Marina A. Zenkova. Artificial Nucleases

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1 Marina A. Zenkova Artificial Nucleases

3 Introduction 1 DNA Hydrolysis : Mechanism and Reactivity 3 N.H. WILLIAMS 1 Introduction 3 2 The Importance of the Background Reaction 3 3 Mechanism 4 4 Spontaneous Hydrolysis 7 5 C-O Cleavage 8 6 P-O Cleavage 9 7 Base Catalysis 10 8 Acid Catalysis 12 9 Conclusion 1 3 References 1 4 Active Site of Ribonuclease A 1 9 R.T. RAINES 1 Introduction Mechanism of Catalysis Active-Site Residues Histidine 12 and Histidine Lysine Phenylalanine Aspartic Acid Glutamine Catalytic Rate Enhancement Envoi 29 References 29

4 Structural Considerations Concerning Cleavage of RNA 3 3 R. KIERZE K 1 Introduction Facts About the Influence of Oligoribonucleotid e Structure on Cleavage of Phosphodiester Bonds How to Cleave Oligoribonucleotides Cleavage Requires a Single-Stranded Characte r of the Oligoribonucleotide Sequence and Position of the Scissile Phosphodiester Bond Within the Oligomer is Important for Cleavage Oligoribonucleotide Length Affects Cleavag e of Diester Bond The Functional Groups of the Pyrimidine Nucleobase s Flanking the Cleaved Phosphodiester Bond Affect Cleavage The Functional Groups of the Purine Nucleobases Flankin g the Cleaved Phosphodiester Bond Influence Cleavage The C5 Substituents of Uridine Affect the Hydrolysis Rate of the UA Phosphodiester Bond Chimeric DNA/RNA Oligomers Affect the Cleavag e of Phosphodiester Bonds The Motives of RNA Structure are Affected by Spontaneous Cleavage The Effects of Polyamines on the Cleavag e of Oligoribonucleotides Mechanism of Phosphodiester Bond Cleavage 44 4 Conclusions 46 References 46 Cleavage of RNA by Imidazole 49 V.V. VLASSOV and A.V. VLASSOV 1 Introduction 49 2 Imidazole as the Simplest Mimi c of the Ribonuclease Catalytic Structure 50 3 Mechanism of RNA Cleavage by Imidazole Imidazole as a Reagent for Probing RNA Structure 54 5 Conclusions 5 9 References 59

5 Principles of Nucleic Acid Cleavage by Metal Ions 6 1 A. DALLAS, A.V. VLASSOV, and S.A. KAZAKO V 1 Introduction General Mechanisms for the Cleavage of Nucleic Acids Basic Properties of Metal Ions in Solution Metal Ion Binding to Nucleic Acids Transesterification and Hydrolytic Cleavage of Nucleic Acids Catalyzed by Metal Ions Efficacy of Cleavage of Nucleic Acids by Metal Ions Possible Mechanism of Metal Ion Catalysis Nucleic Acid Structure and Specificity of Metal-Catalyzed Cleavage Reactions Oxidative Cleavage of Nucleic Acids Induced by Metal Ions Cleavage Reactions Promoted by Metal Ions in High Oxidation States Cleavage Reactions Involving Metal-Induce d Oxygen Radicals Probing Metal Binding Sites in RNA by Metal-Induced Cleavage 8 1 References 8 3 Allosterically Controlled Ribozymes as Artificial Ribonucleases M. IYo, H. KAWASAKI, M. MIYAGISHI, and K. TAIRA 1 Introduction Maxizymes are Allosterically Controllable Ribozymes Expression of Ribozymes in Cells The Design of Allosterically Controllable Maxizymes Allosteric Control of Ribozyme Activity Selection of Allosterically Controllable Ribozymes in Vitro Maxizymes Truncated Hammerhead Ribozymes that Functio n as Dimers General Design of an Allosterically Controllable Maxizyme The Antitumor Effects of an Allosterically Controllable Maxizyme General Applications of Maxizyme Technology Conclusion 104 References 104

6 Small Ribonuclease Mimics 11 1 I.L. KUZNETSOVA and V.N. SIL'NIKOV 1 Introduction RNA-Cleaving Compounds RNA-Cleaving Compounds Mimickin g Ribonucleases A and Ti Mimics of the Active Center of Nuclease S Design of Active Centers of Natural Enzymes Spatial Organization of RNA-Cleaving Groups in Active Centers of RNases and Nucleases S and Sm RNA-Binding Groups Design of Artificial Ribonucleases Mimicking RNase A Artificial Ribonucleases with Polycycli c RNA-Binding Domains Polycationic RNA-Binding Groups Specificity of RNA Cleavage Effects of Buffer on the Cleavage Mechanism of RNA Cleavage with the Artificial Ribonucleases ABLkCm and nlm Potential Applications of Small Ribonuclease Mimics Conclusions 125 References 126 Copper-Containing Nuclease Mimics : Synthetic Models and Biochemical Applications 129 S. VERMA, S.G. SRIVATSAN, and C. MADHAVAIAH 1 Introduction Model Systems Mechanistic Pathways Copper Complexes with Synthetic Ligands Hydrolysis of Phosphate Diesters Cleavage of Nucleic Acids Copper Complexes of Natural Ligands Outlook 14 5 References 145

7 RNA-Cleaving Oligonucleotide-Peptide Conjugates 15 1 N.L. MIRONOVA, D.V. PYSHNYI, and E.M. IVANOVA 1 Introduction Proteins Displaying Ribonuclease Activity Natural Ribonuclease Small Natural Peptides Synthetic Polypeptides Conjugates of RNA-Cleaving Peptides with Constructs Capable of Binding to RNA Conjugates of Enzymes and Oligonucleotides Conjugates of Short Peptides and Intercalators Oligonucleotide-Peptide Conjugates Displayin g Ribonuclease Activity Influence of Peptide Structure on the Efficacy of RNA Cleavage Site-Directed RNA Hydrolysis by Peptidyloligonucleotides Hydrolysis ofrna by the Conjugate s of Random Oligonucleotides Influence of Oligonucleotide Sequence on the Specificity of RNA Cleavage Cleavage of Short RNA Discussion 16 8 References 170 Sequence Selective Artificial Ribonuclease s Employing Metal Ions as Scissors 17 3 A. KUZUYA, R. MIZOGUCHI, and M. KOMIYAM A 1 Introduction Significance of Artificial Ribonucleases Molecular Design of Artificial Ribonucleases Metal Ion Catalysts for RNA Cleavage Divalent Metal Ions and Their Complexes Trivalent Lanthanide Ions and Their Complexes Sequence-Selective Artificial Ribonuclease s with Covalently Attached Catalysts Attaching the Catalysts to the End of DNA Oligomers [Lanthanide Complex]/DNA Hybrids [Dinuclear Metal Complex]/DNA Hybrids 179

8 3.2 Attaching the Catalysts at an Internal Position Within DNA Oligomers Noncovalent Systems for Sequence-Selective RNA Scission Molecular Design Site-Selective RNA Scission by Lanthanide Ions Requirements for the Sequence-Selective RNA Activation Site-Selective RNA Scission by Non-Lanthanide Ions Mechanism of the Site-Selective Scission Prospect 18 6 References 18 6 Site-Specific Artificial Ribonucleases : Conjugates of Oligonucleotides with Catalytic Groups 18 9 M.A. Zenkova and N.G. Beloglazova 1 Introduction Oligonucleotide Conjugate-Based Artificial Ribonucleases Conjugates of Oligonucleotides and Metal Complexes Conjugates of Oligonucleotide s and RNA-Cleaving Molecules Design of Artificial Ribonucleases for Site-Specifi c RNA Cleavage Synthetic Approaches Effect of the Catalytic Structure Locatio n in the Conjugate Structure RNA Sequences Optimal for Site-Specific Cleavage Site-Specific Cleavage of Cellular RNA Site-Specific RNA Cleavage by Conjugate s of Oligonucleotides with Imidazole-Based Catalytic Groups Mono- and Bis-Imidazole-Containing Conjugates Binary Systems of Oligonucleotide Conjugates Conjugates with Anthracene-Based Linkers Conjugates with Multiple Imidazole Residues in the Catalytic Domain Conclusions 21 6 References 216

9 DNA and RNA Cleavage Mediated by Phenanthroline-Cuprou s Oligonucleotides : From Properties to Applications 22 3 J.C. FRANcOIS, M. FARIA, D. PERRIN, and C. GIOVANNANGEL I 1 Introduction The 1,10-Phenanthroline-Cuprous Complex Background Structural Probes for Nucleic Acid-Containing Complexes Phenanthroline Conjugates Conjugation of Biomolecules to Phenanthroline Neighborhood Sensors Oligonucleotide-Phenanthrolin e as Site-Specific Ribonuclease Oligonucleotide-Phenanthroline Targeted to Double-Stranded DNA Artificial Endonucleases for in Vitro Applications Biological Activities of Oligonucleotide-Phenanthroline Phenanthroline Cleavage Activity Inside Cells Modulation of DNA Metabolism Induced by Oligonucleotide-Phenanthroline Conclusion 23 7 References 23 8 Sequence-Specific Cleavage of Double-Stranded DNA 24 3 A.S. BOUTORINE and P.B. ARIMOND O 1 Introduction DNA Cleavage by Natural Enzymes and Their Conjugates Restriction Endonucleases Conjugates of Nucleases with Oligonucleotides The Achilles Heel Cleavage Method Sequence-Specific Cleavage Using Conjugate d Chemical Reagents Direct Cleavage by Sequence-Specific Conjugates 3.2 of Metal Complexes Alkylating Reagents Conjugate d 24 7 to Sequence-Specific Molecules DNA Photocleavage Photo cleavage by Blue Light-Absorbing Reagents Long-Distance Electron Transfer in Photocleavage Reactions Photocleavage by Red Light-Absorbing Reagents Recruitment of Intracellular Enzyme s for Sequence-Specific DNA Cleavage 255

10 5.1 RecA Protein Recruitment of Topoisomerase s by Conjugated Topoisomerase Inhibitors Application of the Non-Specific Single-Stranded DNA Cleaving Agents for Site-Specific Scissio n of Double-Stranded DNA Conclusions 26 0 References 26 1 Bleomycin-Oligonucleotide Conjugates as Site-Specific Nucleases P.E. VOROBJEV and V.F. ZARYTOVA 1 Introduction Structure and Properties of Bleomycins Conjugates of Bleomycin with Oligonucleotides : Synthesis and Structure Cleavage of Nucleic Acid s by Bleomycin-Oligonucleotide Conjugates Site-Specific Cleavage of Single-Stranded DNA Fragment s by Bleomycin-Oligonucleotide Conjugates Cleavage of RNA by Bleomycin-Oligonucleotide Conjugates Cleavage of Double-Stranded DNA by Triplex-Formin g Bleomycin-oligonucleotide Conjugates Catalytic Degradation of DNA Target b y Oligonucleotide-Bleomycin Conjugate Bleomycin-Oligonucleotide Conjugate s in Tandem Sets with Effectors as Efficient Nucleases Conclusion 284 References 284 Subject Index 289

Chapter 3 Nucleic Acids, Proteins, and Enzymes

3 Nucleic Acids, Proteins, and Enzymes Chapter 3 Nucleic Acids, Proteins, and Enzymes Key Concepts 3.1 Nucleic Acids Are Informational Macromolecules 3.2 Proteins Are Polymers with Important Structural