| Contributors | p. xiii |
| Preface | p. xvii |
| Folate-Mediated One-Carbon Metabolism | p. 1 |
| Overview | p. 2 |
| Introduction to Cytoplasmic One-Carbon Metabolism | p. 4 |
| Introduction to Mitochondrial One-Carbon Metabolism | p. 24 |
| Nuclear Folate-Mediated One-Carbon Metabolism | p. 28 |
| Acknowledgments | p. 29 |
| References | p. 29 |
| Mathematical Models of Folate-Mediated One-Carbon Metabolism | p. 45 |
| Introduction | p. 46 |
| Structure and Function of the Cycles | p. 49 |
| Why Mathematical Modeling? | p. 51 |
| Model Development | p. 61 |
| Blood Versus Intracellular Metabolite Concentrations | p. 66 |
| Modeling Gene-Gene and Gene-Environment Interactions | p. 67 |
| Modeling and Simulation have Revealed Novel Homeostatic Mechanisms | p. 70 |
| Steady States and Fluctuations | p. 75 |
| Conclusions | p. 77 |
| Acknowledgments | p. 78 |
| References | p. 78 |
| Folate Deprivation, the Methionine Cycle, and Alzheimer's Disease | p. 83 |
| Introduction | p. 84 |
| Folate Metabolism, the Transmethylation Pathway, and AD | p. 85 |
| The Transsulfuration Pathway-Homocysteine Elimination and Glutathione Metabolism | p. 90 |
| References | p. 94 |
| Molecular Mechanisms of Adaptation to Folate Deficiency | p. 99 |
| Folate Metabolism | p. 101 |
| Pathological States Associated with Folate Deficiency or Nutritional Folate Insufficiency | p. 105 |
| Molecular Mechanisms of Adaptation to Folate Deprivation | p. 108 |
| References | p. 131 |
| Structure and Function of the Reduced Folate Carrier: A Paradigm of a Major Facilitator Superfamily Mammalian Nutrient Transporter | p. 145 |
| Introduction | p. 146 |
| MFS of Transporters | p. 147 |
| Folate Transport in Tissue Folate Homeostasis and Physiology: Role of Multiple Transport Systems for Folate Uptake and Efflux | p. 150 |
| Role of RFC in Antifolate Chemotherapy | p. 152 |
| Functional Properties of RFC | p. 154 |
| Biochemistry of RFC | p. 156 |
| Cloning of RFC cDNAs That Restore Transport to Transport-Impaired Cultured Cells | p. 158 |
| Topological Structure of RFC | p. 159 |
| Insights into Structural and Functional Determinants of RFC from Studies of Mutant RFC Poteins | p. 164 |
| Conclusions | p. 173 |
| Acknowledgment | p. 175 |
| References | p. 175 |
| Renal Conservation of Folates: Role of Folate Transport Proteins | p. 185 |
| Introduction | p. 186 |
| Physicochemical Properties, Protein Binding, and Water Solubility | p. 186 |
| Role of Folates in Genomic Stability | p. 188 |
| Folates and the Kidney | p. 188 |
| Folate Transport Proteins | p. 189 |
| Localization of Putative Folate Transporters in Kidney | p. 192 |
| Clinical Studies of Renal Handling of Folates and Antifolates | p. 193 |
| Role of Renal Folate Conservation in Ethanol-Related Folate Deficiency | p. 196 |
| Role of Folate Transport Processes in Renal Conservation of Folates and Antifolates | p. 197 |
| References | p. 198 |
| Exploitation of the Folate Receptor in the Management of Cancer and Inflammatory Disease | p. 203 |
| Introduction | p. 204 |
| Aspects of the FR | p. 205 |
| Exploitation of the FR for Disease Management | p. 208 |
| Future Prospects | p. 225 |
| References | p. 226 |
| Folate Receptor Expression in Pituitary Adenomas: Cellular and Molecular Analysis | p. 235 |
| Introduction | p. 236 |
| Methods | p. 238 |
| Result | p. 242 |
| Discussion | p. 259 |
| Acknowledgments | p. 263 |
| References | p. 263 |
| Regulation of Human Dihydrofolate Reductase Activity and Expression | p. 267 |
| Introduction | p. 268 |
| Structure and Binding of Dihydrofolate, MTX, and NADPH | p. 269 |
| Mechanism of DHFR Catalysis | p. 272 |
| Alternative Substrates: Folic Acid and Dihydrobiopterin | p. 273 |
| Genomic Organization of DHFR | p. 274 |
| Human Dihydrofolate Reductase Pseudogenes | p. 276 |
| Transcriptional Regulation | p. 276 |
| Polymorphisms of DHFR | p. 280 |
| Posttranscriptional Regulation of DHFR | p. 283 |
| Translational Regulation of DHFR | p. 283 |
| Acknowledgments | p. 287 |
| References | p. 287 |
| Catalysis of Methyl Group Transfers Involving Tetrahydrofolate and B[subscript 12] | p. 293 |
| Introduction to Methyltransferases and Their Cofactors | p. 294 |
| Three Component Systems Required for B[subscript 12]/THF-Dependent Methyltransferases | p. 296 |
| Biological Systems Impacted by B[subscript 12] and Folate-Dependent Methyltransferases | p. 297 |
| Structure and Function of B[subscript 12] in Methyltransferases | p. 301 |
| Activation of the Methyl Group Donors | p. 307 |
| Activation of the Methyl Group Acceptors: Zn Thiolates and NiFeS Clusters | p. 314 |
| Acknowledgments | p. 317 |
| References | p. 317 |
| Methyltetrahydrofolate in Folate-Binding Protein Glycine N-Methyltransferase | p. 325 |
| Introduction | p. 326 |
| 5-Methyltetrahydrofolate in Folate Metabolism | p. 326 |
| Folate-Binding Enzymes | p. 330 |
| Glycine N-Methyltransferase | p. 331 |
| GNMT as Methyltetrahydrofolate-Binding Protein | p. 335 |
| Conclusions | p. 340 |
| Acknowledgments | p. 341 |
| References | p. 341 |
| Mechanism-Based Inhibitors of Folylpoly-[gamma]-Glutamate Synthetase and [gamma]-Glutamyl Hydrolase: Control of Folylpoly-[gamma]-Glutamate Homeostasis as a Drug Target | p. 347 |
| Introduction | p. 348 |
| Folylpoly-[gamma]-Glutamate Homeostasis as a Drug Target | p. 350 |
| Design of Fluoroglutamate-Containing Folates and Antifolates as FPGS or GH Alternate Substrates and/or Inhibitors | p. 354 |
| Synthesis of Fluorine-Containing Folates and Antifolates from the Corresponding Fluoroglutamates and Related Fluoroamino Acids | p. 356 |
| Design of Phosphorus-Containing Pseudopeptides as FPGS Inhibitors | p. 361 |
| Design of Epoxide-Containing Peptidomimetics as GH Inhibitors | p. 366 |
| Conclusions | p. 366 |
| Acknowledgment | p. 367 |
| References | p. 367 |
| Methylenetetrahydrofolate Reductase, Common Polymorphisms, and Relation to Disease | p. 375 |
| Introduction | p. 376 |
| Conclusions | p. 386 |
| References | p. 386 |
| Mitochondrial Methylenetetrahydrofolate Dehydrogenase, Methenyltetrahydrofolate Cyclohydrolase, and Formyltetrahydrofolate Synthetases | p. 393 |
| Introduction | p. 394 |
| Yeast Mitochondria Contain a Trifunctional Dehydrogenase-Cyclohydrolase-Synthetase | p. 395 |
| Mammalian Mitochondrial Methylenetetrahydrofolate Dehydrogenase | p. 395 |
| Mitochondrial Formyltetrahydrofolate Synthetase | p. 403 |
| Conclusion | p. 405 |
| References | p. 408 |
| The Structure and Mechanism of 6-Hydroxymethyl-7, 8-Dihydropterin Pyrophosphokinase | p. 411 |
| Introduction | p. 412 |
| Structural and Mechanistic Studies on EcoHPPK | p. 413 |
| Structures of HPPKs from Other Organisms | p. 421 |
| Kinetics | p. 424 |
| Relationship of HPPK to Other Pyrophosphoryl Transfer Enzymes | p. 426 |
| Concluding Remarks | p. 429 |
| References | p. 430 |
| Index | p. 435 |
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