Biocatalysis : an industrial perspectiveBiocatalysis AnIndustrialPerspective Editedby...
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Biocatalysis An Industrial Perspective Edited by Gonzalo de Gonzalo University ofSeville, Spain Email: gdegonzalo@us. es and Pablo Dommguez de Maria Sustainable Momentum, SL, Las Palmas de Gran Canaria, Spain Email: dominguez@sustainable-momentum. net ROYAL SOCIETY OF CHEMISTRY THE QUEEN'S AWARDS FOR ENTERPRISE: INTERNATIONAL TRADE 2013
Transcript of Biocatalysis : an industrial perspectiveBiocatalysis AnIndustrialPerspective Editedby...
BiocatalysisAn Industrial Perspective
Edited by
Gonzalo de Gonzalo
University ofSeville, SpainEmail: gdegonzalo@us. es
and
Pablo Dommguez de Maria
Sustainable Momentum, SL, Las Palmas de Gran Canaria, SpainEmail: dominguez@sustainable-momentum. net
ROYALSOCIETYOF CHEMISTRY
THE QUEEN'S AWARDS
FOR ENTERPRISE:
INTERNATIONAL TRADE
2013
Contents
Part I: Context and Challenges for Industrial Biocatalysis
Chapter 1 An Appreciation of Biocatalysis in the Swiss ManufacturingEnvironment 3
Rebecca Buller, Katrin Hecht, Marco Antonio Mirata and
Hans-PeterMeyer
1.1 Introduction 3
1.1.1 Biocatalysis in the Swiss ManufacturingEnvironment 7
1.1.2 Current Status 7
1.1.3 Patent Analysis 14
1.2 Selected Enzyme Classes Used in the Swiss
Manufacturing Environment 16
1.2.1 Oxidoreductases EC1 17
1.2.2 Transferases EC2 22
1.3 Challenges 25
1.3.1 Regulation 25
1.3.2 Development Time 30
1.3.3 Technological Lock-in 32
1.3.4 Public Perception 32
1.3.5 Education 33
1.4 Opportunities 35
1.4.1 Starting Materials 35
1.4.2 Sustainability and Greenness 36
1.4.3 Swiss Industrial Biocatalysis Consortium 36
1.4.4 New Business Ideas 37
Catalysis Series No. 29
Biocatalysis: An Industrial PerspectiveEdited by Gonzalo de Gonzalo and Pablo Dominguez de Maria
© The Royal Society of Chemistry 2018Published by the Royal Society of Chemistry, www.rsc.org
ix
X Contents
1.5 Future Directions 37
Acknowledgements 39
References 39
Chapter 2 Biocatalysis - A Greener Alternative in Synthetic Chemistry 44
Madhuresh Kumar Sethi, Purbita Chakrabortyand Rohit Shukla
2.1 Introduction 44
2.2 Motivation for Industry to Use/Research on
Biocatalysis 47
2.3 Challenges Faced by Biocatalysis in Industry 49
2.4 Prospects 52
2.5 Overview of Current Enzyme-based Processes
Implemented/In-progress at Industrial, Commercial
Scale 52
2.6 Our Experience in Some Chemoenzymatic Projects 56
2.6.1 Protease-mediated Synthesis of ValganciclovirIntermediate 58
2.6.2 Chemoenzymatic Synthesis ofOptically Pure
Rivastigmine Intermediate Using ADH from
Baker's Yeast and KRED 58
2.6.3 Preparation of Deoxynojirimycin, Key
Intermediate of an Anti-diabetic Drug 60
2.7 Potential Safety Aspects 66
2.8 Conclusions 67
Abbreviations 68
Glossary 68
References 70
Chapter 3 Biocatalytic Synthesis of Small Molecules - Past, Present
and Future 77
Roland Wohlgemuth
3.1 Introduction 77
3.2 Biocatalytic Conversions of Racemates 78
3.2.1 Biocatalytic Resolution of Racemates 79
3.2.2 Biocatalytic Deracemizations 79
3.3 Biocatalytic Desymmetrizations 80
3.4 Biocatalytic Asymmetric Oxidations and Reductions 81
3.4.1 Biocatalytic Asymmetric Oxidations 81
3.4.2 Biocatalytic Asymmetric Reductions 83
3.5 Biocatalytic Asymmetric Hydrolysis and AcylationReactions 84
3.5.1 Biocatalytic Asymmetric Hydrolysis Reactions 85
3.5.2 Biocatalytic Asymmetric Acylation Reactions 86
Contents xi
3.6 Biocatalytic Asymmetric Transfer Reactions 86
3.7 Biocatalytic Asymmetric Addition and Elimination
Reactions 88
3.8 Summary and Outlook 89
References 90
Chapter 4 EntreChem: Building a Sustainable Business Case
in Biotechnology: From Biocatalysis to SyntheticBiology 98
Javier Gonzalez Sabin and Francisco Moris
4.1 Introduction 98
4.2 Biocatalysis 99
4.2.1 Enantiopure Chiral Building Blocks 99
4.2.2 Cascade Processes Taking Advantage of
Biocatalysis 100
4.3 Drug Development 105
4.3.1 Natural Products in Drug Discovery 105
4.3.2 EntreChem's Approach to Natural Products
Drug Discovery 107
4.3.3 Aureolic Acids: The Quest for Clinically Viable
"Mithralogs" 109
4.3.4 Collismycin Analogs as Immunosuppressiveand Neuroprotective Drugs 112
4.3.5 Glycosylated Indolocarbazoles as Potent and
Selective Kinase Inhibitors 115
4.4 Business Models in Biocatalysis and Natural
Products Drug Discovery 117
References 121
Part II: Biocatalysis: from Pharmaceuticals to Bulk
Chemistry
Chapter 5 Bristol-Myers Squibb: Preparation of Chiral
Intermediates for the Development of Drugs and APIs 127
Ramesh N. Patel
5.1 Introduction 127
5.2 Anti-Alzheimer's Drug. Enzymatic Preparation of
(i?)-5,5,5-Trifluoronorvaline 128
5.3 Cholesterol Lowering Agents 130
5.3.1 Enantioselective Enzymatic Acylation of
Racemic Alcohol 130
5.3.2 Enzymatic Synthesis of (3S,5i?)-Dihydroxy-6-(benzyloxy)hexanoic Acid, Ethyl Ester 131
xii Contents
5.4 Calcitonin Gene-related Peptide Receptors
Antagonists (Migraine Treatment): EnzymaticPreparation of (#)-2-Amino-3-(7-methyl-l//-indazol-5-yl)propanoic Acid 132
5.5 Antidiabetic Drugs 134
5.5.1 Saxagliptin: Enzymatic Synthesis of (S)~N-Boc-3-hydroxyadamantylglycine 134
5.5.2 Saxagliptin: Enzymatic Synthesis oiN-Cbz-
4,5-dehydro-L-prolineamide and N-Boc-4,5-
dehydro-L-prolineamide 136
5.5.3 Saxagliptin: Enzymatic Ammonolysis of (5S)-4,5-Dihydro-lH-pyrrole-l ,5-dicarboxylic Acid,1-(l,l-Dimethylethyl)-5-ethyl Ester 137
5.5.4 GLP-1 Receptor Agonists: EnzymaticPreparation of (S)-Amino-3-[3-{6-(2-methylphenyl)}pyridyl]-propionic Acid 138
5.6 Antihypertensive Drugs 140
5.6.1 Enzymatic Synthesis of [S)-6-Hydroxynorleucine 140
5.6.2 Vanlev: Enzymatic Synthesis of AllysineEthylene Acetal 141
5.6.3 Vanlev: Enzymatic Synthesis ofThiazepine 142
5.6.4 Captopril: Enzymatic Preparation of (S)-3-Benzoylthio-2-methylpropanoic Acid 143
5.7 Antiviral Drugs. Case Study: Atazanavir 144
5.7.1 Atazanavir: Enzymatic Synthesis of
(S)-Tertiary-leucine 144
5.7.2 Atazanavir: Enzymatic Preparation of [1S,2R)-
[3-Chloro-2-hydroxy-l-(phenylmethyl)propyl]carbamic Acid, 1,1-Dimethyl-ethyl Ester 146
5.8 Antianxiety Drug. Buspirones: EnzymaticPreparation of 6-Hydroxybuspirone 147
5.9 Antiviral Drugs. Hepatitis B Viral (HBV) Inhibitor:
Enzymatic Asymmetric Hydrolysis and Acetylation 149
5.10 Chemokine Receptor Modulators: EnzymaticDesymmetrization of Dimethyl Ester 150
5.11 Anticancer Drugs 151
5.11.1 Paclitaxel Semisynthetic Process 151
5.11.2 Water-soluble Taxane Derivatives 154
5.11.3 Epothilones: Epothilone B and
Epothilone F 155
5.11.4 IGF-1 Receptor Inhibitor: EnzymaticPreparation of (5)-2-Chloro-l-(3-chlorophenyl)ethanol 157
5.11.5 Retinoic Acid Receptor Agonist:Enzymatic Preparation of 2-(i?)-Hydroxy-2-(l',2',3',4'-tetrahydro-l',l',4',4'-tetramethyl-6'-naphthalenyl)acetate 158
Contents xiii
5.12 Microbial Hydroxylation of Mutilin and
Pleuromutilin 158
5.13 Conclusions 160
Acknowledgements 161
References 161
Chapter 6 Johnson Matthey: A Technology Provider Perspective to
Biocatalysis in the Fine Chemicals Industry 168
Elina Siirola, AhirPushpanath, Desmond M. Schofieldand Paolo Braiuca
6.1 Introduction 168
6.2 Commercial Considerations 170
6.2.1 Technology Value 170
6.2.2 Manufacturing 172
6.2.3 Market Analysis 172
6.2.4 Catalyst Portfolio 173
6.3 Technical Considerations 174
6.3.1 Enzyme Recruitment 175
6.3.2 Enzyme Engineering 179
6.3.3 Process Improvement 182
6.4 Conclusions 186
Acknowledgements 188
References 188
Chapter 7 EnzymeWorks: Recent Advances in Enzyme
Engineering for Chemical Synthesis 190
KuiK. Chan, JuXin, Xiaoliang Liang, LizengPengBin Sun andJunhua Tao
7.1 Introduction to EnzymeWorks 190
7.1.1 Current Status of Biocatalyst Development 191
7.2 Biocatalysis in the Food and Beverage Industry 192
7.2.1 Introduction of Stevia Development 193
7.2.2 Plant Family 1 UDP-glycosyltransferaseApplications 194
7.2.3 Chemoenzymatic Synthesis of
Rebaudioside M 199
7.2.4 Enzyme Immobilization and Whole Cell
Biosynthesis Development 201
7.2.5 Future Perspectives on Biocatalysis in the
Food and Beverage Industry 202
7.3 Ketoreductase (KRED) Applications 202
7.3.1 Ibrutinib Development 205
7.3.2 Future Perspectives on Ketoreductase
(KRED) Biocatalysis 208
7.4 Biocatalysis in the Antibiotic Industry 208
7.4.1 Introduction to Cephalosporin C Acylase (CCA) 210
xiv Contents
7.4.2 Gene Expression, Structure and CatalyticMechanism of Acylases 212
7.4.3 Recent Advances in Cephalosporin C Acylase(CCA) Development 216
7.4.4 Future Perspectives on Acylase Biocatalysis 217
7.4.5 Introduction to Deacetoxycephalosporin C
Synthase 217
7.4.6 Deacetoxycephalosporin C SynthaseStructure and Mechanism 219
7.4.7 Recent Advances in DeacetoxycephalosporinC Synthase Development 220
7.4.8 Future Perspectives ofAntibiotic
Biocatalysis 222
7.5 Future Perspectives of Biocatalyst Development 222
References 223
Chapter 8 Almac: An Industrial Perspective of Ene Reductase
(ERED) Biocatalysis 229
Gareth Brown, Thomas S. Moody, Megan Smyth and
StephenJ. C. Taylor
8.1 Introduction 229
8.1.1 Almac Group 229
8.1.2 Biocatalysis at Almac 230
8.1.3 The Rise of Biocatalysis 230
8.2 Introduction to Alkene Reduction 231
8.3 An Introduction to Ene Reductases and How
They Work 232
8.4 Examples of Ene Reductase Reactions Reportedin the Literature 233
8.4.1 Ene Reductases as Part of a Reaction
Sequence 234
8.4.2 Ene Reductases and Solvents 239
8.4.3 Challenges of Co-factor Recycle 240
8.4.4 Avoiding the Use of Nicotinamide
Co-factors 241
8.4.5 Impact of Synthetic Biology 245
8.4.6 Ene Reductases in Reverse: Oxidation 247
8.4.7 Thermophilic Ene-reductases 248
8.4.8 Alternative Screening Methods 248
8.5 Example of Utilisation of an ERED at Industrial
Scale 249
8.6 Transition of Ene Reductases to Mainstream
Biocatalytic Use 251
8.7 Conclusions 252
Acknowledgements 253
References 253
Contents xv
Chapter 9 GSK: Biocatalyst Discovery and Optimisation 257
Marcelo Kern, Gheorghe-Doru Roiban, Andrew Fosberryand Radka Snajdrova
9.1 Introduction 257
9.2 Biocatalyst Discovery 260
9.2.1 Design of Enzyme Panels 260
9.2.2 Imine Reductase Panel - Importance and
Applicability 260
9.3 Biocatalyst Optimisation 268
9.3.1 Nelarabine Case Study 269
9.4 Conclusions 272
Acknowledgements 273
References 273
Chapter 10 PETROBRAS: Efforts on Biocatalysis for Fuels and
Chemicals Production 276
Aline Machado de Castro andJose Andre Cavalcanti
da Silva
10.1 PETROBRAS Overview 276
10.2 Hydrolysis of Lignocellulosic and StarchyBiomass 277
10.3 Synthesis of Solvents 280
10.3.1 Glycerol Carbonate 280
10.3.2 Butyl Acetate 281
10.4 Synthesis and Degradation of Polymers 282
10.4.1 Synthesis of Polyesters 282
10.4.2 Depolymerization of Poly(ethyleneterephthalate) 284
10.5 Synthesis of Biolubricants 285
10.6 Synthesis of Biodiesel 289
10.7 Concluding Remarks 292
References 292
Chapter 11 MetGen: Value from Wood - Enzymatic Solutions 298
Klara R. Birikh, Matti W. Heikkila, Alex Michine,
Antoine Mialon, Toni Gronroos, Petri Ihalainen, Antti
Varho, Veera Hamalainen, Anu Suonpaa and Sami-Pekka
Rantanen
11.1 Introduction 298
11.1.1 METGEN - Masters of Enzyme Technologyand Genetic Engineering 298
11.1.2 Biocatalysis of Wood - Motivation and
Challenges 300
11.2 Enzymes in Pulp and Paper 301
Contents
11.2.1 Enzymes in Pulp & Paper Industry Sector -
Business Aspect 301
11.2.2 Major Enzyme Components for Wood
Applications 302
11.2.3 Enzyme Development - from Laboratoryto Industry 304
11.2.4 MetZyme® LIGNO 305
11.2.5 MetZyme® BRILA 309
11.2.6 Concluding Remarks on Enzymes in Pulpand Paper 313
11.3 Biorefinery Enzymes 313
11.3.1 Renewable Chemical Industry Segment -
Business Aspect 313
11.3.2 Wood Biorefinery Concept 314
11.3.3 Biomass Hydrolysis - Chemicals and Enzymes 315
11.3.4 Biomass Is Not Oil; It Is More Like Soupof the Day 316
11.3.5 Beyond Sugars 317
11.3.6 Biorefinery Enzymes - Concluding Remarks 320
11.3.7 Wood in Pulp and Paper and Biorefinery -
Common Problems or Window for
Opportunity? 320
Abbreviations 320
References 320
Part III: Biocatalyst Optimization with Industrial
Perspectives
Chapter 12 LentiKafs: Industrial Biotechnology, Experiencesand Visions 325
Radek Stloukal, Jarmila Watzkovd and Kristyna Turkovd
12.1 Introduction 325
12.2 Lentikats Biotechnology 326
12.2.1 Potential of Lentikats Biotechnology 327
12.2.2 Properties of Lentikats Biotechnology 329
12.2.3 Production of Lentikats Biocatalyst 330
12.3 Experiences in Wastewater Treatment 331
12.3.1 Municipal Wastewater Treatment 331
12.3.2 Industrial Wastewater Treatment 332
12.3.3 Special Applications 332
12.3.4 Advantages of Lentikats Biotechnology in
Wastewater Treatment 332
Contents xvii
12.3.5 Product Lines 333
12.3.6 Wastewater Treatment Applications 334
12.4 Experiences in the Pharmaceutical & Food Industry 338
12.4.1 Food Technology Industry 338
12.4.2 Pharmaceutical Industry 338
12.4.3 Bio-based Chemicals Industry 339
12.4.4 Advantages of Lentikats Biotechnology in
the Pharmaceutical & Food Industry 339
12.4.5 Application Examples in the Pharmaceutical
& Food Industry 339
12.4.6 Pharmaceutical & Food Applications 342
12.5 Vision 343
References 344
Chapter 13 EziG: A Universal Platform for Enzyme Immobilisation 345
Karim Engelmark Cassimjee and Hans-Jurgen Federsel
13.1 Introduction 345
13.2 A General Methodology for Enzyme Reuse 348
13.2.1 The Potential of Biocatalysis by Far Exceeds
Its Current Exploitation 348
13.2.2 Unlocking the Potential of Enzymes 349
13.2.3 Immobilised Enzymes for the
Pharmaceutical Industry 350
13.2.4 The Reusable Enzyme Utopia - Enzymes
Anchored in Space 350
13.2.5 The EziG Technology 351
13.2.6 Standardised Procedure for Immobilisation 354
13.2.7 Lower Cost Materials versus HighPerformance 354
13.3 Case Studies 355
13.3.1 In-reactor Enzyme Immobilisation 355
13.3.2 Two-phase System in Flow for in situ
Product Removal 356
13.3.3 Candida antarctica Lipase B (CalB) 357
13.3.4 Co-immobilisation for Cascade Reactions 358
13.4 Prospects 359
13.4.1 Stability versus Activity - Replacing LowCost Catalysts 359
13.4.2 Biocatalysis in Flow - Towards ManufacturingProcesses in Continuous Mode 360
13.5 Conclusions 360
Acknowledgements 361
References 361
xviii Contents
Chapter 14 Cross-linked Enzyme Aggregates (CLEAs): FromConcept to Industrial Biocatalyst 363
RogerA. Sheldon
14.1 Introduction: Biocatalysis is Green and
Sustainable 363
14.2 Immobilisation of Enzymes 364
14.3 The CLEA Technology 365
14.3.1 The Concept 365
14.3.2 Preparation of CLEAs 366
14.3.3 Physical Properties of CLEAs 369
14.3.4 Advantages and Limitations of CLEAs 370
14.3.5 Reactor Design 371
14.4 Scope of the CLEA Technology 373
14.4.1 Hydrolase CLEAs 373
14.4.2 Oxidoreductase and Lyase CLEAs 376
14.5 Multi-and Combi-CLEAs 378
14.6 Magnetic CLEAs: The New Frontier 381
14.7 Applications of CLEAs, Combi-CLEAs and
mCLEAs 384
14.7.1 1G and 2G Biofuels Production 385
14.7.2 Food and Beverages Processing 387
14.7.3 Synthesis of Semi-synthetic Penicillin
and Cephalosporin Antibiotics 388
14.7.4 Removal of Dyes, Pharma Residues and
Endocrine Disruptors from Waste
Water 389
14.7.5 Other Potential Applications 389
14.8 Conclusions and Future Prospects 390
References 390
Chapter 15 SynBiocat: Protein Purification, Immobilization and
Continuous-flow Processes 397
Diana Weiser, Zoltdn Boros, JozsefNagy, Gdbor Hornydnszky,Evelin Bell, Peter Sdtorhelyi and Ldszld Poppe
15.1 Introduction 397
15.2 SynBiocat - From Protein Purification to
Continuous-flow Processes 398
15.2.1 Enzyme Production and
Purification 400
15.2.2 Enzyme Immobilization 405
15.2.3 Desktop Bioreactor Applications 418
15.3 Conclusion 423
List of Abbreviations 424
Acknowledgements 425
References 425
Contents xix
Part IV: Emerging Industrial Biocatalysis
Chapter 16 Microvi: MicroNiche Engineering for Biocatalysisin the Water and Chemical Industries 433
Ameen Razavi andFatemeh Shirazi
16.1 Introduction to Microvi 433
16.2 Microvi's MicroNiche Engineering Platform 436
16.3 Case Study: MicroNiche Biocatalysts for Water
Purification 443
16.4 Producing Case Study: MicroNiche Biocatalystsfor Biobased Chemicals 449
16.5 Conclusions 454
References 455
Chapter 17 Nofima: Peptide Recovery and Commercialization byEnzymatic Hydrolysis ofMarine Biomass 459
Birthe Vang, Themis Altintzoglou, Ingrid Mage, Sileshi G.
Wubshet, Nils K. Afseth and Ragnhild D. Whitaker
17.1 Nofima: The Company 459
17.2 Hydrolysis ofMarine Biomass 461
17.2.1 Chemical Hydrolysis of Marine Biomass 461
17.2.2 Enzymatic Hydrolysis of Marine Biomass 462
17.3 Enzymes Used for Bioconversion 464
17.4 Quality and Classification ofMarine Biomass 465
17.5 Functional Properties and Bioactivities of
Hydrolyzed Marine Biomass 466
17.6 Commercialization of Products from Marine
Biomass 471
17.7 Conclusions 472
17.8 Case Examples 472
17.8.1 Marealis - Producing a Nutraceutical from
Shrimp Peels 472
17.8.2 Polybait AS - Producing Fishing Bait
from Fisheries By-products 473
References 473
Chapter 18 COz Solutions: A Biomimetic Approach to Mitigate C02Emissions - The Use ofCarbonic Anhydrase in an
"Industrial Lung" 477
Eric Madore and Sylvie Fradette
18.1 Introduction 477
18.2 Conventional Post-combustion C02 Capture
Technologies 478
XX Contents
18.3 CSI'Technology: An Industrial Lung 481
18.4 Selection and Development of a Robust CA 484
18.4.1 Elevated Ionic Strength 485
18.4.2 HighpH 486
18.4.3 Temperatures Above 60 °C 486
18.4.4 Effect of High Surface Volume Ratio 486
18.4.5 Effect of High Shear Stress 487
18.4.6 Effect of Contaminants 487
18.4.7 Effect of Solid-Liquid Interface 488
18.4.8 Carbonic Anhydrase Development 488
18.5 Technology Validation/Demonstration at Pilot Scale 491
18.6 Conclusions 494
Acknowledgements 494
References 495
Subject Index 497
