The decay of quinoid- and 7,8-dihydropterins

Kapitel in diesem Buch

1. Frontmatter I
2. Preface VII
3. Adrien Albert XI
4. Alois Niederwieser XII
5. Tetsuo Shiota XIII
6. Contents XV
7. I CHEMISTRY OF PTERINS AND FOLATES
8. Recent progress in pteridine chemistry 3
9. Synthesis of pteridines for immunoassay of biopterin and neopterin isomers 17
10. Design of new mechanism-based substrates for dihydrofolate reductase 23
11. New methods for the synthesis of quinazoline antifolates and poly-y-glutamyl metabolites of folates and antifolates 31
12. The decay of quinoid- and 7,8-dihydropterins 43
13. Synthesis of 6-acetyl-2,4-diamino-7,8-dihydro-9//-pyrimido-[4,5-b][l,4]- diazepine, an amino analog of 6-acetyldihydrohomopterin 49
14. Synthetic approaches to methanopterin 55
15. Synthesis and properties of tetrahydropterins coupled to 1,4-dihydropyridines 59
16. A new synthesis of biopterin and some analogues from epoxyaldehydes 63
17. Synthetic studies on the molybdenum cofactor 67
18. A new regiospecific synthesis of anapterin and primapterin 73
19. A novel and efficient synthesis of folylpolyglutamates 77
20. Reaction of acidic anhydride and pyridine with folic acid and classical antifolates 81
21. Quinazoline antifolate thymidylate synthase inhibitors: Synthesis of analogues containing heterocyclic isosteres of the para-aminobenzoate unit 86
22. Synthesis of tetrahydro-8-deazabiopterin 90
23. Synthesis and enzymic properties of new mechanism based substrates for dihydrofolate reductase of the 8-substituted pterin class. 94
24. Imidazolines as carbon-transfer vehicles: models of the tetrahydrofolate (and other) coenzymes 98
25. Asymmetric synthesis and absolute configuration of 5,10-dideaza- 5,6,7,8-tetrahydropteroic acid and 5,10-dideaza-5,6,7,8-tetrahydrofolic acid 102
26. Synthesis and biological evaluation of a fluorescent analogue of folic acid 106
27. Metal complexes of tetrahydroneopterin 110
28. Syntheses of lipophilic analogues of 2-desamino-2-CH3-NIO-propargyl- 5,8-dideazafolate targeted at the enzyme thymidylate synthase (TS). 114
29. Studies in models of folate cofactors: oxidation of 5-methyltetrahydropterin revisited. 118
30. New strategy in the synthesis of neopterin phosphates 122
31. First regiospecific synthesis of 7-iso-D-neopterin and 7-iso-D-neopterin- 3 '-monophosphate 126
32. II. ANALYSIS OF PTERINS AND FOLATES
33. Detection of pterins in biological material using mass spectrometry 133
34. Mass spectrometric methods for the structural determination of pteridines and folic acid derivatives 140
35. Structural characterization of underivatized pteridines by laser desorption fourier transform mass spectrometry 147
36. New immunoassays for determination of biopterin and neopterin in body fluids 151
37. A new immunoassay for neopterin and biopterin 155
38. Enzyme immunoassay for urinary neopterin 159
39. A competitive enzyme linked ligand sorbent assay (ELLSA) for quantitation of erythrocyte folates 163
40. Preparation of a bovine serum albumin based chiral matrix for resolution of (6R,S)-N⁵-formyltetrahydrofolate. 167
41. Rp-HPLC methods for the isolation and chemical identification of pterins from monocytic blood cells 171
42. Cyclodextrin based HPLC separation of 6-S and 6-R diastereomers of 5,10-dideaza and 5-deazatetrahydrofolates. 177
43. Analysis of folate and antifolate metabolites by mass spectrometry 181
44. A critical assessment of methods for measuring folate in human serum and red blood cells. 188
45. HPLC analysis of intracellular folate compounds after enzymic conversion to the corresponding pteroates 192
46. III. BIOSYNTHESIS AND BIOCHEMISTRY OF PTERINS
47. The Gowland Hopkins Lecture: Biosynthesis of H₄biopterin and related compounds 199
48. The structure of_q-Bh₂ - chemistry and biochemistry 213
49. Pteridines in riboflavin biosynthesis 219
50. Pteridine mimicking antibodies 231
51. 6-Pyruvoyl-tetrahydropterin reductases 238
52. Analysis of 6-pyruvoyl tetrahydropterin synthase, a target gene product of su(s) suppressor in Drosophila 243
53. Synthesis of fluorinated 8-ribityllumazines as "F NMR probes and potential inhibitors of the light riboflavin synthase of Bacillus subtilis 249
54. Studies on the oxidation state and biosynthesis of molybdopterin 255
55. Molybdenum cofactor genes in Drosophila 262
56. DNA photolyase: role of pterin in DNA repair. 268
57. 7-Substituted pterins, a new class of mammalian pteridines 274
58. Methanopterin: A structural and functional folic acid analogon in the biochemistry of methanogenic bacteria. 285
59. Biosynthesis of methanopterin 294
60. Tetrahydrobiopterin is required for the oxidation of arginine to nitric oxide by macrophages. 300
61. Biosynthesis of 7-hydroxybiopterin 306
62. GTP cyclohydrolase I from Escherichia coli. Molecular cloning and crystallization 312
63. Molecular characterization of the GTP cyclohydrolase I gene of Drosophila: analysis of cDNA clones 316
64. Inhibitors of bovine adrenal medullary sepiapterin reductase 320
65. Catalytic implication of the reductase and isomerase activity of sepiapterin reductase in the biosynthesis of tetrahydrobiopterin 324
66. Purification and characterization of sepiapterin reductase from human liver 328
67. Biosynthesis of methanopterin and deazaflavin in Methanobacterium thermoautotrophicum 332
68. Studies on riboflavin synthases of Bacillus subtilis. Amino acid sequence of the a subunit 336
69. Structure of the lumazine synthase/riboflavin synthase complex of Bacillus subtilis: crystallization of hollow reconstitutß₆₀, capsids. 340
70. Biosynthesis of 6,7-dimethyl-8-ribityllumazine. Purification and properties of 3,4-dihydroxy-2-butanone 4-phosphate synthase 344
71. High resolution electron microscopy on crystals of the icosahedral lumazine synthase/riboflavin synthase complex. 348
72. Differential synthesis of LDH A-like proteins and of phosphoproteins in response to the modified deazaguanine-derivative queuine 352
73. Metabolic control in HeLa-cells mediated by the deazaguanine-derivative queuine 356
74. On the biosynthesis of the deazaguanine-derivative queuine: structure of the tgt gene of E. coli 360
75. Changes in the level of biopterin and of queuine-containing tRNA during erythroid differentiation of murine erythroleukemia cells 364
76. Brain contents of biopterins and monoamines after intraperitoneal injections of SUN0588, active 6R-tetrahydrobiopterin, during ontogeny in rats 368
77. The effect of 2,4-diamino-6-hydroxypyrimidine on tetrahydrobiopterin and serotonin in the gastrointestinal tract of mice. 372
78. Differential metabolism of tetrahydrobiopterin in central and peripheral monoamine neurons maintained in culture 376
79. IV. TETRAHYDROBIOPTERIN DEFICIENCY
80. Inborn errors in tetrahydrobiopterin metabolism 383
81. Molecular defects in dihydropteridine reductase deficiency 389
82. Screening and treatment of tetrahydrobiopterin deficiency 393
83. Tetrahydrobiopterin deficient phenylketonuria detected by neonatal screening in Taiwan 402
84. Prenatal diagnosis of 6-pyruvoyl tetrahydropterin synthase deficiency in East Asia. 408
85. Heterogeneity of tetrahydrobiopterin deficiency: combined phenylalaninetetrahydrobiopterin loading test 414
86. Unusual case of atypical PKU: peripheral or central form of PPH4S deficiency 418
87. Development of vision in BH₄, deficiency 422
88. Fetal guinea-pig model of tetrahydrobiopterin deficiency 426
89. Unexpected favorable clinical results of therapy in late diagnosed DHPR deficiency 430
90. Systematic investigation for biopterin defects in hyperphenylalaninemic patients 434
91. Neuroradiological improvement after one year of therapy in a case of DHPR deficiency 438
92. V. PTERINS VARIOUS
93. Lumazine protein and the bioluminescence of photobacterium 445
94. Binding of pteridine derivatives to lumazine apoprotein 457
95. Hormonal imbalance by pteridine treatment in diapausing Pieridae induces mutations in the progeny of treated Drosophila melanogaster 462
96. N-acetyltransferase activity in Pieris brassicae 466
97. VI. BIOLOGY OF PTERINS
98. Pteridines and the immune response. 473
99. Neopterin elevation and interferon induction in viral diseases 485
100. Tetrahydrobiopterin in human T cells: control of its biosynthesis by interferon-y and interleukin 2 - modulator function in interleukin 2 perception 491
101. Effects of BH₄ on the synthesis of serotonin in brain slices and synaptosomes: implications for the use of BH₄ as a therapeutic agent 497
102. Regulation of cellular proliferation by tetrahydrobiopterin 505
103. Characterisation of the mutation in dihydropteridine reductase deficiency 511
104. Urinary excretion of total pteridines in cancer 515
105. Alterations of interferon-gamma-induced monocyte activation by immunomodulating compounds determined by neopterin production 519
106. Levels of neopterin, biopterin, 5-hydroxyindoleacetic acid, and homovanillic acid in cerebrospinal fluid of sick neonates and infants 523
107. Urinary neopterin levels in healthy children 527
108. Urinary neopterin factor in viral and bacteriological children infections 530
109. Urinary neopterin levels in liver transplant 534
110. The effect of IL-2, neopterin and immunomodulators on neopterin release from macrophages and PBMC 538
111. Membrane transport of unconjugated pteridines. The model of human erythrocytes. 543
112. Encephalopathy and abnormal cerebrospinal fluid pteridine profile. Fact or artefact ? 547
113. Informativity of pteridine measurements in the survey of organ transplantations 551
114. Effect of triamteren on urinary excretion of pterins in different rat strains 555
115. Pteridines and retinal degenerations in rats and humans 559
116. Pterins in bovine, rat, quail and human retina 563
117. Comparison of urinary biopterin in rats with various housing and enviromental conditions 567
118. Differences in the quantity and distribution of urinary pterins in various species of mammals 571
119. Total biopterin levels in the ventricular CSF of Parkinson's disease and essential tremor 575
120. Urinary xanthopterin and derivatives as indicators of liver disease 579
121. Genetic control of dihydropterin oxidase activity in Drosophila melanogaster 583
122. A controlled system for supplementation experiments in Drosophila melanogaster 587
123. New eye-color mutants affecting the biosynthesis of pteridines and ommochromes in Drosophila melanogaster 591
124. Search for 6- and 7-biopterins in human saliva 595
125. VII. TETRAHYDROBIOPTERIN-DEPENDENT MONOOXYGENASES
126. Regulation of the aromatic amino acid hydroxylases 601
127. Expression of rat liver dihydropteridine reductase in Escherichia coli 612
128. Escherichia coli dihydropteridine reductase is a trifunctional enzyme with dihydrofolate reductase activity. 616
129. Rat liver preparations with glyceryl etherase activity 620
130. Purification and characterization of a membrane associated folate binding protein from human leukemic CCRF-CEM cells 624
131. On the effects of high protein diet and of starvation on phenylalanine hydroxylase activities in rats. 628
132. Effects of experimental diabetes on phenylalanine hydroxylase activities in rats 632
133. Molecular defects of PKU in Italy differ from those of other European countries 636
134. The oxidation of tetrahydropteridines by phenylalanine hydroxylase 640
135. Interaction of catecholamines and tetrahydropterins with bovine liver phenylalanine hydroxylase 644
136. Studies of tetrahydrobiopterin uptake in rat brain synaptosomes 648
137. The influence of cofactor side-chain chirality on the activity and regulation of phenylalanine and tyrosine and hydroxylases 652
138. Limited denaturation stimulates tetrahydrobiopterin-dependent activity of rat liver phenylalanine hydroxylase 656
139. Effect of limited proteolysis on structure and activity of phenylalanine hydroxylase 660
140. Tetrahydropterin as a possible natural cofactor in the Drosophila phenylalanine hydroxylation system 664
141. Interaction of substrate analog inhibitors with rat liver dihydropteridine reductase 668
142. Simultaneous purification of phenylalanine hydroxylase, phenylalanine hydroxylase stimulator protein, and dihydropteridine reductase from rat liver 672
143. VIII. FOLATES
144. A. DIHYDROFOLATE REDUCTASE
145. NMR and mutagenesis studies of dihydrofolate reductase 681
146. Spectroscopic studies of the interaction of ligands with dihydrofolate reductase 694
147. Comparison between human and bacterial dihydrofolate reductase structures 702
148. Mutagenesis of human dihydrofolate reductase structure as a probe of enzyme function 708
149. Folate and dihydrofolate reduction by mouse dihydrofolate reductase 716
150. Kinetic mechanism of recombinant human dihydrofolate reductase 722
151. The kinetic mechanism of the reaction catalyzed by an R-plasmid (R-67) dihydrofolate reductase from E.coli. 728
152. Mechanism based inhibitors of dihydrofolate reductase. 734
153. Trimetrexate resistant L. casei and S. faecium 740
154. Second site revertants of E. coli dihydrofolate reductase 744
155. Structural and energetic aspects of the reaction pathway and transition state for hydride-ion transfer in dihydrofolate reductase 748
156. Cloning of trimethoprim-resistant dihydrofolate reductase from multiresistant staphylococci and expression in E. coli 752
157. Role of TRP-24 in binding and catalysis for human dihydrofolate reductase (DHFR) 756
158. Mutation at hydrophobic residues in dihydrofolate reductase 760
159. Determination of the functional role of phenylalanine-31 of recombinant human dihydrofolate reductase by site-directed mutagenesis 765
160. Molecular modeling studies and crystal structure determination of pteridine antifolate-DHFR enzyme interactions 769
161. Allelic variants of Chinese hamster dihydrofolate reductase 773
162. B: THYMIDYLATE SYNTHASE
163. Thymidylate synthase - structural and functional considerations 781
164. Defining the catalytic role of specific amino acids in thymidylate synthase by site-specific mutagenesis 795
165. Studies of the effects of mutagenesis on a conserved active site arginine residue in thymidylate synthase 805
166. Dual role of serine hydroxymethyltransferase in the synergy of fluorouracil and leucovorin: effects of L-serine and glycine on H₄PteGlu/5,10-CH₂-H₄PteGlu ratios; and H₄PteGlu-catalyzed release of fluoride ion from alpha-fluoro-beta alanine. 811
167. Interaction of N⁴-hydroxy-dCMP and N⁴-hydroxy-5-FdCMP with L1210 thymidylate synthase differing in sensitivity towards 5- FdUMP Inhibition 817
168. Mechanism of thymidylate synthase inhibition by N⁴-Hydroxy-dCMP 821
169. Thymidylate synthase activity in bronchoalveolar lavage cells as a possible marker in lung cancer diagnosis 825
170. Purification and properties of Hymenolepis diminuta and regenerating rat liver thymidylate synthases 829
171. Influence of FdUMP on the binding of methotrexate to thymidylate synthase 833
172. Efficient expression of mammalian thymidylate synthase in Escherichia coli 836
173. Catalytic role of histidine-147 in Escherichia coli thymidylate synthase 840
174. Variation among human thymidylate synthase enzymes in folate affinity 844
175. Evaluation of in vivo inhibition of thymidylate synthase in patients with colorectal cancer treated with 5-fluorouracil 848
176. Effect of leucovorin on 5-fluorouracil induced inhibition of thymidylate synthase in murine colon cancer 852
177. Feedback inhibition of thymidylate synthase by dihydrofolate polyglutamates cannot account for partial depletion of tetrahydrofolate cofactors by antifolates 856
178. Kinetic studies on thymidylate synthase from Lactobacillus casei 860
179. C. METHIONINE SYNTHASE
180. Studies on the cobalamin-dependent methionine synthase from Escherichia coli K12 869
181. Foimyl phosphate as an intermediate in the N¹⁰-formyltetrahydrofolate synthetase reaction. 873
182. Enzymes of homocysteine remethylation and transsulfuration in methionine or cholesterol induced atherosclerosis in rabbits 877
183. Biochemical changes in porcine neural tissue after inactivation of methionine synthase by nitrous oxide. 881
184. Increased synthesis of AdoMet but not of methionine during testosterone stimulation of polyamine biosynthesis in mouse kidney 885
185. D. ENZYMOLOGY AND METABOLISM
186. Role of folylpolyglutamate synthetase in the regulation of folate and antifolate metabolism. 891
187. NAD-dependent methylenetetrahydrofolate dehydrogenase-cyclohydrolase present in transformed mammalian cells 896
188. Gammaglutamyl hydrolases 903
189. Human methenyltetrahydrofolate synthetase 910
190. Folate catabolism in man and the rat 916
191. Effects of growth rate on y-glutamyl hydrolase in Ehrlich ascites carcinoma cells 922
192. Folylpolyglutamate synthesis in Neurospora crassa. Wild type FPGS activity and transformation of polyglutamate deficient mutants using cosmid vectors containing the met-6 gene 926
193. Cloning and expression of the gene encoding Lactobacillus casei folylpolyglutamate synthetase in Escherichia coli 930
194. Effect of treatments with different anticonvulsant drugs on folate pattern in rat liver. 934
195. A sensitive new microassay useful for measurement and purification of mammalian folylpolyglutamate synthetase 938
196. Tissue differences in N⁵ formyltetrahydrofolate metabolism 944
197. E. FOLATES IN ENDOGENOUS PURINE METABOLISM
198. Glycinamide ribonucleotide transformylase from E. coli: characterization and inhibition. 951
199. Estimation of the flux control coefficient of glycineamide ribonucleotide transformylase for purine biosynthesis de novo 957
200. Monocyclic 5-deazatetrahydrofolate analogues as inhibitors of de novo purine biosynthesis 961
201. Inhibition of glycinamide ribonucleotide transformylase, methotrexate transport, and the growth of MCF-7 cells by 5,8-dideazafolates 965
202. F. FOLATES, VARIOUS
203. Formation of methylcobamide from methyltetrahydrofolate by acetogenic bacteria: enzymology and redox chemistry. 971
204. Incorporation of the ring carbon of histidine into coenzymes of folylpolyglutamates. 977
205. In vivo effect of folic acid on fragile-site expression 981
206. IX. ANTIFOLATES
207. A. DEAZADERIVATIVES
208. New synthetic studies on deazafolates 987
209. Molecular modeling studies on deazatetrahydrofolates 995
210. Biochemical pharmacology of deazatetrahydrofolates 1001
211. Synthesis and evaluation of l-deaza-7,8-dihydropteridines and ring analogues 1009
212. In vitro and in vivo activity of the GAR transformylase inhibitor 5-deazacyclotetrahydrofolate 1015
213. vitro and in vivo studies with 2-desamino-2-CH₃-N¹⁰-propargyl-5,8- dideazafolate (ICI 198583), an inhibitor of thymidylate synthase 1023
214. Comparative studies on the activity of methotrexate and the analog 10-ethyl-10-deaza-aminopterin (10-EdAM) against head and neck carcinoma cell lines and xenografts. 1027
215. Transport of 5,10-dideazatetrahydrofolic acid (DDATHF) in CCRF-CEM sensitive and methotrexate resistant cell lines 1031
216. Synthesis and structure-activity relationship studies of 5,10- dideazatetrahydrofolic acid (DDATHF) 1035
217. Synthesis and antifolate properties of 5-alkyl-5-deazaaminopterin analogues modified in the 10-position 1039
218. Synthesis and biological evaluation of 2-desamino-2-methyl-5,10- dideazatetrahydrofolate 1043
219. Quinazoline antifolate thymidylate synthase inhibitors: potent cytotoxic agents containing heterocyclic isosteres of the para-amino benzoate unit 1048
220. Antifungal activity of some 2,4-diamino-5-methyl-6-alkyl quinazoline 1052
221. Membrane transport characteristics of the thymidylate synthase inhibitor 2-desamino-2-methyl-N¹⁰-propargyl-5,8-dideazafolic acid. 1056
222. Synthesis and potential antitumor activity of 5-deaza analogs of 5,10- methylenetetrahydrofolic acid 1060
223. Theoretical studies of the structures and conformations of triazine antifolates 1064
224. In vitro and in vivo metabolism of 5-DACTHF, an acyclic tetrahydrofolate analog 1068
225. Measurement of retained thymidylate synthase (TS) inhibition by antifolates in whole cells in vitro 1072
226. Substitution on the benzene ring of quinazoline antifolates that inhibit thymidylate synthase 1076
227. Inhibition of de novo purine synthesis by deazatetrahydrofolates 1080
228. B.Methotrexates
229. Resistance to methotrexate in experimental models and in patients 1089
230. Methotrexate peptides as cancer chemotherapeutic agents 1100
231. Biochemical determinants of methotrexate selectivity 1110
232. Mechanisms underlying methotrexate inactivity in human head and neck cancer xenografts 1119
233. Design and synthesis of novel methotrexate derivatives for antibody directed drug targeting 1123
234. Methotrexate (MTX) transport and cytotoxity of MTX and trimetrexate (TMQ) for human squamous cell carcinoma (SCC) of the head and neck grown at low folate concentrations 1127
235. Folate enhancement of antifolate synergism in lymphoma cells 1131
236. Amino acid oxidation and dihydrofolate reductase inactivation photosensitized by a diaminopteridine 1137
237. Synchronisation of U937 and SW626 cancer cell lines of human origin using methotrexate 1141
238. New inhibitors of plasmodial folate synthesis - comparison of cell-free, whole cell and in vivo activities for single drugs and drug combinations 1145
239. Effect of vincristine on methotrexate cytotoxicity and accumulation in MCF-7 cells, a human breast cancer cell line 1150
240. The y-tetrazole analog of methotrexate: design, synthesis and biological activity 1154
241. Effect of intravenous 24 hr infusions of methotrexate on unconjugated pteridine metabolism 1158
242. Covalent labeling of dihydrofolate reductase and folate transport proteins by fluorescein methotrexate 1162
243. Study of methotrexate polyglutamate formation in cultured leukemic cells 1166
244. C. Various Antifolates
245. Folyl polyglutamates in metabolism and chemotherapy 1173
246. Biological determination of selective antitumor action of 4-amino-folate analogs 1185
247. Inhibition of the thymidylate synthase cycle of leukemia cells by antifolates: The usefulness of the cellular tritium release assay 1192
248. Fluoroglutamate-containing folates and antifols: probing the role of polyglutamylation in vitro 1198
249. Therapeutic strategies for 5-fluorouracil-leucovorin based upon cellular metabolic characteristics in human colon adenocarcinoma xenografts 1203
250. The lack of response of human colonic tumor cell lines to biochemical modulation by folinic acid. 1209
251. Folinic acid as a source of intracellular 5,10-methylenetetrahydrofolate in human carcinoma cells 1213
252. Structure activity relationships of multidrug resistance 1217
253. Enhancement of the cytotoxicity of fluoropyrimidines to human carcinoma cell lines by leucovorin 1221
254. D. Transport And Absorption Of Folates And Antifolates
255. Methotrexate transport via the high-affinity folate binding protein of L1210 cells. 1227
256. Combined affinity and ion pair liquid chromatographies for direct analysis of tissue folate composition 1238
257. Tumor cell sensitivity and resistance to folate analogues: the role of carrierand receptor-mediated transport systems 1247
258. Lysosomal permeability to methotrexate polyglutamates 1253
259. Folic acid metabolism in placental cells associated with neural tube defects 1257
260. Homologous membrane folate binding proteins in human placenta 1262
261. A high-affinity folate binding protein in human amniotic fluid 1268
262. Interaction of N-hydroxy(sulfo)succinimide active esters with the reduced folate/methotrexate transport system from human CCRF-CEM leukemia cells 1272
263. Renal uptake and metabolism of 5-methyltetrahydrofolate in the rat 1276
264. Methotrexate- and folate-lipid conjugates of defined chemical structures as new antifolate analogs and transport probes 1280
265. Characterization of receptor-mediated (anti)folate uptake in human CCRF-CEM cells 1284
266. Author Index 1289
267. Subject Index 1297
268. List of Participants 1319
269. Backmatter 1341