Artificial Metalloenzymes and MetalloDNAzymes in Catalysis From Design to Applications

An important reference for researchers in the field of metal-enzyme hybrid catalysis

Artificial Metalloenzymes and MetalloDNAzymes in Catalysis offers a comprehensive review of the most current strategies, developed over recent decades, for the design, synthesis, and optimization of these hybrid catalysts as well as material about their application. The contributors—noted experts in the field—present information on the preparation, characterization, and optimization of artificial metalloenzymes in a timely and authoritative manner.

The authors present a thorough examination of this interesting new platform for catalysis that combines the excellent selective recognition/binding properties of enzymes with transition metal catalysts. The text includes information on the various applications of metal-enzyme hybrid catalysts for novel reactions, offers insights into the latest advances in the field, and contains an informative perspective on the future: 

• Explores the development of artificial metalloenzymes, the modern and strongly evolving research field on the verge of industrial application
• Contains a comprehensive reference to the research area of metal-enzyme hybrid catalysis that has experienced tremendous growth in recent years
• Includes contributions from leading researchers in the field
• Shows how this new catalysis combines the selective recognition/binding properties of enzymes with transition metal catalysts

Written for catalytic chemists, bioinorganic chemists, biochemists, and organic chemists, Artificial Metalloenzymes and MetalloDNAzymes in Catalysis offers a unique reference to the fundamentals, concepts, applications, and the most recent developments for more efficient and sustainable synthesis.

Preface xiii

1 Preparation of Artificial Metalloenzymes 1
Jared C. Lewis and Ken Ellis-Guardiola

1.1 Introduction 1

1.2 ArM Formation via Metal Binding 2

1.2.1 Repurposing Natural Metalloenzymes 2

1.2.1.1 Carboxypeptidase A 3

1.2.1.2 Carbonic Anhydrase 3

1.2.1.3 Metallo-β-lactamase 4

1.2.1.4 Ferritin 5

1.2.2 Exploiting SerendipitousMetal Binding by Proteins 6

1.2.3 Designing Metal-Binding Sites in Scaffold Proteins 8

1.2.4 Introducing Metal-Binding Sites Using Unnatural Amino Acids 11

1.3 ArM Formation via Supramolecular Interactions 13

1.3.1 Cofactor Binding 14

1.3.1.1 Heme Proteins 14

1.3.1.2 Xylanases 16

1.3.1.3 Serum Albumins 17

1.3.1.4 Lactococcal Multidrug Resistance Regulator 18

1.3.1.5 NikA 18

1.3.1.6 Antibodies 19

1.3.2 Cofactor Anchoring 20

1.3.2.1 (Strept)avidin 20

1.3.2.2 Other Anchoring Scaffolds 22

1.3.2.3 Carboxyanhydrase 22

1.4 ArM Formation via Covalent Linkage 23

1.4.1 Activated Serine and Cysteine Residues 23

1.4.2 Lysine Residues 27

1.4.3 Cysteine Residues 27

1.4.4 Azido Phenylalanine 30

1.5 Conclusion 31

Acknowledgments 32

References 32

2 Preparation of MetalloDNAzymes 41
Claire E. McGhee, Ryan J. Lake, and Yi Lu

2.1 Introduction 41

2.2 In Vitro Selection of MetalloDNAzymes in the Presence of Metal Ions 44

2.2.1 Designing a DNAzyme Pool 45

2.2.1.1 Sequence Space 45

2.2.1.2 Choosing the Length of a Random Region 46

2.2.2 Performing In Vitro Selection 46

2.2.2.1 Isolation of Reactive DNA Sequences 47

2.2.2.2 Negative Selection 49

2.2.2.3 Pool Regeneration 49

2.2.2.4 Monitoring Selection Progress 51

2.2.2.5 Sequencing 51

2.2.2.6 Sequence Analysis 52

2.2.3 Optimization of DNAzymes via Truncation and Cis-to-Trans Transformation 52

2.2.4 Reselection of DNAzymes 53

2.3 From In Vitro Selection to Design of MetalloDNAzymes in the Presence of Metallocofactors 53

2.4 Design and Preparation of DNA-Based Hybrid Catalysts 54

2.4.1 Supramolecularly Anchored DNA-Based Hybrid Catalysts 54

2.4.2 Covalently Anchored DNA-Based Hybrid Catalysts 57

2.5 Summary and Future Directions 58

Acknowledgments 59

References 59

3 Experimental Characterization Techniques of Hybrid Catalysts 69
Juan Mangas-Sánchez and Eduardo Busto

3.1 Introduction 69

3.2 Characterization of Modified Naturally Occurring Metalloproteins 69

3.3 Characterization of New Metalloenzymes Created from Metal-Free Proteins 73

3.3.1 Characterization of Metalloenzymes Obtained through Direct Metal Salt Complexation 73

3.3.2 Characterization of Metalloenzymes Obtained via Covalent Anchorage 77

3.3.3 Characterization of ArtificialMetalloenzymes via Non-covalent Supramolecular Anchoring 84

3.3.4 Experimental Characterization of ArtificialMetalloenzymes with Dual Activities 87

3.4 Characterization of DNAzymes 88

3.5 Conclusions 92

Acknowledgments 92

References 92

Contents vii

4 Computational Studies of Artificial Metalloenzymes: From Methods and Models to Design and Optimization 99
Jaime Rodríguez-Guerra, Lur Alonso-Cotchico, Giuseppe Sciortino, Agustí Lledós, and Jean-Didier Maréchal

4.1 Introduction 99

4.2 From Computational Transition Metal Catalysis to Artificial Metalloenzymes Design 100

4.3 The Toolbox of the Artificial Enzyme Modeler 105

4.3.1 Few Generalities on Molecular Modeling 105

4.3.2 Accurate Physical Models 106

4.3.3 Simplified Physical Models 109

4.3.4 Advantages of MM-Like Methods 109

4.3.5 Hybrid and Multiscale Models 112

4.4 Application of ComputationalMethods to the Optimization and Design of ArtificialMetalloenzymes 113

4.4.1 Modifying Naturally Occurring Metalloenzymes 113

4.4.1.1 Optimizing Biomolecule–Cofactor and Biohybrid–Substrate Binding 113

4.4.1.2 Accounting for Changes in the First Coordination Sphere 115

4.4.1.3 Computational Redesign of Native Metalloenzyme Activity and Selectivity 116

4.4.1.4 Mechanistic Elucidation of Redesigned Metalloenzymes 117

4.4.2 Generation of ArtificialMetalloenzymes from Metal-Free Enzymes 119

4.4.2.1 De Novo ArtificialMetalloenzymes: A General Overview 119

4.4.2.2 The Particularities of De Novo Metalloenzymes 121

4.4.2.3 Protein Interactions with Artificial Cofactors 122

4.4.2.4 Substrate Binding and Complete Mechanism 125

4.5 Outlook 127

4.6 Conclusion 128

Acknowledgments 128

References 129

5 Directed Evolution of Artificial Metalloenzymes: Bridging Synthetic Chemistry and Biology 137
Ruijie K. Zhang, David K. Romney, S. B. Jennifer Kan, and Frances H. Arnold

5.1 Evolution Enables Chemical Innovation 137

5.1.1 Strategies for Directed Evolution 138

5.1.2 Directed Evolution as an UphillWalk in the Protein Fitness Landscape 139

5.2 Directed Evolution Applied to Natural Metalloenzymes 140

5.2.1 Enhancing the Stability of a Carbonic Anhydrase 140

5.2.2 Expanding the Scope of P450-Catalyzed Oxidation Reactions 142

5.3 Directed Evolution of Hemoproteins for Abiological Catalysis 144

5.3.1 Nonnatural Carbene Transfer Reactions with Engineered P450BM3 Variants 145

5.3.2 Nonnatural Nitrene Transfer Reactions with Engineered P450BM3 Variants 146

5.3.3 Engineering Cytochrome c for Nonnatural Catalysis 151

5.3.4 Engineering Myoglobin for Nonnatural Catalysis 151

5.3.5 Directed Evolution of Myoglobin-Derived Catalysts Created through Metal-Ion Replacement 154

5.4 Metalloenzymes with Artificial Cofactors or Metal-Binding Sites 155

5.4.1 Artificial Hydrolase with Biotic Metal Ions in De Novo Binding Sites 155

5.4.2 Artificial Hydrogenases Derived from Streptavidin 157

5.4.3 Cross-Coupling with a Pd–Streptavidin Conjugate 160

5.4.4 Alkene Metathesis Catalyzed by an Ru–Streptavidin Conjugate 160

5.4.5 Carbene Transfer with Conjugate of Rhodium and Proline Oligopeptidase 162

5.5 Conclusion 164

Acknowledgments 166

References 166

6 Artificial Metalloenzymes for Hydrogenation and Transfer Hydrogenation Reactions 171
Manuel Basauri-Molina and Robertus J. M. Klein Gebbink

6.1 Impact of Metallohydrogenases in the Field of Artificial Metalloenzymes 171

6.2 Biotinylated Metal Complexes in Avidin and Streptavidin 173

6.2.1 Hydrogenation of N-Protected Amino Acids 173

6.2.2 Transfer Hydrogenation of Ketones 178

6.2.3 Transfer Hydrogenation of Imines 180

6.2.4 ATHases in Cascade Reactions 182

6.3 Artificial Enzymes with Covalent Metalloprotein Constitution 184

6.3.1 Papain and Photoactive Yellow Protein 184

6.3.2 Serine Proteases 188

6.3.3 Human Carbonic Anhydrase 191

6.4 Chemocatalysts Embedded in Protein Motifs 191

6.5 Conclusions 193

References 194

7 Hybrid Catalysts for Oxidation Reactions 199
Christine Cavazza, CarolineMarchi-Delapierre, and StéphaneMénage

7.1 Metal Switch 201

7.2 Structural Modulation of Natural Enzymes 201

7.3 Cofactor Replacement: Reconstitution Strategy 206

7.4 Rational Design of Enzymes 209

7.5 De Novo Synthetic Active Site 211

7.6 De Novo Protein Scaffold 216

7.7 Concluding Remarks 219

References 220

8 Hybrid Catalysts as Lewis Acid 225
Gerard Roelfes, Ivana Drienovská, and Lara Villarino

8.1 Introduction 225

8.2 C–C Bond-Forming Reactions 225

8.2.1 Diels–Alder Reactions 225

8.2.1.1 DNA-Based Hybrid Catalysts 226

8.2.1.2 Metallopeptide-Based Hybrid Catalyst 231

8.2.1.3 Protein-Based Hybrid Catalysts 231

8.2.2 Conjugate Addition Reactions 236

8.2.2.1 Michael Addition 236

8.2.2.2 Friedel–Crafts Alkylation 238

8.3 C–X Bond-Forming Reactions 240

8.3.1 Oxa-Michael Additions 240

8.3.1.1 DNA-Based Hybrid Catalyst 242

8.3.1.2 Protein-Based Hybrid Catalysts 242

8.3.2 Fluorinations 243

8.4 Hydrolytic Reactions 244

8.4.1 DNA-Based Hybrid Catalyst 244

8.4.2 Protein-Based Hybrid Catalyst 244

8.5 Conclusions and Outlook 246

References 246

9 Hybrid Catalysts for C–H Activation and Other X–H Insertion Reactions 253
Thomas R.Ward andMichelaM. Pellizzoni

9.1 General Introduction 253

9.2 ArtificialMetalloenzymes for C–H Insertion 253

9.2.1 Introduction 253

9.2.2 ArtificialMetalloenzymes Based on the Biotin–Streptavidin Technology 254

9.2.3 ArtificialMetalloenzymes Based on the Myoglobin Scaffold 257

9.2.4 ArtificialMetalloenzymes Based on POP Scaffold 260

9.2.4.1 Si–H insertion 260

9.2.4.2 Cyclopropanation 261

9.3 Repurposing Hemoproteins for C–H Insertion Reactions 262

9.3.1 Introduction 262

9.3.2 Cyclopropanation 262

9.3.3 Aziridination 265

9.3.4 C–H Amination 266

9.3.5 N–H Insertion 269

9.3.6 S–H Insertion 271

9.3.7 Sulfimidation 274

9.3.8 Sigmatropic Rearrangement 275

9.3.9 Halogenation 276

9.4 Conclusion 279

References 279

10 Hybrid Catalysts for Other C–C and C–X Bond Formation Reactions 285
Peter J. Deuss,Megan V. Doble, Amanda G. Jarvis, and Paul C.J. Kamer

10.1 Introduction 285

10.2 Allylic Substitution 286

10.2.1 Chiral Phosphane Ligands Based on Chiral Building Blocks from Nature 286

10.2.2 Phosphane-Modified Synthetic Polypeptides 287

10.2.3 Phosphane-Modified Proteins 289

10.2.4 Oligonucleotides-Based Hybrid Catalysts 291

10.3 Palladium-Catalyzed Cross-Coupling Reactions 296

10.4 Hydroformylation 302

10.5 Phenylacetylene Polymerization 304

10.6 Olefin Metathesis 307

10.7 Summary and Future Trends 312

Acknowledgments 314

References 314

11 Metal–Enzyme Hybrid Catalysts in Cascade and Multicomponent Processes 321
Boi Hoa San, Jess Gusthart, Seung Seo Lee, and Kyeong Kyu Kim

11.1 Introduction 321

11.2 Metal-Based Catalyst Hybrids with Enzymes for Cascade and Multicomponent Processes 322

11.2.1 Gold Nanoparticle-Based Enzyme Hybrid 324

11.2.2 Palladium and Platinum Nanoparticle-Based Enzyme Hybrids 326

11.2.3 Other Metals Used for Metal–Enzyme Hybrid Catalysts 330

11.2.4 Organometallic Material Hybrid with Protein/Enzyme 333

11.3 Design Strategy for Metal–Enzyme Hybrid Catalysts in Multicomponent Cascade Reactions 334

11.3.1 Design Strategies for DevelopingMultistep Reactions in Metal–Enzyme Hybrid Catalysts 335

11.4 Reaction Mechanisms of Metal–Enzyme Hybrid Catalysts in Multicomponent Cascade Reactions 339

11.4.1 Examples of Cascade Reactions 340

11.4.2 Mechanisms of Commonly Used Enzymes 341

11.5 Conclusion and Future Perspectives 343

Acknowledgments 343

References 343

12 Metalloenzyme-Inspired Systems for Alternative Energy Harvest 353
Markus D. Kärkäs, Oscar Verho, and Björn Åkermark

12.1 Introduction: Artificial Photosynthesis 353

12.2 Hydrogen Evolution 355

12.2.1 Hydrogenases: Iron-Based Metalloenzymes for Hydrogen Evolution 355

12.2.2 Other Metal-Based Biohybrid Systems for Hydrogen Production 363

12.3 Hybrid Systems for OverallWater Splitting 364

12.4 Bioinspired Systems for O2 Reduction 364

12.4.1 Simple Bioelectrodes for Applications in Biosensing 366

12.4.2 Multicatalytic Hybrid Systems for More Efficient Bioelectrodes 367

12.4.3 Future Directions in Bioelectrocatalysis Research 370

12.5 Conclusions and Outlook 372

Acknowledgments 373

References 373

13 Synthesis and Application of Hybrid Catalysts with Metalloenzyme-Like Properties 383
Jose M. Palomo

13.1 Introduction 383

13.2 Synthesis of Pd Nanobiohybrids (Pd(0)NPs-Enzyme Hybrids) 384

13.3 Synthesis of Au Nanobiohybrids 387

13.4 Synthesis of Ag Nanobiohybrids 391

13.5 Synthesis of Cu Nanobiohybrids 392

13.6 Synthesis of Pt Nanobiohybrids 394

13.7 Chemical Applications of Nanobiohybrids 395

13.7.1 Synergistic Effect 396

13.7.2 Dual Activity in Cascade Processes 396

13.8 Conclusions 399

Acknowledgments 400

References 400

Index 405

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