Ribozymes and Rna Catalysis

, by Lilley, David M. J.; Eckstein, Fritz

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ISBN: 9780854042531 | 0854042539
Cover: Hardcover
Copyright: 5/1/2008

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The discovery that RNA could act as a macromolecular catalyst in the cell, signified a paradigm shift in molecular biology. Ribozymes and RNA Catalysis takes the reader through the origins of catalysis in RNA and necessarily includes significant discussion of structure and folding. The main focus of the book concerns chemical mechanism with extensive comment on how, despite the importance of RNA catalysis in the cell, its origins are still poorly understood and often controversial. The reader is given an outline of the important role of RNA catalysis in many aspects of cell function, including RNA processing and translation. There has been a significant coming together in the field of RNA in recent years and this book offers a compelling review of the whole field to date. Written by leading experts in their field, who in turn review the structural and mechanistic data for all known ribozymes this book is well suited for undergraduates, postgraduates and researchers in catalytic chemistry as well as those in related fields who require a unique overview of the subject.

Ribozymes and RNA Catalysis: Introduction and Primer
What are Ribozymes?	p. 1
What is the Role of Ribozymes in Cells?	p. 1
Ribozymes Bring about Significant Rate Enhancements	p. 4
Why Study Ribozymes?	p. 4
Folding RNA into the Active Conformation	p. 5
The Catalytic Resources of RNA - Making a Lot of a Little	p. 6
Mechanisms and Catalytic Strategies of Ribozymes	p. 7
Impact of New Methodologies to Study Ribozymes	p. 8
Finally	p. 8
References	p. 8
Proton Transfer in Ribozyme Catalysis
Scope of Chapter and Rationale	p. 11
Overview of Proton Transfer Chemistry	p. 12
General Considerations for Proton Transfer in RNA Enzymes	p. 17
Classes of Protonation Sites in RNA	p. 17
Driving Forces for pK_a Shifting in RNA	p. 18
Quantitative Contributions of Proton Transfer to RNA Catalysis	p. 19
Proton Transfer in Small Ribozymes: Five Case Studies	p. 20
Why Small Ribozymes?	p. 20
Proton Transfer in the Hepatitis Delta Virus Ribozyme	p. 22
Proton Transfer in the Hairpin Ribozyme	p. 27
Proton Transfer in the Hammerhead Ribozyme	p. 28
Proton Transfer in the VS Ribozyme	p. 29
Proton Transfer in the glmS Ribozyme	p. 30
Conclusion and Perspectives	p. 31
Acknowledgement	p. 32
References	p. 32
Finding the Hammerhead Ribozyme Active Site
Introduction	p. 37
Background	p. 38
Experimental Data	p. 40
Mechanistic Hypothesis Leads to Identification and Functional Test of Active Site Components	p. 40
Structural Hypothesis - Large-scale Conformational Changes are Required for Catalysis	p. 41
Molecular Modeling of a Hammerhead Active Fold that Satisfies Structural and Biochemical Constraints	p. 43
Current Status and Future Prospects	p. 46
Acknowledgements	p. 46
References	p. 46
Hammerhead Ribozyme Crystal Structures and Catalysis
Introduction	p. 48
A Catalytic RNA Prototype	p. 49
A Small Ribozyme	p. 49
Chemistry of Phosphodiester Bond Isomerization	p. 50
Hammerhead Ribozyme Structure	p. 51
Catalysis in the Crystal	p. 53
Making Movies from Crystallographic Snapshots	p. 53
An Ever-growing List of Concerns	p. 55
Occam's Razor Can Slit Your Throat	p. 56
Structure of a Full-length Hammerhead Ribozyme	p. 57
Do the Minimal and Full-length Hammerhead Crystal Structures have Anything in Common?	p. 59
How Does the Minimal Hammerhead Work?	p. 60
A Movie Sequel with a Happy Ending	p. 61
Concluding Remarks	p. 62
Acknowledgements	p. 62
References	p. 62
The Hairpin and Varkud Satellite Ribozymes
Nucleolytic Ribozymes	p. 66
Hairpin Ribozyme	p. 66
Structure of the Hairpin Ribozyme	p. 67
Metal Ion-dependent Folding of the Hairpin Ribozyme	p. 69
Observing the Cleavage and Ligation Activities of the Hairpin Ribozyme	p. 71
Mechanism of the Hairpin Ribozyme	p. 73
VS Ribozyme	p. 76
Structure of the VS Ribozyme	p. 77
Structure of the Substrate	p. 80
Location of the Substrate	p. 80
Active Site of the VS Ribozyme	p. 82
Candidate Catalytic Nucleobases	p. 82
Mechanism of the VS Ribozyme	p. 84
Some Striking Similarities between the Hairpin and VS Ribozymes	p. 88
Acknowledgements	p. 88
References	p. 88
Catalytic Mechanism of the HDV Ribozyme
Introduction	p. 92
Hepatitis Delta Virus Biology	p. 92
Cleavage Reactions of Small Ribozymes	p. 93
HDV Ribozyme Structure	p. 95
Determination of Crystal Structures	p. 95
Structure Overview	p. 97
Active Site	p. 97
Catalytic Strategies for RNA Cleavage	p. 99
The Active Site Nucleobase: C75	p. 100
Exogenous Base Rescue Reactions	p. 101
Role of C75 in HDV Catalysis	p. 103
Resolving the Kinetic Ambiguity	p. 105
Reaction in the Absence of Divalent Cations	p. 105
Sulfur Substitution of the Leaving Group	p. 106
Metal Ions in the HDV Ribozyme	p. 108
Structural Metal Ions	p. 108
Catalytic Metal Ions	p. 111
Contributions of Non-active-site Structures to Catalysis	p. 112
Dynamics in HDV Function	p. 113
Varieties of Experimental Systems	p. 115
Models for HDV Catalysis	p. 117
Conclusion	p. 119
Acknowledgements	p. 120
References	p. 120
Mammalian Self-Cleaving Ribozymes
Introduction	p. 123
General Features of Small Self-cleaving Sequences	p. 124
Genome-wide Selection of Self-cleaving Ribozymes	p. 124
CPEB3 Ribozyme	p. 125
Expression of the CPEB3 Ribozyme	p. 126
Structural Features of the CPEB3 and HDV Ribozymes	p. 127
Linkage of HDV to the Human Transcriptome	p. 129
Possible Biological Roles of Self-cleaving Ribozymes	p. 130
Closing Remarks	p. 131
References	p. 131
The Structure and Action of glmS Ribozymes
Introduction	p. 134
Biochemical Characteristics of glmS Ribozymes	p. 136
Divalent Metal Ions Support Structure and Not Chemistry	p. 136
Ligand Specificity of glmS Ribozymes	p. 137
Evidence for a Coenzyme Role for GlcN6P	p. 139
Atomic-resolution Structure of glmS Ribozymes	p. 141
Secondary and Tertiary Structures of glmS Ribozymes	p. 141
Metabolite Recognition by glmS Ribozymes	p. 143
Mechanism of glmS Ribozyme Self-cleavage	p. 145
Can glmS Ribozymes be Drug Targets?	p. 148
Conclusions	p. 149
References	p. 150
A Structural Analysis of Ribonuclease P
Introduction	p. 153
Chemistry of RNase P RNA	p. 155
Universal	p. 155
S_N2-type Reaction	p. 155
pH-Dependence of the Reaction: Hydroxide Ion as the Nucleophile	p. 157
Metal Ions in Catalysis	p. 157
Phylogenetic Variation and Structure of RNase P RNA	p. 158
Early Studies of the RNase P RNA Structure	p. 159
Crystallographic Studies of Bacterial RNase P RNAs	p. 160
Modeling an RNase P RNA:tRNA Complex	p. 162
Modeling the Bacterial RNase P Holoenzyme	p. 163
Substrate Recognition	p. 165
Archaeal and Eucaryal Holoenzymes - More Proteins	p. 166
Concluding Remarks	p. 170
Acknowledgements	p. 171
References	p. 171
Group I Introns: Biochemical and Crystallographic Characterization of the Active Site Structure
Group I Intron Origins	p. 178
Group I Intron Self-splicing	p. 178
What has Changed in Group I Intron Knowledge in the Last Decade	p. 181
Structure of Group I Introns	p. 181
Crystallography of Group I Introns	p. 181
Tetrahymena LSU P4-P6 Domain	p. 182
Tetrahymena Intron Catalytic Core	p. 183
Twort orf142-I2 Ribozyme	p. 183
Azoarcus sp. BBH72 tRNA^Ile Intron	p. 184
Structural Basis for Group I Intron Self-splicing	p. 184
Recognition of the 5'-Splice Site	p. 185
Does the Ribozyme Undergo Conformational Changes upon PI Docking?	p. 186
A Binding Pocket for Guanosine	p. 187
Packed Stacks	p. 189
Biochemical Characterization of the Structure	p. 191
Metal Ion Binding and Specificity Switches	p. 191
Identification of Ligands to the Catalytic Metal Ions	p. 192
Correlation with Metal Ion Binding Sites within the Crystal Structures	p. 193
Nucleotide Analog Interference Techniques	p. 194
What Makes a Catalytic Site?	p. 196
Back to the Origins	p. 197
References	p. 198
Group II Introns: Catalysts for Splicing, Genomic Change and Evolution
Introduction: The Place of Group II Introns Among the Family of Ribozymes	p. 201
The Basic Reactions of Group II Introns	p. 201
The Biological Significance of Group II Introns	p. 204
Evolutionary Significance	p. 204
Significance and Prevalence in Modern Genomes	p. 204
The Potential Utility of Group II Introns	p. 204
Domains and Parts: The Anatomy of a Group II Intron	p. 205
Domain 1	p. 206
Domain 2	p. 206
Domain 3	p. 206
Domain 4	p. 206
Domain 5	p. 206
Domain 6	p. 207
Other Domains and Insertions	p. 207
Alternative Structural Organization and Split Introns	p. 208
A Big, Complicated Family: The Diversity of Group II Introns	p. 208
Group II Intron Tertiary Structure	p. 209
Group II Intron Folding Mechanisms	p. 211
A Slow, Direct Path to the Native State	p. 211
A Folding Control Element in the Center of D1	p. 212
Proteins and Group II Intron Folding	p. 212
Setting the Stage for Catalysis: Proximity of the Splice Sites and Branch-site	p. 213
Recognition of Exons and Ribozyme Substrates	p. 213
Branch-site Recognition and the Coordination Loop	p. 213
A Single Active-site for Group II Intron Catalysis	p. 215
The Group II Intron Active-site: What are the Players?	p. 216
Active-site Players in D1 and Surrounding Linker Regions	p. 217
Domain 3 and the J2/3 Linker	p. 217
Domain 5: Structural and Catalytic Regions	p. 218
The Chemical Mechanism of Group II Intron Catalysis	p. 219
Proteins and Group II Intron Function	p. 221
Maturases	p. 221
CRM-domain Plant Proteins	p. 221
ATPase Proteins	p. 221
Group II Introns and Their Many Hypothetical Relatives	p. 222
Group II Introns: RNA Processing Enzymes, Transposons, or Tiny Living Things?	p. 223
References	p. 223
The GIR1 Branching Ribozyme
Introduction	p. 229
Distribution and Structural Organization of Twin-ribozyme Introns	p. 231
Biological Context	p. 234
Three Processing Pathways of a Twin-ribozyme Intron	p. 234
Processing of the I-DirI mRNA	p. 235
Conformational Switching in GIR1	p. 236
Biochemical Characterization	p. 238
GIR1 Catalyzes Three Different Reactions	p. 239
Characterization of the Branching Reaction	p. 240
Biochemistry of GIR1	p. 240
Modelling the Structure of GIR1	p. 241
Overall Structure	p. 242
Coaxially Stacked Helices	p. 242
Junctions and Tertiary Interactions Involving Peripheral Elements	p. 245
The Active Site	p. 245
Phylogenetic Considerations	p. 247
Concluding Remarks	p. 248
References	p. 249
Is the Spliceosome a Ribozyme?
Introduction	p. 253
Similarity to Group II Self-splicing Introns	p. 253
Role of snRNA in the Spliceosome Active Site	p. 255
Conformation of the U2-U6 Complex and Parallels to Group II Intron Structures	p. 260
RNA-mediated Regulation in the Spliceosome	p. 262
References	p. 266
Peptidyl Transferase Mechanism: The Ribosome as a Ribozyme
Introduction: Historical Background	p. 270
The Ribosome	p. 271
Peptidyl Transfer Reaction	p. 272
Characteristics of the Reaction off the Ribosome	p. 273
Enzymology of the Peptidyl Transfer Reaction	p. 274
Potential Mechanisms of Rate Acceleration by the Ribosome	p. 274
Experimental Approaches to Reaction on the Ribosome	p. 275
pH-Rate Profiles	p. 277
Activation Parameters	p. 278
The Active Site	p. 279
Structures of the Reaction Intermediates	p. 281
Conformational Rearrangements of the Active Site	p. 282
Induced Fit	p. 282
Role of the P-site Substrate	p. 283
Conformational Flexibility of the Active Site	p. 284
Probing the Catalytic Mechanism: Effects of Base Substitutions	p. 285
Importance of the 2'-OH of A76 of the P-site tRNA	p. 286
Conclusions and Evolutionary Considerations	p. 287
References	p. 288
Folding Mechanisms of Group I Ribozymes
Introduction	p. 295
Multi-domain Architecture of Group I Ribozymes	p. 296
RNA Folding Problem	p. 297
Hierarchical Folding of tRNA	p. 297
Coupling of Secondary and Tertiary Structure	p. 298
Late Events: Formation of Tertiary Domains in the Tetrahymena Ribozyme	p. 298
Time-resolved Footprinting of Intermediates	p. 298
Misfolding of the Intron Core	p. 300
Peripheral Stability Elements	p. 300
Kinetic Partitioning among Parallel Folding Pathways	p. 301
Theory and Experiment	p. 301
Single Molecule Folding Studies	p. 301
Estimating the Flux through Footprinting Intermediates	p. 302
Kinetic Partitioning In Vivo	p. 302
Early Events: Counterion-dependent RNA Collapse	p. 302
Compact Non-native Form of bI5 Ribozyme	p. 303
Small Angle X-ray Scattering of Tetrahymena Ribozyme	p. 303
Native-like Folding Intermediates in the Azoarcus Ribozyme	p. 304
Early Folding Intermediates of the P4-P6 RNA	p. 305
Counterions and Folding of Group I Ribozymes	p. 305
Metal Ions and RNA Folding	p. 305
Valence and Size of Counterions Matter	p. 306
Specific Metal Ion Coordination and Folding	p. 307
Protein-dependent Folding of Group I Ribozymes	p. 307
Stabilization of RNA Tertiary Structure	p. 308
Stimulation of Refolding by RNA Chaperones	p. 308
Conclusion	p. 309
References	p. 309
Subject Index	p. 315
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