Tetrahydrobiopterin Deficiency. Analysis from an International Survey

Chapters in this book

1. Frontmatter I
2. Preface V
3. Acknowledgments VII
4. Contents IX
5. How it all Began: A Brief History of the Pteridine Symposia 1
6. The Gowland Hopkins Lecture: The Mechanisms of Action of Folate and Pterin Requiring Enzymes 13
7. Section A: Chemistry of Pterins and Folates
8. Side-Chain Chemistry of Pteridines 31
9. A General Method for the Synthesis of 10-Substituted-10-Deaza Folate Analogues 45
10. Synthesis and Properties of Pyrimidodiazepines as Ring-Strained Probes of Pterin Utilizing Enzymes 51
11. Summary: Pterin and Folate Chemistry 55
12. A Facile Method for Preparing 2,4-Diamino-5,8-Dideazapterins 57
13. Synthesis of 5,10-Dideaza-5,6,7,8-Tetrahydrofolic Acid (DDATHF) and Analogs 61
14. Synthetic Routes to Methotrexate- and Folic Acid-Polyglutamates of High Chemical and Enantiomeric Purity 65
15. In Vivo and In Vitro Evaluations of 5-[4-(Substituted Aryl)-1- Piperazinyl]-6-Alkyl-2,4-Pyrimidinediamines as Antitumor Agents 69
16. The Electrochemical Oxidation of Tetrahydropterin Derivatives 73
17. A Practical Synthesis of (6R)- and (6S)-5,6,7,8-Tetrahydrobiopterins 77
18. Chemical Synthesis and Properties of Quinonoid (6R)-Dihydrobiopterin 81
19. Pyrazine-Ring Conformations of Tetrahydropterins and Quinonoid-Dihydropterins 85
20. Hydrogenation of Silylated Pterins in Benzene Solution 91
21. N(5)-Alkylation of Polyacetylated 5,6,7,8-Tetrahydroneopterins 95
22. Oxidations Photosensitized by Pterins and Diaminopteridines 99
23. Structure of the Riboflavin Synthase/Lumazine Synthase Complex. Arrangement and Chain Folding of Subunits in the Icosahedral Capsid 103
24. Use of C18 Silica Cartridges to Purify and Characterize Pterins 107
25. Synthesis and Structure-Activity Relationships of Tetrahydrobiopterin Cofactor Analogues 111
26. Synthesis, Purification and Properties of a New Class of Pteridine Derivatives 115
27. Summary: Chemistry of Pterins 121
28. Section B: Biosynthesis and Biochemistry of Pterins
29. Biosynthesis of Tetrahydrobiopterin and Related Compounds in Drosophila melanogaster 125
30. Tetrahydrobiopterin Biosynthesis in Man 141
31. The Biosynthesis of Tetrahydrobiopterin in the Bovine Adrenal Medulla 151
32. The Biosynthesis of Tetrahydrobiopterin in Rat Brain 169
33. Summary: Biosynthesis of Tetrahydrobiopterin 183
34. The Metabolic Role of Tetrahydrobiopterin 185
35. Spectroscopic Studies on Tyrosine 3-Monooxygenase from Bovine Adrenal Medulla: A Blue Iron Protein 201
36. Queuine-Lacking tNRAs in Relation to the Grade of Malignancy of Specific Tumors, Possible Role of Pteridines 205
37. Pteridine Synthesis During Interaction of Interleukin 2 with T Lymphocytes - Modulator Function in IL-2 Signal Transmission 209
38. Section C: Biology of Pterins
39. Dopamine Neurons in Culture: A Model System for Examination of Neuronal Biopterin Metabolism 215
40. Role of the Pituitary in the Regulation of Tetrahydrobiopterin Biosynthesis in the Non-Neuronal Tissues 219
41. Distribution of GTP Cyclohydrolase-I, Neopterin, and Biopterin in the Human Brain 223
42. Enzymatic Synthesis of 6,7-Dimethyl-8-Ribityllumazine 227
43. A Model for Hyperphenylal aninaemia Due to Tetrahydrobiopterin Deficiency 231
44. The Effect of Biopterin and its Reduced Derivatives on Cultured Human Lymphocytes 235
45. Developmental Aspects of Biopterin Metabolism in Human 239
46. Screening for Biopterin Defects Among Hyperphenylalaninemic Patients: Report of a Canadian Program After 3 Years 243
47. Need for Therapy in utero of Fetuses with Tetrahydrobiopterin Deficiency 247
48. Pteridine Metabolism in Patients Suffering from Amyotrophic Lateral Sclerosis 251
49. Urinary Neopterin in Cocaine-Abusing Individuals 257
50. Features of Neopterin Determination in Clinical Use 263
51. Diurnal Variation in Urinary Pterin Excretion in Man 267
52. The Relationship between Pteridines and Colour Dimorphism in the Scorpion Fly 271
53. Pteridine Biosynthesis and Manifestation of Pigment Phenotypes in Normal and Neoplastic Cells of Goldfish in Vitro 275
54. Light Depending Regulations of Pteridines in the Retina 279
55. Differences in the Regulation of Tetrahydrobiopterin Biosynthesis in Neuronal Cells in Culture 283
56. NADPH- and NADH-Specific Dihydropteridine Reductase in Teratocarcinoma Cells in Culture: Effect of Nerve Growth Factor Treatment of the Cells on the Enzyme Activities 287
57. Reversibility of α-Diketo Reductase Activity by Sepiapterin Reductase 291
58. Non-Enzymatic Synthesis of "Drosopterins" from Dihydropterin and 2-Amino-4-0xo-6-Acetyl-3H, 9H-7,8-Dihydropyrimido [4,5b] [1,4]Diazepine 295
59. BH4 Biosynthesis: ¹H-NMR Evidence for the Pyruvoyl-Tetrahydropterin-Synthase Catalyzed Formation of 6-Pyruvoyl-Tetrahydropterin from Dihydroneopterin Triphosphate 299
60. Catabolism of Tetrahydrobiopterin in Man 305
61. Pteridine Biosynthesis in Human Amniocytes and Chorionic Villi 309
62. The Role of the Kidney in Biopterin Metabolism 315
63. Tetrahydrobiopterin-Producing Enzyme Activities in Liver of Animals and Man 319
64. Effect of 3-Hydroxykynurenine on GTP Cyclohydrolase Activity and on the Pteridine Pattern in Drosophila melanogaster 323
65. Tetrahydrobiopterin Metabolism in Normal Brain, Senile Dementia of the Alzheimer Type and Down's Syndrome 327
66. Summary: Biology of Pteridines 331
67. Biosynthesis of Pteridines and Metabolism of Aromatic Amino Acids in Drosophila melanogaster 335
68. The Inhibition of tRNA Transglycosylases by Pteridines as a Mean for Metabolic Control of Gene Expression 339
69. Modulation of Dopamine Synthesis by Nerve Terminal Autoreceptors: A Role for Tetrahydrobiopterin? 347
70. A Monoclonal Antibody Reacting with All Three Aromatic Amino Acid Hydroxylases 351
71. Alterations in Cofactor-Dependent Activity of Phenylalanine Hydroxylase as a Function of pH 355
72. Interaction of a Monoclonal Antibody with Rat Liver Phenylalanine Hydroxylase 359
73. The Effect of Dietary Iron on the Activity of Rat Liver Phenylalanine Hydroxylase 363
74. Strict Requirement of Fe²⁺ for Tryptophan 5-Monooxygenase from Mouse Mastocytoma, P-815 369
75. Tetrahydrobiopterin and the Regulation of Catecholamine Synthesis in Bovine Adrenal Medullary Chromaffin Cells 373
76. Cofactor Activity of Tetrahydropterins for Tyrosine Hydroxylation in PC12 Pheochromocytoma Cells 377
77. Summary: Pterin-Dependent Biological Reactions 381
78. Tetrahydrobiopterin Deficiency. Analysis from an International Survey 385
79. Cofactor Specificity of 6,6-Disubstituted Tetrahydropterins, and their Potential in the Treatment of Neurological Disorders 391
80. Normal Concentrations of Tetrahydrobiopterin in the Cerebrospinal Fluid of Patients with Dihydropteridine Reductase Deficiency 395
81. Prenatal Diagnosis of Tetrahydrobiopterin Deficiency 399
82. Defective Biopterin Biosynthesis in a Chinese Infant 403
83. Correlation of Dihydropterine Reductase Cross Reacting Material with Non-Responsiveness to a Tetrahydrobiopterin Load 407
84. Neopterin and Dihydroneopterins in Serum of Controls and Patients with Various Diseases. Circadian Rhythm of Neopterin. Influence of Cortisol? 411
85. Neopterin Content and GTP-Cyclohydrolase Activity of Blood Cells of Controls and Patients Positive for LAV/HTLV-III Antibodies 415
86. Neopterin in Bone Marrow Transplant Monitoring: An Improvement in its Use for GVHD Diagnosis 419
87. Importance of Neopterin Determination in Individuals at Risk for AIDS 427
88. Biochemical Aspects of Pteridines During Interaction Between Activated T-Lymphocytes and Monocytes/Macrophages in Patients 431
89. Summary: Pterins and Human Illness 443
90. Section D: Folates and Pterins in Mammalian Tissues
91. Folates in Tissues and Cells. Support for a "Two-Tier" Hypothesis of Regulation of One-Carbon Metabolism 447
92. Elevation in the Rate of Cellular Folate Catabolism in Mid-Pregnancy in the Rat 467
93. The Red Blood Cell as a Storage Site for Folic Acid 471
94. Methotrexate and Biopterin Levels in Blood Following Low Dose Administration for Psoriasis 475
95. Summary: Folates in Tissue and Cells 479
96. Folate Rescue of N₂O-Induced Inhibition in Murine Lymphocytes 481
97. Folate Absorption and Metabolism in Alcohol Fed Rats 485
98. Chronic and Acute Effects of Ethanol on Renal Clearance and Urinary Excretion of Folate in Rats 489
99. Effect of Chronic Anticonvulsant Treatment on Folate Concentrations in the Rat 495
100. Alcohol Induced Methyl Group Wastage as a Possible Cause of Fatty Liver 505
101. Folate Catabolism in the Syrian Golden Hamster 509
102. The Level of Folate Catabolism in Normal Human Populations, Suggesting that the Current Level of RDA for Folate is Excessive 513
103. Microdetermination of Folate Monoglutamates in Serum by High-Performance Liquid Chromatography with Electrochemical Detection 517
104. Folate Status in Psychiatric Patients: Relationship with CSF Neurotransmitter Metabolites 523
105. Folate, Thiamine and Vitamin B₁₂ Levels in Outpatient Epileptics 527
106. Effect of Aspirin Ingestion on Folate Bioavailability Evaluated by Rat Liver Bioassay 531
107. Brush Border Pteroylpolyglutamate Hydrolase in Pig Jejunum 539
108. Use of CI-920 in the Characterization of the Methotrexate Transport Defect in a Resistant Human Leukemic CCRF-CEM Cell Line 543
109. The Effect of Oxidative Stress on Methotrexate (MTX) Transport by Rat Hepatocytes 547
110. Folate Transport by Pig Intestinal Brush Border Vesicles 551
111. Depressed Folate Transfer Across the Mammary Gland Secondary to Iron Deficiency in the Rat 555
112. Studies on the Mechanism of Folate Transport in Isolated Hepatocytes 559
113. Analysis of the pH and Na₊ Dependence of Intestinal Folate Transport 563
114. Intestinal Transport of Folate. Characterization of the Transport Events at the Brush Border and the Basolateral Membranes 567
115. The Synthesis of Some Novel Probes of Folate Transport and Binding 571
116. Photoaffinity Probes of Dihydrofolate Reductase and of the Membrane Carrier for Folate Analogues 575
117. The Use of Biosynthetic Radioactive Folylpolyglutamates to Study Intestinal Digestion and Absorption of Folate 579
118. Selective Inhibition of Bacterial Carboxypeptidase G and Pancreatic Conjugase by 2-Mercaptomethylglutaric Acid 583
119. Summary: Folate Absorption and Transport 587
120. Studies on Glycine-N-Methyltransferase 593
121. Folate Binding Protein from Pediococcus Cerevisiae Strains Possessing Active Transport Systems for Folates 597
122. Immobilized Folate Binding Protein from Cow's Milk Used for Quantitation of Folate 603
123. Characterization of Rabbit Antibodies Against the Folate Binding Protein from Cow's Milk 607
124. Section E: Enzymology of Folates
125. 1. Thymidylate Synthase
126. Genetic and Chemical Studies on Thymidylate Synthase 613
127. Active Site Probes of Thymidylate Synthetase 631
128. Resonance-Raman Spectroscopic Identification of the Transient Intermediates Formed in the Native Ternary Complex with Thymidylate Synthase 639
129. The Reversal of the Cytotoxicity of Folate-Based Thymidylate Synthase Inhibitors in Cultures L1210 Cells 645
130. Thymidylate Synthase Activity in the Tapeworm, Hymenolepis diminuta 651
131. Identification of Poly G Bound to Thymidylate Synthase 655
132. Methotrexate Derivates of Deoxyuridylate Showing Inhibitory Properties for Thymidylate Synthetase from Lactobacillus casei 659
133. Comparison of Thymidylate Synthase Isolated from Mouse Normal and Tumour Tissues 663
134. Thymidylate Synthase Interaction with Analogues of dUMP and 5-Fluorid- 2'-Deoxyuridine-5'-Phosphate with Modified Phosphate Groups 667
135. An In Vitro System for Studies on Inhibition of the Thymidylate Cycle 671
136. N¹⁰-Propargyl-5,8-Dideazafolic Acid Polyglutamates as Inhibitors of Thymidylate Synthase and their Intracellular Formation 675
137. Sequential CMF in Metastatic Breast Cancer: An Attempt to Increase Effectiveness by Means of Biochemical Modulation 681
138. Model Studies of Thymidylate Synthase Reaction 687
139. Synergistic Interaction Between Folinic Acid and the Fluoropyrimidines 691
140. 2. Methionine Biosynthesis
141. Methionine Biosynthesis 697
142. Impaired Formylation and Uptake of Tetrahydrofolate by Rat Small Gut Following Cobalamin Inactivation 709
143. Heterogeneity in Functional Methionine Synthase Deficiency 713
144. Summary: Methionine Biosynthesis 717
145. 3. Folyl Polyglutamate Synthetase
146. Folylpoly-γ-glutamate Synthetase 719
147. Cytotoxic Effects and Inhibition of Folylpolyglutamate Synthetase by Folate Analogs Containing 2, Omega-Diaminoalkanoic Acids 729
148. An Upstream Gene Regulates the Expression of Folylpolyglutamate Synthetase-Dihydrofolate Synthetase in Escherichia coli 733
149. Occurence and Synthesis of Pteroyl-γ-glutamyl-γ-glutamyl-poly-α-glutamates in Escherichia coli 737
150. Summary: Folylpolyglutamate Synthesis 741
151. The Metabolism of Pteroylpolyglutamates 743
152. Dihydropteroyl Hexaglutamate and T4 Phage Baseplate Assembly 757
153. Effects of Polyglutamylation on Folate Cofactor and Antifolate Activity in the Thymidylate Synthase Cycle of Permeabilized Murine Leukemia L1210 Cells 763
154. Summary: Pteroylpolyglutamate metabolism 767
155. 4. Dihydrofolate Reductase
156. Recent Advances in the Study of Dihydrofolate Reductase 769
157. The 2.8 Å Structure of a Type II Plasmid Encoded Dihydrofolate Reductase 789
158. Mutations in the Human Dihydrofolate Reductase 793
159. Theoretical Studies of the Structure, Conformational and Electronic Properties of Anticancer Folate Inhibitors 799
160. Binding of Inhibitors with Spin-Labeled Side Chains to Dihydrofolate Reductase (DHFR) from Several Species 803
161. Affinity Labeling of Dihydrofolate Reductase with an Iodoacetyl Lysine Analogue of Methotrexate 807
162. Escherichia coli Dihydrofolate Reductase Isolated as a Folate Complex 811
163. Dihydrofolate Reductase from Soybean Seedlings 815
164. Use of Antibodies as Structural Probes of Dihydrofolate Reductases and Enzyme-Ligand Complexes 819
165. Cooperativity in Inhibitor Binding to Neisseria gonorrhoeae Dihydrofolate Reductase 823
166. pH Studies of the Reaction Catalyzed by Dihydrofolate Reductase from E. coli 827
167. Effects of pH on Reactions Catalyzed by Dihydrofolate Reductase from Chicken Liver 831
168. Unconjugated Dihydropterin Substrates for Bovine Liver Dihydrofolate Reductase 835
169. Enzymatic Characterization of Recombinant Human Dihydrofolate Reductase Produced in E. coli 839
170. Levels of Folates and Methotrexate Polyglutamate Formation in Chinese Hamster Ovary Cells Lacking Dihydrofolate Reductase 843
171. Methotrexate in Adjuvant Arthritis 847
172. Computer Graphic Modeling in Drug Design: Conformational Analysis and Active-Site Modeling of Lipophilic Diaminopyrimidines 851
173. Effect of Antifolates 10-Methyl- and 10-Ethyl-10-Deaza-Aminopterin on a Human Breast Cancer Cell Line 855
174. Biochemical and Cytotoxic Effects of the Erythro- and Threo-Isomers of Gamma-Fluoro-Methotrexate 861
175. 5. Other Folate Enzymes
176. C₁-Tetrahydrofolate-Synthase, a Multifunctional Enzyme Involved in Purine Metabolism, and its Related Monofunctional Enzymes 865
177. The Interaction of Tetrahydropteroylpolyglutamates with 10-Formyltetra-Hydrofolate Synthetase 887
178. Summary: Folates in C 1 Metabolism 891
179. Chemical Aspects of Dimethylglycine Dehydrogenase and Sarcosine Dehydrogenase 893
180. Folate Normalizes Elevated PRPP Levels of Folate-Deficient HL-60 Cells 897
181. Stereochemistry of Hydride Transfer to NADP+ by Methylene Tetrahydrofolate Dehydrogenase from Pig Liver 901
182. The Effects of Thyroxine Status on Hepatic Levels of 10-Formyltetrahydrofolic Acid: NADP Oxidoreductase 905
183. Interaction of Homocysteine with Methionine Synthetase 909
184. Minor Form of Human Hepatic Betaine: Homocysteine S-Methyltransferase 913
185. Studies of Cobalamin-Dependent Methionine Synthase from Escherichia coli B 917
186. Inhibition of Methylenetetrahydrofolate Reductase by Adenosyl Methionine 921
187. Regulation of Folate Homeostasis 925
188. An Endogenous Inhibitor of Neurospora Folylpolyglutamate Synthetase 929
189. Folylpolyglutamate Hydrolase from Beef Liver 933
190. Use of Mammalian Cell Transformation to Isolate Genomic Sequences Encoding Human Folylpolyglutamate Synthetase (FPGS) and Dihydrofolate Reductase (DHFR) 937
191. Section F: Methotrexate and Other Anti-Folates
192. Antifolates: Expanding Horizons in 1986 945
193. Deaza Derivatives of Tetrahydrofolic Acid. A New Class of Folate Antimetabolite 953
194. Structure Activity Relationships of Novel Triazine Antifolates 959
195. The Effect of 7-Hydroxymethotrexate on the Antitumor Activity and Host Toxicity of Methotrexate In Vivo 963
196. Summary: The Biology of Antifolates 967
197. Crystal Structure of Methotrexate and its Conformational Comparison with Related Structures 969
198. Effect of Methotrexate on Reduced Folates and Thymidylate Synthesis During Growth of L1210 Cells 973
199. Dihydrofolate Reductase from Human Osteosarcoma Cells Resistant to Methotrexate 977
200. Evidence for Direct Inhibition of Metabolic Pathways as a Mechanism of Action of Methotrexate 981
201. Inhibition of Dihydrofolate Reductase and Thymidylate Synthase by Methotrexate Polyglutamate Analogues Lacking "Internal" α-Carboxyl Groups 985
202. The Antifolate Activity of Poly-γ-Glutamyl Derivatives of Methotrexate, 10-Deazaaminopterin and 10-Ethyl-10 Deazaaminopterin 989
203. Polyglutamation of the Thymidylate Synthase Inhibitor, N¹⁰-Propargyl-5,8-Dideazafolic Acid (CB 3717), in Organs of Ehrlich Ascites Carcinoma-Bearing Mice 993
204. 5,8-Dideazafolates as Substrates for Folypoly-γ-Glutamate Synthetase from Pig Liver 997
205. 5-Substituted-5-Deaza Analogues of Classical Antifolates 1001
206. Azido-Substituted Antifolate Drugs: Synthesis, Structure, and Activity 1005
207. Summary: Novel Antifolates 1009
208. Author Index 1011
209. Subject Index 1017
210. List of Participants 1033
211. Backmatter 1051