BOOK
Arylamine N-acetyltransferases In Health And Disease: From Pharmacogenetics To Drug Discovery And Diagnostics
(2018)
Additional Information
Book Details
Table of Contents
| Section Title | Page | Action | Price |
|---|---|---|---|
| Contents | v | ||
| Contributors | ix | ||
| Foreword | xiii | ||
| Preface | xix | ||
| Acknowledgements | xxi | ||
| In Memoriam | xxiii | ||
| SECTION 1 Human Arylamine N-Acetyltransferases | 1 | ||
| Chapter 1.1 Drug Metabolism and Pharmacogenetics Then and Now | 3 | ||
| Introduction | 4 | ||
| Identification of Pharmacogenetic Variation in NAT | 4 | ||
| Methods for detection of pharmacogenetic variation | 8 | ||
| Current Knowledge of NAT Genes in Humans | 14 | ||
| NAT2 | 19 | ||
| NAT1 | 19 | ||
| Reaction Mechanism, Substrate Specificity and Basis of Slow Acetylation in Humans | 21 | ||
| Structural studies | 24 | ||
| Tools Available for Study of NAT Proteins | 32 | ||
| Conclusions | 33 | ||
| References | 34 | ||
| Chapter 1.2 The Human Arylamine N-Acetyltransferase Type 2 Gene: Genomics and Cardiometabolic Risk | 43 | ||
| Human Arylamine N-Acetyltransferase 2: An Enzyme for Drug, Carcinogen and Xenobiotic Metabolism | 44 | ||
| NAT2 acetylator phenotype | 45 | ||
| Acetylator phenotype: pharmacogenetic properties | 47 | ||
| Acetyl-CoA-dependent and independent activity | 48 | ||
| NAT2 polymorphisms | 49 | ||
| Tissue and substrate specificity: Enterohepatic circulation | 49 | ||
| Population diversity | 50 | ||
| NAT2 Genomics for Diabetes and Cardiometabolic Diseases | 51 | ||
| NAT2 and GWAS of insulin resistance | 51 | ||
| NAT2 variation: GWAS hits for insulin sensitivity | 52 | ||
| Association with other glycemic traits, triglyceride and coronary artery disease risk | 56 | ||
| Glucose homeostasis and diabetic risk | 56 | ||
| Body detoxification capacity and urine metabotypes | 57 | ||
| Advanced glycation end products and skin fluorescence | 57 | ||
| NAT2 Functional Genomics | 59 | ||
| Structural and functional evaluation of NAT2 variants | 59 | ||
| (MOUSE)Nat1-knockout mice | 59 | ||
| (MOUSE)Nat1-KO mice develop insulin resistance and mitochondrial dysfunction | 60 | ||
| Genetic manipulation of NAT2 in the CRISPR era | 61 | ||
| NAT2: a potential therapeutics target for the treatment of insulin resistance | 62 | ||
| Concluding Remarks | 62 | ||
| References | 63 | ||
| Chapter 1.3 Human Arylamine N-Acetyltransferase Type 2: Phenotypic Correlation with Genotype-A Clinical Perspective | 69 | ||
| Human Arylamine N-Acetyltransferase 2: Phenotypic Correlation with Genotype; A Clinical Perspective | 70 | ||
| NAT2 Pharmacogenomics Information Can be Used at Diverse Levels | 71 | ||
| The Challenges of NAT2 Phenotype Inference | 72 | ||
| Procedures for Inferring NAT2 Phenotype from Genotype | 72 | ||
| Refinement in Phenotype Inference: Functional Heterogeneity of Slow-NAT2 Alleles | 77 | ||
| Clinical Perspective | 78 | ||
| Acknowledgements | 85 | ||
| References | 85 | ||
| Chapter 1.4 Human Arylamine N-Acetyltransferase Type 1 | 91 | ||
| Human NAT1 Overview | 91 | ||
| Endogenous Role of NAT1 | 92 | ||
| Folate and methionine metabolism | 92 | ||
| Cell growth and survival | 97 | ||
| Cancer cell biology | 99 | ||
| NAT1 as a Cancer Biomarker and Novel Therapeutic Target | 102 | ||
| Conclusion | 104 | ||
| References | 105 | ||
| Chapter 1.5 Arylamine N-Acetyltransferases in Normal and Abnormal Embryonic Development\r | 109 | ||
| Introduction | 110 | ||
| Expression of NATs during Human Embryogenesis | 111 | ||
| Role of NATs in Murine Embryonic Development | 111 | ||
| Consequences of deleting (MOUSE)Nat2 | 112 | ||
| Consequences of overexpressing (HUMAN)NAT1 on murine development | 118 | ||
| Birth defects in (MOUSE)Nat2 knockouts and (HUMAN)NAT1 transgenic mouse models | 119 | ||
| Role of (HUMAN)NAT1/(MOUSE)NAT2 in Critical Homeostatic Processes | 121 | ||
| NATs and Human Susceptibility to Birth Defects | 123 | ||
| Transcriptional and Epigenetic Control of NAT Expression | 126 | ||
| Conclusions | 128 | ||
| Acknowledgements | 128 | ||
| References | 129 | ||
| Chapter 1.6 Expression and Activity of Arylamine N-Acetyltransferases in Organs: Implications on Aromatic Amine Toxicity | 133 | ||
| NAT Expression in Humans | 134 | ||
| Introduction | 134 | ||
| NAT genes and transcripts | 135 | ||
| Protein expression | 137 | ||
| NAT mediated reactions | 138 | ||
| Methods to measure NAT1 and NAT2 activities | 138 | ||
| NAT genetic polymorphisms | 140 | ||
| Toxicological Implications | 141 | ||
| Uptake of AAs and HAAs and principles of their metabolic transformation | 141 | ||
| NAT Expression at the Primary Exposure Sites Skin | 144 | ||
| Lung | 146 | ||
| Intestine | 147 | ||
| NAT Expression and Activity in Liver | 149 | ||
| NAT Expression in Peripheral Blood | 150 | ||
| NAT Expression and Activity in the Excretion Organs | 151 | ||
| Bladder | 151 | ||
| Intestine | 153 | ||
| NAT Expression and Activity in Breast | 153 | ||
| NAT Expression and Activity in the Prostate | 155 | ||
| NAT Expression and Activity in the Nervous System | 156 | ||
| NAT Expression and Activity in Human Embryonic Development | 156 | ||
| Concluding Remarks | 157 | ||
| References | 157 | ||
| Chapter 1.7 Arylamine N-Acetyltransferases in Anthropology | 165 | ||
| Introduction | 166 | ||
| The Human Acetylation Polymorphism: A Historical Perspective | 167 | ||
| Patterns of Genetic Diversity and Haplotype Structure at NAT Loci | 168 | ||
| NAT2 | 168 | ||
| NAT1 | 178 | ||
| NATP | 184 | ||
| Determining the Role of Natural Selection in Shaping Genetic Variation at NAT Loci | 185 | ||
| Future Prospects | 189 | ||
| References | 190 | ||
| SECTION 2 Arylamine N-Acetyltransferases in Other Eukaryotic Organisms | 195 | ||
| Chapter 2.1 The Genomics and Evolution of Arylamine N-Acetyltransferases in Animals | 197 | ||
| Introduction | 198 | ||
| NATs in the Lower Taxonomic Ranks of Metazoa | 199 | ||
| NATs in Vertebrates | 201 | ||
| NATs in Mammals | 202 | ||
| NATs in Primates | 213 | ||
| The Evolutionary History of Animal NATs | 216 | ||
| Molecular evolution of NATs in vertebrates | 217 | ||
| Molecular evolution of NATs in primates | 218 | ||
| Spatial variation of selective pressures along the NAT protein sequence | 222 | ||
| Future Prospects | 223 | ||
| Acknowledgements | 223 | ||
| References | 223 | ||
| Chapter 2.2 Genetically Modified NAT Mouse Models | 231 | ||
| Introduction | 232 | ||
| The Mouse NAT Acetylation Polymorphism | 234 | ||
| NAT Mutation and Knockout Mouse Models | 236 | ||
| ‘Humanised’ NAT Transgenic Mouse Models | 238 | ||
| The Role of NATs in Chemically-Induced Mouse Liver Tumourigenesis | 243 | ||
| Elucidation of Potential Endogenous Roles for NATs | 245 | ||
| Conclusions | 250 | ||
| Acknowledgements | 250 | ||
| References | 250 | ||
| Chapter 2.3 Arylamine N-Acetyltransferases in Eukaryotic Microorganisms | 255 | ||
| Background | 256 | ||
| The Distribution and Phylogeny of Microbial NATs | 257 | ||
| NAT Genes in Eukaryotic Microorganisms | 260 | ||
| NAT genes in protists | 260 | ||
| NAT genes in fungi | 262 | ||
| The Roles of Fungal NATs | 266 | ||
| NATs in plant-associated fungi — Implications for agriculture | 266 | ||
| NATs in biodegrading fungi — Implications for bioremediation | 272 | ||
| Enzyme functions of fungal NATs | 274 | ||
| Concluding Remarks | 278 | ||
| Acknowledgements | 278 | ||
| References | 278 | ||
| SECTION 3 Arylamine N-Acetyltransferases in Prokaryotic Organisms | 283 | ||
| Chapter 3.1 Bacterial Arylamine N-Acetyltransferases: From Structures to Applications | 285 | ||
| Early Studies on Bacterial NAT | 286 | ||
| Structural and Mechanistic Features of Bacterial NAT Enzymes | 288 | ||
| Three-dimensional structures of bacterial NATs | 288 | ||
| Interaction with substrates | 292 | ||
| Catalytic mechanisms | 293 | ||
| From Functions to Applications | 294 | ||
| Involvement of bacterial NATs in drug resistance | 294 | ||
| Bacterial NATs as putative drug targets | 296 | ||
| Possible use of bacterial NAT as remediation tools | 296 | ||
| Concluding Remarks | 297 | ||
| Acknowledgement | 297 | ||
| References | 297 | ||
| Chapter 3.2 Arylamine N-Acetyltransferase in Mycobacteria | 303 | ||
| Endogenous Role of Arylamine N-Acetyltransferase in Mycobacteria | 304 | ||
| Genomic Organisation of Arylamine N-Acetyltransferase Gene Clusters in Mycobacteria\r | 307 | ||
| The nat Gene Network Regulation and Effect on the Endogenous Functions | 311 | ||
| Structural Aspects of Arylamine N-Acetyltransferases in Mycobacteria | 315 | ||
| Validation of Arylamine N-Acetyltransferase in M. tuberculosis as Novel Therapeutic Target | 318 | ||
| Concluding Remarks | 319 | ||
| References | 320 | ||
| SECTION 4 Arylamine N-Acetyltransferases and Disease | 325 | ||
| Chapter 4.1 Arylamine N-Acetyltransferase Type 2 Polymorphism and Human Urinary Bladder and Breast Cancer Risks | 327 | ||
| Introduction | 328 | ||
| NAT2 Polymorphism and Urinary Bladder Cancer Risk | 329 | ||
| NAT2 Polymorphism and Breast Cancer Risk | 333 | ||
| Conclusions | 343 | ||
| References | 347 | ||
| Chapter 4.2 Human Arylamine N-AcetyltransferaseType 1 and Breast Cancer | 351 | ||
| The Pharmacological Roles of (HUMAN)NAT1 | 352 | ||
| Overexpression of (HUMAN)NAT1 in Breast Cancer Cells | 353 | ||
| Breast cancer: Incidence and stratification | 353 | ||
| Microarray and proteomic analyses of breast cancer tissues | 355 | ||
| Studies utilising human breast cancer cell lines in vitro | 357 | ||
| Genetic Hypotheses | 361 | ||
| The Putative Physiological Role of (HUMAN)NAT1 in Breast Cancer | 363 | ||
| Challenges in Breast Cancer Diagnosis and Therapy | 364 | ||
| Utilising Chemical Genetics (Pharmacological Inhibition) to Target (HUMAN)NAT1 | 365 | ||
| Identification of (HUMAN)NAT1 Inhibitors | 366 | ||
| Identification of (HUMAN)NAT1 inhibitors using a high-throughput screening approach | 368 | ||
| Rhodanine analogues as (HUMAN)NAT1 inhibitors | 372 | ||
| Naphthoquinones as (HUMAN)NAT1 inhibitors | 372 | ||
| Identification of (HUMAN)NAT1 inhibitors using a virtual screening approach | 375 | ||
| Future Directions | 377 | ||
| References | 379 | ||
| Chapter 4.3 Mycobacterial Arylamine N-Acetyltransferases and Tuberculosis | 385 | ||
| Introduction | 386 | ||
| Development of NAT Inhibitors | 390 | ||
| NAT activity assay | 390 | ||
| High-throughput screening for NAT inhibitors | 391 | ||
| NAT Inhibitors and their Development as Potential Anti-tuberculars | 392 | ||
| Triazoles | 395 | ||
| Piperidinols | 398 | ||
| 3,5-diaryl-1H-pyrazoles | 403 | ||
| β-amino alcohols | 403 | ||
| TZD-sultam | 404 | ||
| ElectroShape-Based Screening for NAT Inhibitors | 404 | ||
| Conclusions/Future Directions | 405 | ||
| References | 406 | ||
| Epilogue Arylamine N-Acetyltransferase Nomenclature | 411 | ||
| Background | 412 | ||
| The History and Current Status of NAT Nomenclature | 412 | ||
| The Future of NAT Nomenclature | 416 | ||
| Concluding Remarks | 418 | ||
| Acknowledgements | 418 | ||
| References | 419 | ||
| Index | 421 |