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Arylamine N-acetyltransferases In Health And Disease: From Pharmacogenetics To Drug Discovery And Diagnostics

Arylamine N-acetyltransferases In Health And Disease: From Pharmacogenetics To Drug Discovery And Diagnostics

Sim Edith | Laurieri Nicola


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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