Preface ........................................................ XV
List of Contributors ......................................... XVII
Volume 1
Part I. Chemistry and Biology - Historical and
Philosophical Aspects
1. Chemistry and Biology - Historical and Philosophical
Aspects ...................................................... 3
Gerhard Quinkert, Holger Wallmeier, Norbert Windhab,
and Dietmar Reichert
1.1. Prologue .............................................. 3
1.2. Semantics ............................................. 4
1.2.1. Synthesis - Genesis - Preparation ............. 4
1.2.2. Synthetic Design - Synthetic Execution ........ 8
1.2.3. Preparative Chemistry - Synthetic Chemistry ... 9
1.3. Bringing Chemical Solutions to Chemical Problems ..... 10
1.3.1. The Present Situation ........................ 10
1.3.2. Historical Periods of Chemical Synthesis ..... 12
1.3.3. Diels-Alder Reaction - Prototype of a
Synthetically Useful Reaction ................ 16
1.4. Bringing Chemical Solutions to Biological Problems ... 18
1.4.1. The Role of Evolutionary Thinking in
Shaping Biology .............................. 18
1.4.2 On the Sequence of Chemical Synthesis
(Preparation) and Biological Analysis
(Screening) ................................... 20
1.5. Bringing Biological Solutions to Chemical Problems ... 45
1.5.1. Proteins [99] ................................ 45
1.5.2. Antibodies ................................... 52
1.6. Bringing Biological Solutions to Biological
Problems ............................................. 53
1.7. EPILOGUE ............................................. 54
1.7.1. The Fossil Fuel Dilemma of Present Chemical
Industry ..................................... 54
1.7.2. Two Lessons From the Wealth of Published
Total Syntheses .............................. 55
Acknowledgments ...................................... 58
References ........................................... 59
Part II. Using Natural Products to Unravel Biological Mechanisms
2. Using Natural Products to Unravel Biological Mechanisms ..... 71
2.1. Using Small Molecules to Unravel Biological
Mechanisms ........................................... 71
Michael A. Lampson and Tarun M. Kapoor
Outlook .................................................... 71
2.1.1. Introduction ................................. 71
2.1.2. Use of Small Molecules to Link a Protein
Target to a Cellular Phenotype ............... 72
2.1.3. Small Molecules as Probes for Biological
Processes .................................... 77
2.1.4. Conclusion ................................... 89
References ................................................. 90
2.2. Using Natural Products to Unravel Cell Biology ....... 95
Jonathan D. Gough and Craig M. Crews
Outlook .................................................... 95
2.2.1. Introduction ................................. 95
2.2.2. Historical Development ....................... 95
2.2.3. General Considerations ....................... 96
2.2.4. Applications and Practical Examples .......... 96
2.2.5. Future Development .......................... 109
2.2.6. Conclusions ................................. 109
Acknowledgments ........................................... 110
References ................................................ 110
3. Engineering Control Over Protein Function Using
Chemistry .................................................. 115
3.1. Revealing Biological Specificity by Engineering
Protein-Ligand Interactions ......................... 115
Matthew D. Simon and Kevan M. Shokat
Outlook ................................................... 115
3.1.1. Introduction ................................ 115
3.1.2. The Selection of Resistance Mutations to
Small-molecule Agents ....................... 116
3.1.3. Exploiting Sensitizing Mutations to
Engineer Nucleotide Binding Pockets ......... 126
3.1.4. Engineering the Ligand Selectively of Ion
Channels .................................... 130
3.1.5. Conclusion .................................. 134
References ................................................ 136
3.2. Controlling Protein Function by Caged Compounds ..... 140
Andrea Giordano, Sirus Zarbakhsh, and
Carsten Schultz
3.2.1. Introduction ................................ 140
3.2.2. Photoactivatable Groups and Their
Applications ................................ 140
3.2.3. Caged Peptides and Proteins ................. 150
3.2.4. Caged Proteins by Introduction of
Photoactive Residues via Site Directed,
Unnatural Amino Acid Mutagenesis ............ 156
3.2.5. Small Caged Molecules Used to Control
Protein Activity ............................ 159
3.2.6. Conclusions ................................. 168
References ................................................ 168
3.3. Engineering Control Over Protein Function;
Transcription Control by Small Molecules ............ 174
John T. Koh
Outlook ................................................... 174
3.3.1. Introduction ................................ 174
3.3.2. The Role of Ligand-dependent
Transcriptional Regulators .................. 175
3.3.3. Engineering New Ligand Specificities into
NHRs ........................................ 179
3.3.4. The Requirement of "Functional
Orthogonality" .............................. 180
3.3.5. Overcoming Receptor Plasticity .............. 180
3.3.6. Nuclear Receptor Engineering by Selection ... 183
3.3.7. Ligand-dependent Recombinases ............... 184
3.3.8. Complementation/Rescue of Genetic Disease ... 186
3.3.9. De Novo Design of Ligand-binding Pockets .... 188
3.3.10. Light-activated Gene Expression from Small
Molecules ................................... 189
References ................................................ 191
4. Controlling Protein-Protein Interactions ................... 199
4.1. Chemical Complementation: Bringing the Power of
Genetics to Chemistry ............................... 199
Pamela Peralta-Yahya and Virginia W. Cornish
Outlook ................................................... 199
4.1.1. Introduction ................................ 199
4.1.2. History/Development ......................... 202
4.1.3. General Considerations ...................... 208
4.1.4. Applications ................................ 216
4.1.5. Future Development .......................... 222
References ................................................ 223
4.2. Controlling Protein-Protein Interactions Using
Chemical Inducers and Disrupters of Dimerization .... 227
Tim Clackson
Outlook ................................................... 227
4.2.1. Introduction ................................ 227
4.2.2. Development of Chemical Dimerization
Technology .................................. 228
4.2.3. Dimerization Systems ........................ 229
4.2.4. Applications ................................ 237
4.2.5. Future Development .......................... 245
4.2.6. Conclusion .................................. 245
Acknowledgments ........................................... 246
References ................................................ 246
4.3. Protein Secondary Structure Mimetics as Modulators
of Protein-Protein and Protein-Ligand
Interactions ........................................ 250
Hang Yin and Andrew D. Hamilton
Outlook ................................................... 250
4.3.1. Introduction ................................ 250
4.3.2. History and Development ..................... 252
4.3.3. General Considerations ...................... 253
4.3.4. Applications and Practical Examples ......... 255
4.3.5. Future Developments ......................... 264
4.3.6. Conclusion .................................. 265
Acknowledgments ........................................... 265
References ................................................ 265
5. Expanding the Genetic Code ................................. 271
5.1. Synthetic Expansion of the Central Dogma ............ 271
Masahiko Sisido
Outlook ................................................... 271
5.1.1. Introduction ................................ 272
5.1.2. Aminoacylation of tRNA with Nonnatural
Amino Acids ................................. 274
5.1.2.2. Micelle-mediated Aminoacylation .... 275
5.1.2.3. Ribozyme-mediated Aminoacylation ... 276
5.1.2.4. PNA-assisted Aminoacylation ........ 277
5.1.2.5. Directed Evolution of Existing
aaRS/tRNA Pair to Accept
Non-natural Amino Acids ............ 278
5.1.3. Other Biomolecules That Must Be Optimized
for Nonnatural Amino Acids .................. 281
5.1.3.2. Adaptability of EF-Tu to
Aminoacyl-tRNAs Carrying
a Wide Variety of Nonnatural
Amino Acids ........................ 283
5.1.3.3. Adaptability of Ribosome to Wide
Variety of Nonnatural Amino
Acids .............................. 283
5.1.4. Expansion of the Genetic Codes .............. 284
5.1.4.2. Four-base Codons ................... 285
5.1.4.3. "Synthetic Codons" That Contain
Nonnatural Nucleobases ............. 286
5.1.5. In vivo Synthesis of Nonnatural Mutants ..... 287
5.1.6. Application of Nonnatural Mutagenesis -
Fluorescence Labeling ....................... 289
5.1.7. Future Development and Conclusion ........... 291
Acknowledgments ........................................... 291
References ................................................ 291
Part III. Engineering Control Over Protein Function Using
Chemistry
6. Forward Chemical Genetics .................................. 299
Stephen J. Haggarty and Stuart L. Schreiber
Outlook ................................................... 299
6.1. Introduction ........................................ 299
6.2. History/Development ................................. 302
6.3. General Considerations .............................. 307
6.3.1. Small Molecules as a Means to Perturb
Biological Systems Conditionally ............ 307
6.3.2. Forward and Reverse Chemical Genetics ....... 308
6.3.3. Phenotypic Assays for Forward
Chemical-Genetic Screening .................. 311
6.3.4. Nonheritable and Combinations of
Perturbations ............................... 316
6.3.5. Multiparametric Considerations: Dose
and Time .................................... 318
6.3.6. Sources of Phenotypic Variation: Genetic
versus Chemical Diversity ................... 318
6.3.7. The "Target Identification" Problem ......... 319
6.3.8. Relationship between Network Connectivity
and Discovery of Small-molecule Probes ...... 323
6.3.9. Computational Framework for Forward
Chemical Genetics: Legacy of Morgan
and Sturtevant .............................. 325
6.3.10. Mapping of Chemical Space Using Forward
Chemical Genetics ........................... 326
6.3.11. Dimensionality Reduction and Visualization
of Chemical Space ........................... 330
6.3.12. Discrete Methods of Analysis of Forward
Chemical-genetic Data ....................... 334
6.4. Applications and Practical Examples ................. 336
6.4.1. Example 1: Mitosis and Spindle Assembly ..... 336
6.4.2. Example 2: Protein Acetylation .............. 338
6.4.3. Example 3: Chemical-genomic Profiling ....... 340
6.5. Future Development .................................. 344
6.6. Conclusion .......................................... 347
Acknowledgments ........................................... 348
References ................................................ 349
7. Reverse Chemical Genetics Revisited ........................ 355
7.1. Reverse Chemical Genetics - An Important Strategy
for the Study of Protein Function in Chemical
Biology and Drug Discovery .......................... 355
Rolf Breinbauer, Alexander Hillisch,
and Herbert Waldmann
7.1.1. Introduction ................................ 355
7.1.2. History/Development ......................... 356
7.1.3. General Considerations ...................... 361
7.1.4. Applications and Practical Examples ......... 366
7.1.5. Future Developments ......................... 376
7.1.6. Conclusion .................................. 379
Acknowledgments ........................................... 380
References ................................................ 380
7.2. Chemical Biology and Enzymology: Protein
Phosphorylation as a Case Study ..................... 385
Philip A. Cole
Outlook ................................................... 385
7.2.1. Overview .................................... 385
7.2.2. The Enzymology of Posttranslational
Modifications of Proteins ................... 387
References ................................................ 401
7.3. Chemical Strategies for Activity-based
Proteomics .......................................... 403
Nadim Jessani and Benjamin F. Cravatt
Outlook ................................................... 403
7.3.1. Introduction ................................ 403
7.3.2. History/Development ......................... 404
7.3.3. General Considerations ...................... 407
7.3.4. Applications and Practical Examples ......... 415
7.3.5. Future Development .......................... 421
7.3.6. Conclusions ................................. 422
Acknowledgments ........................................... 423
References ................................................ 423
8. Tags and Probes for Chemical Biology ....................... 427
8.1. The Biarsenical-tetracysteine Protein Tag:
Chemistry and Biological Applications ............... 427
Stephen R. Adams
Outlook ................................................... 427
8.1.1. Introduction ................................ 427
8.1.2. History and Design Concepts of the
Tetracysteine-biarsenical System ............ 429
8.1.3. General Considerations ...................... 430
8.1.4. Practical Applications of the Biarsenical-
tetracysteine System ........................ 439
8.1.5. Future Developments and Applications ........ 453
8.1.6. Conclusions ................................. 454
Acknowledgments ........................................... 454
References ................................................ 454
8.2. Chemical Approaches to Exploit Fusion Proteins for
Functional Studies .................................. 458
Anke Arnold, India Sielaff, Nils Johnsson,
and Kai Johnsson
Outlook ................................................... 458
8.2.1. Introduction ................................ 458
8.2.2. General Considerations ...................... 459
8.2.3. Applications and Practical Examples ......... 463
8.2.4. Conclusions and Future Developments ......... 476
Acknowledgments ........................................... 477
References ................................................ 477
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