DNA Topoisomearases: Biochemistry and Molecular Biology (eBook)

Leroy F. Liu (Herausgeber)

eBook Download: PDF

1994 | 1. Auflage
320 Seiten
Elsevier Science (Verlag)
978-0-08-058120-0 (ISBN)

Infos

Each volume of Advances in Pharmacology provides a rich collection of reviews on timely topics. Emphasis is placed on the molecular basis of drug action, both applied and experimental.

Inhalt

Front Cover 1
Advances in Pharmacology: DNA Topoisomerases: Biochemistry and Molecular Biology 4
Copyright Page 5
Contents 6
Contributors 14
Preface 16
Chapter 1. DNA Topoisomerases as Targets of Therapeutics: An Overview 18
I. History and Classification of DNA Topoisomerases 18
II. Catalysis of DNA Breakage and Rejoining by DNA Topoisomerases 22
III. Catalysis of DNA-Dependent ATP Hydrolysis by Type II DNA Topoisomerases and Ligand-Dependent Allosteric Changes of the Enzymes 24
IV. Biochemical Basis of DNA Topoisomerase-Targeting Therapeutics 26
V. Biological Basis of DNA Topoisomerase-Targeting Drugs 26
VI. Newly Identified DNA Topoisomerases 27
VII. Similarities and Differences among DNA Topoisomerases 29
VIII. Concluding Remarks 30
References 30
Chapter 2. Biochemistry of Bacterial Type I DNA Topoisomerases Yuk-Ching Tse-Dinh 38
I. Introduction 38
II. Escherichia coli DNA Topoisomerase I 40
III. Escherichia coli DNA Topoisomerase III 45
IV. Thermophilic Archaebacterial Type I Topoisomerases 47
V. Site-Specific Type I Topoisomerase Activities 49
References 51
Chapter 3. The Biochemistry and Biology of DNA Gyrase 56
I. Reactions of DNA Gyrase 56
II. Structure of DNA Gyrase and Its Complex with DNA 58
III. Inhibitors of DNA Gyrase 60
IV. Mechanism of the DNA Supercoiling Reaction 62
V. Biological Functions of DNA Gyrase 62
VI. DNA Supercoiling and Transcription 64
References 78
Chapter 4. Mechanism of Catalysis by Eukaryotic DNA Topoisomerase I 88
I. Introduction 88
II. Summary of Reactions Catalyzed by Eukaryotic Type I Topoisomerase 89
III. Methods for Uncoupling Closure from Nicking 89
IV. Mode of Action of Camptothecin 90
V. Specificity 91
VI. Structure of Nicked Intermediate and Mechanism of the Reaction 93
VII. Summary 95
References 96
Chapter 5. The DNA Binding, Cleavage, and Religation Reactions of Eukaryotic Topoisomerases I and II 100
I. Eukaryotic DNA Topoisomerase I 100
II. Eukaryotic Topoisomerase I 106
References 114
Chater 6. Roles of DNA Topoisomerases in Chromosomal Replication and Segregation 120
I. Introduction: Topological Problems of Replication and Chromosome Segregation 120
II. Overview of the Functions of Multiple Topoisomerases in Chromosomal Mechanics in Prokaryotic Cells 121
III. Functions of Topoisomerases in DNA Replication in Prokaryotes 123
IV. Eukaryotic Replication: Initiation and Elongation 129
V. Chromosome Segregation in Bacteria 134
VI. Chromosome Segregation at Mitosis and Meiosis 138
VII. Problems and Paradigms 143
References 144
Chapter 7. Roles of DNA Topoisomerases in Transcription 152
I. Introduction 152
II. Effect of Transcription Elongation on DNA Conformation and Structure 153
III. Transcription Elongation Affects DNA Functions 157
IV. DNA Topoisomerases as Regulators of Transcription-Induced DNA Supercoiling 159
V. Conclusion 160
References 160
Chapter 8. DNA Topoisomerase-Mediated lllegitimate Recombination 164
I. Introduction 164
II. Illegitimate Recombination Mediated by Type I Topoisomerases 166
III. DNA Gyrase-Mediated Illegitimate Recombination 168
IV. Illegitimate Recombination Mediated by Type II DNA Topoisomerases of Phage T4 173
V. Illegitimate Recombination Mediated by Mammalian DNA Topoisomerase 174
VI. Concluding Remarks 176
References 176
Chapter 9. Cellular Regulation of Mammalian DNA Topoisomerases 184
I. Introduction 184
II. Topoisomerase Modifications 185
III. Regulation of Topoisomerases during Different Physiological States 187
IV. Promoter Activity Analyses 197
V. Perspectives 198
References 199
Chapter 10. Structure of Eukaryotic Type I DNA Topoisomerase 208
I. Sizes of Proteins, Transcripts, and Genes 209
II. Regulation of the Expression of Topoisomerase I Genes 209
III. Sequence Homologies among DNA Topoisomerase I 210
IV. Resistance to the Anticancer Drug Camptothecin 214
References 215
Chapter 11.Type II DNA Topoisomerase Genes 218
I. Introduction 218
II. Bacterial DNA Gyrases 218
III. Bacterial Topoisomerase IV Genes 230
IV. T-Even Bacteriophage Topoisomerase Genes 231
V. Eukaryotic Type II Topoisomerase Genes 232
VI. Multiple Topoisomerase II Genes in Eukaryotes 237
VII. Animal Virus-Encoded Topoisomerase II Gene 238
VIII. Concluding Remarks 238
References 239
Chapter 12.Major Advances in Antibacterial Quinolone Therapy 244
I. Introduction 244
II. Chemistry 244
III. Mechanism of Action 245
IV. Antimicrobial Activity in Vitro 247
V. Factors Affecting the Activity of Fluoroquinolones 252
VI. Combination of Fluoroquinolones with Other Antimicrobial Agents 252
VII. Resistance of Bacteria to Fluoroquinolones 253
VIII. Pharmacology 254
IX. Clinical Use 258
X. Use of Quinolones in Pediatrics 266
XI. Use of Fluoroquinolones in Immunocompromised Patients 267
XII. Prophylactic Use of Quinolones 267
XIII. Adverse Effects 268
XIV. Conclusions 269
References 270
Chapter 13.4-Quinolones and the Physiology of DNA Gyrase 280
I. Introduction 280
II. Gyrase and the Control of DNA Supercoiling 281
III. Effects of Quinolones on DNA Supercoiling 284
IV. Quinolone-Induced DNA Lesions 285
V. Quinolones and the Inhibition of DNA Synthesis 290
VI. Effects of Quinolones on Gene Expression 291
VII. Bactericidal Action of Quinolones 291
VIII. Bacterial Resistance to Quinolones 292
IX. Concluding Remarks 294
References 294
Chapter 14. Molecular Mechanisms of DNA Gyrase Inhibition by Quinolone Antibacterials 302
I. Introduction 302
II. Binding of Quinolones to DNA and to the Gyrase-DNA Complex 304
III. The Inhibition Model and Its Implications 309
IV. Concluding Remarks 316
References 318
Index 322
Contents of Previous Volumes 328

Textauszug

DNA Topoisomerases as Targets of Therapeutics: An Overview

James C. Wang    Department of Cellular and Molecular Biology, Harvard University, Cambridge, Massachusetts 02138

I History and Classification of DNA Topoisomerases

The genesis of DNA topoisomerases as drug targets illustrates the potential benefit of research motivated by curiosity and curiosity alone. The discovery of the double-helix structure of DNA led immediately to the realization that the separation of two intertwined chains in a long duplex DNA, during replication, for example, might be problematic. Watson and Crick (1953) wrote in one of their epic papers on DNA:

Since the two chains in our model are intertwined, it is essential for them to untwist if they are to separate. As they make one complete turn around each other in 34 Å, there will be about 150 turns per million molecular weight, so that whatever the precise structure of the chromosome a considerable amount of uncoiling would be necessary. It is well known from microscopic observation that much coiling and uncoiling occurs during mitosis, and though this is on a much larger scale it probably reflects similar processes on a molecular level. Although it is difficult at the moment to see how these processes occur without everything getting tangled, we do not feel that this objection will be insuperable.

The mechanical problem of separating two intertwined chains became a topological one a decade later with the discovery of covalently closed circular DNA: duplex DNA rings each made of two intertwined single-stranded rings of complementary nucleotide sequences (Weil and Vinograd, 1963; Dulbecco and Vogt, 1963). In such a molecule, the two single-stranded rings are topologically linked, and therefore cannot come apart without at least one transient break in one of the two strands.

A fundamental parameter describing the order or extent of topological linkage of two intertwined rings is the linking number. Imagine that a duplex DNA ring n base pairs (bp) in contour length is placed flat on a planar surface. The linking number Lk is then the number of times the two single strands revolve around each other (see Appendix I in Volume 29B for a more precise definition and discussions). If the DNA is in its most stable structure, under physiological conditions the right-handed double-helix makes one full turn every 10.5 bp, and therefore its linking number Lk° is expected to be n/10.5; the superscript in the symbol Lk° specifies the most stable or relaxed state of the molecule.

When Lk of a DNA ring is greater or smaller than Lk° for the same molecule, the molecule is strained. Similar to a torsionally unbalanced rope, DNA rings with values of Lk that deviate significantly from the corresponding values of Lk° would often assume contorted forms; because a duplex DNA is made of two coiled chains to begin with, such contorted double-helical molecules are referred to as being supercoiled, superhelical, or supertwisted (Vinograd et al., 1965). Figure 1 depicts electron micrographs of a supercoiled and a relaxed DNA ring.

Fig. 1 Electron micrographs illustrating a relaxed (left) and a supercoiled (right) DNA molecule. The size of the DNA is about 10,000 bp. (From Wang, 1980.)

DNA rings that differ only in their linking numbers are topological isomers, or topoisomers. The linking number of a covalently closed circular DNA cannot be altered without at least transiently breaking one of the two DNA strands; the same holds for interconversion between any pair of topoisomers. In other words, Lk is a topological invariant. Lk°, however, is not. By specifying Lk° as the linking number of the DNA in its most stable structure, the quantity becomes dependent on the experimental conditions, as “the most stable structure” is dependent on the experimental conditions.

The above description sets the stage for the unexpected entrance of the first DNA topoisomerase. It is now widely known that covalently closed DNAs from natural sources are often negatively supercoiled, meaning that Lk is lower than Lk° for such a DNA (Vinograd et al., 1965; Bauer, 1978). When the extent of supercoiling of intracellular coliphage λ DNA was examined, it was found that cell extracts of Escherichia coli contained an activity capable of converting the negatively supercoiled form of λ DNA rings to the relaxed form (Wang, 1969). Initially, it was thought that the activity might be an endonuclease, which, in the presence of excess DNA ligase, would convert the supercoiled form to the relaxed form. Upon purification of the activity, then termed the “ω protein,” it became clear that it represented a new class of enzyme that does both the breakage and rejoining of DNA strands (Wang, 1971). Eight years later, the term “DNA topoisomerase” was coined for an enzyme that catalyzes the inter-conversion of DNA topoisomers (Wang and Liu, 1979), and the E. coli ω protein became E. coil DNA topoisomerase I.

Shortly after the discovery of the E. coli enzyme, an activity capable of relaxing supercoiled DNA was found in mouse cell extracts (Champoux and Dulbecco, 1972); this activity has subsequently been termed mouse DNA topoisomerase I. It turns out that E. coli and mouse DNA topoisomerase I represent two ubiquitous subgroups of DNA topoisomerases. Both are classified as type I DNA topoisomerases, enzymes that break transiently one strand at a time to form a gate for the passage of another strand through it; in terms of their amino acid sequences and reaction mechanisms, however, these two subgroups are rather distinct (see Chapters 2 and 4).

The discovery of type II DNA topoisomerases started with the seminal finding of an ATP-dependent DNA supercoiling activity in E. coli cell extracts (Gellert et al., 1976). During the course of studying site-specific recombination catalyzed by phage λ Int protein, it was observed that the negatively supercoiled DNA substrate could be replaced by the covalently closed relaxed form only if the latter was incubated with a fraction from E. coli cells in the presence of ATP. Purification of the essential activity from this fraction led to the identification of E. coli DNA gyrase, a ubiquitous enzyme subsequently found in all eubacteria. Bacterial gyrase is a member of a family of evolutionarily and structural related DNA topoisomerases; other members of the family include phage T4 DNA topoisomerase (Liu et al., 1979; Stetler et al., 1979) and eukaryotic DNA topoisomerase II (Baldi et al., 1980; Hsieh and Brutlag, 1980).

Several key observations contributed to the realization that the type II enzymes, in addition to their ATP requirement, possess mechanistic features that are distinct from those of their type I cousins. First, it was observed in 1977 that in the presence of nalidixic or oxolinic acid, a quinolone drug that targets bacterial gyrase, the addition of a protein denaturant to the gyrase–DNA complex resulted in the formation of double-stranded breaks in the DNA, with protein molecules covalently linked to the 5′ ends (Sugino et al., 1977; Gellert et al., 1977). Second, several of the type II enzymes were found to catalyze knotting/unknotting and catenation/decatenation of covalently closed double-stranded DNA rings (Kreuzer and Cozzarelli, 1980; Liu et al., 1980; Baldi et al., 1980; Hsieh and Brutlag, 1980). The type I enzymes were known to catalyze knotting/unknotting and catenation/decatenation of single-stranded DNA rings (Liu et al., 1976; Champoux, 1977; Kirkegaard and Wang, 1978), or double-stranded DNA rings with single-stranded nicks or gaps, but not covalently closed duplex rings (Tse and Wang, 1980; Brown and Cozzarelli, 1981). Third, when linking number changes catalyzed by the type II enzymes where quantitated, it was found that they occur in steps of two (Brown and Cozzarelli, 1979; Liu et al., 1980; Hsieh and Brutlag, 1980). All of these results can be explained by the catalysis of the passage of one double-stranded DNA segment through a transient double-stranded DNA break in another, and this feature distinguishes the type II enzymes from the type I enzymes. Within the type II DNA topoisomerase subgroup, only bacterial gyrase can catalyze negative supercoiling, and the other members, in spite of their ATP requirement, can relax negatively or positively supercoiled DNA, but not the reverse action (See Chapters 3 and 5).

II Catalysis of DNA Breakage and Rejoining by DNA Topoisomerases

A remarkable characteristic of type I DNA topoisomerases is that they require no cofactors in their catalysis of topological transformations of DNA. This finding, which was first made in 1971 in the study of purified E. coli...

Produkt-Details

• Erscheint lt. Verlag: 7.11.1994
• Mitarbeit: Herausgeber (Serie): M. W. Anders, J. Thomas August, Joseph T. Coyle, Ferid Murad
• Sprache: englisch
• Themenwelt: Sachbuch/Ratgeber
• Themenwelt: Medizin / Pharmazie ► Medizinische Fachgebiete ► Neurologie
• Themenwelt: Medizin / Pharmazie ► Medizinische Fachgebiete ► Onkologie
• Themenwelt: Medizin / Pharmazie ► Medizinische Fachgebiete ► Pharmakologie / Pharmakotherapie
• Themenwelt: Medizin / Pharmazie ► Medizinische Fachgebiete ► Psychiatrie / Psychotherapie
• Themenwelt: Naturwissenschaften ► Biologie ► Biochemie
• Themenwelt: Naturwissenschaften ► Biologie ► Genetik / Molekularbiologie
• Themenwelt: Naturwissenschaften ► Biologie ► Zellbiologie
• Themenwelt: Naturwissenschaften ► Physik / Astronomie ► Angewandte Physik
• Themenwelt: Technik
• ISBN-10: 0-08-058120-X / 008058120X
• ISBN-13: 978-0-08-058120-0 / 9780080581200