Society for his research activity in BIOCATALYSIS.
His research activity is documented by more than 150 publications reporting on the isolation and characterization of different groups of enzymes (hydrolases, dehydrogenases, oxynitrilases, aldolases, laccases, glycosyltransferases), and on the use of these biocatalysts for the selective modification of different natural compounds (steroids, alkaloids, terpenes, sugars and natural glycosides).

Wolf-Dieter Fessner obtained his PhD from the University of Freiburg, following which he carried out postdoctoral research at Harvard University with George Whitesides and at the University of Southern California with George Olah. Since 1998 he has been Full Professor of Organic Chemistry at the Technische Universität Darmstadt. His primary research interest is focused on the development of practical methods for enzymatic carbon-carbon bond formation and oligosaccharide synthesis, and on the interface between chemical and biological catalysis.
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