Chemistry and Biology of Pteridines and Folates

Front Matter....Pages i-xxvi
Natural Pteridines -A Chemical Hobby....Pages 1-16
Properties and Reactions of Pteridines Carrying Functionalised Side Chains at the 3-Position....Pages 17-20
 N 2 -( N , N -Dimethylaminomethylene)- O 4 -(2- p -Nitrophenyl. Ethyl)-Biopterin: A Versatile Intermediate for a Glycosidation Reaction....Pages 21-24
The Synthesis of Fluorine-Containing Pterins....Pages 25-28
Formation of Fe III or Fe II Complexes with Acetylaceto-Nate and 5,6,7,8-Tetrahydropterin as Ligands and Their Activation of Oxygen....Pages 29-32
Stereoelectronic Effects in the Autoxidative Destruction of Reduced Folate Derivatives....Pages 33-37
Mindo/3 Molecular-Orbital Calculations on the 6R-BH4 Molecule and Its Metabolic Precursors : Conformation and Activity....Pages 39-42
Identification, Stereoconfiguration, Chromatographic and Fluorescence Properties of Natural Pterins....Pages 43-46
The Mechanism of Cofactor Regeneration During Phenylalanine Hydroxylation....Pages 47-54
Structure Function Studies of the Phenylalanine Hydroxylase Active Site and a Summary of Structural Features....Pages 55-57
Expression of Wild Type and Mutant Forms of Human Phenylalanine Hydroxylase in E . Coli ....Pages 59-62
A Re-Examination of the Metal Requirement of Chromobacterium Violaceum Phenylalanine Hydroxylase....Pages 63-66
Histidines 138 and 143 are Copper Binding Ligands in Chromobacterium Violaceum Phenylalanine Hydroxylase....Pages 67-70
Characterization of the Iron Environment in Recombinant Human Tyrosine Hydroxylase, Using Mössbauer and EPR-Spectroscopy....Pages 71-76
Interaction of Substrate and Pterin Cofactor with the Metal of Human Tyrosine Hydroxylase as Determined by 1 H-NMR....Pages 77-80
Mechanistic Studies of Tyrosine Hydroxylase....Pages 81-86
Alleviation of Catecholamine Inhibition of Tyrosine Hydroxylase by Phosphorylation at Serine40....Pages 87-92
Glyceryl Ether Monooxygenase [EC 1.14.16.5]: Stoichiometry and Inhibition....Pages 93-96
The Isolation and Characterization of Clones of 4a-Hydroxytetrahydrobiopterin Dehydratase....Pages 97-102
Molecular Cloning and Recombinant Expression of the Human Liver Phenylalanine Hydroxylase Stimulating Factor Revealed Structural and Functional Identity to the Dimerization Cofactor for the Nuclear Transcription Factor HNF-1α....Pages 103-106
Progress in the Study of Biosynthesis and Role of 7-Substituted Pterins: Function of Pterin-4a-Carbinolamine Dehydratase....Pages 107-110
Spectroscopic Characterization of Human Liver Pterin 4a-Carbinolamine Dehydratase....Pages 111-114
Is Dihydropteridine Reductase an Anomalous Dihydrofolate Reductase, a Flavin-Like Enzyme, or a Short-Chain Dehydrogenase?....Pages 115-121
Two Crystal Structures of Rat Liver Dyhydropteridine Reductase....Pages 123-126
New Inhibitors of Dihydropteridine Reductase (Human Brain)....Pages 127-130
CYS →Ser Mutations in ch-Human Dihydropteridine Reductase....Pages 131-134
The Spectrum of Mutations in Dihydropteridine Reductase Deficiency....Pages 135-138
Cloning and Characterization of Genes Encoding Tetrahydrobiopterin Biosynthetic Enzymes....Pages 139-145
 Drosophila GTP Cyclohyrodrolase: Multiple Isoform Products of a Single Gene Derive from Alternate Transcripts that are Developmentally Regulated and Functionally Specific....Pages 147-155
Studies on GTP Cyclohydrolase I of Escherichia Coli ....Pages 157-162
Partial Purification and Characterization of GTP Cyclohydrolase I from Spinach Leaves....Pages 163-166
Detection and Quantification of GTP Cyclohydrolase I m RNA....Pages 167-170
Localization of GTP Cyclohydrolase I (GTPCH) mRNA in the Rat Brain by in Situ Hybridization....Pages 171-174
Expression of GTP Cyclohydrolase I (GTPCH) mRNA in the Rat: Tissue Distribution and Effect of Reserpine....Pages 175-178
Regulation of Tetrahydrobiopterin Biosynthesis in Cultured Hypothalamic and Mesencephalic Neurons by Cyclic AMP Dependent GTP Cyclohydrolase I Gene Expression....Pages 179-182
Mycophenolic Acid Simultaneously Reduces Intracellular GTP and Tetrahydrobiopterin Levels in Neuro-2A Cells....Pages 183-186
Human Liver 6-Pyruvoyl-Tetrahydropterin Synthase: Expression of the cDNA, Purification and Preliminary Characterization of the Recombinant Protein....Pages 187-190
Enzymatic Properties of 6-Pyruvoyl Tetrahydropterin Synthase Purified from Fat Bodies of Silkworm Larvae....Pages 191-194
Northern Blot Analysis of Sepiapterin Reductase mRNA in Mammalian Cell Lines and Tissues....Pages 195-198
Purification and Properties of Human Sepiapterin Reductase from Placenta....Pages 199-202
Stimulation of Tetrahydrobiopterin Synthesis by Cytokines in Human and in Murine Cells....Pages 203-209
Interferon-γ and Kit Ligand are Primary Regulators of GTP Cyclohydrolase Activity: Mechanisms and Implications....Pages 211-216
Differential Metabolism of Tetrahydrobiopterin in Monoamine Neurons: A Hypothese Based upon Clinical and Basic Research....Pages 217-222
Tissue Distribution of Tetrahydrobiopterin Generating Enzymes....Pages 223-226
Co-Induction of Tetrahydrobiopterin (BH 4 ) Levels and Tyrosine Hydroxylase Activity in Cultured PC12 Cells....Pages 227-230
Long-Term Treatment of PC12 Pheochromocytoma with Dibutyryl Cyclic Amp Increases Biopterin Content in the Cells but Decreases that in the Medium....Pages 231-234
Nicotinic Cholinergic Regulation of Tetrahydrobiopterin Levels in Bovine Adrenal Chromaffin Cells....Pages 235-238
Inter-Relationships between Pterins and Cytokines Produced During Allogeneic Immune Reactions and Possible Use as Early Markers of Immune Activation....Pages 239-242
An Example of the Detection of an Esophageal Carcinoma in Its Very Early Stage by Urinary Xanthopterin Determination....Pages 243-246
Neopterin in Subacute Sclerosing Panencephalitis....Pages 247-250
The 7-Deazaguanine Derivative, Queuine, Regulates Mammalian Cell Proliferation Depending on the Metabolic State....Pages 251-254
Tetrahydrobiopterin Deficiency and an International Database of Patients....Pages 255-261
Tetrahydrobiopterin Deficiency in Portugal: Results of the Screening for Hyperphenylalaninemia....Pages 263-266
A Microtitre Plate Method for Measuring Biopterin with Cryopreserved Crithidia Fasciculata ....Pages 267-270
Oral Administration of Liposomally Entrapped Tetrahydrobiopterin....Pages 271-272
Experimental Research on a Fetal Treatment for Tetrahydrobiopterin Deficiency....Pages 273-276
Experimental Research on a New Treatment for Maternal Phenylketonuria(PKU)....Pages 277-280
Nitric Oxide Synthase: Function and Mechanism....Pages 281-284
Macrophage Nitric Oxide Synthase: Tetrahydrobiopterin Decreases the Nadph Stoichiometry....Pages 285-288
Role of Tetrahydrobiopterin in Cytokine-Stimulated Metabolism of Tryptophan and Hydroxylation of Arginine....Pages 289-294
Tetrahydrobiopterin Synthesis is Induced by LPS in Vascular Smooth Muscle and is Rate-Limiting for Nitric Oxide Production....Pages 295-300
6R-[ 3 H]Tetrahydrobiopterin Binding Activities in Rat Brain....Pages 301-304
Inducible Nitric Oxide Synthase Activity in Hepatocytes is Dependent on the Coinduction of Tetrahydrobiopterin Synthesis....Pages 305-308
Modulation of Nitric Oxide Synthase Activity in Intact Cells by Intracellular Tetrahydrobiopterin Levels....Pages 309-312
6R-L-erythro-5,6,7,8-Tetrahydrobiopterin: A Regulator of Neurotransmitter Release....Pages 313-319
Positron Emission Tomography Studies on Some Neurotransmitter Receptor Systems with 6R-Tetrahydrobiopterin Pretreatment....Pages 321-326
Positron Emission Tomography (PET) Study: The Effects of 6R-L-Erythro-5,6,7,8-Tetrahydrobiopterin (R-THBP, SUN 0588) on the Central Dopamine D 1 , D 2 and D 3 Receptors in Rhesus Monkey....Pages 327-330
6R-L-Erythro-5,6,7,8-Tetrahydrobiopterin (R-THBP, SUN 0588) Acts on the Brain Muscarinic and Nicotinic Cholinergic Receptors as Evaluated by Positron Emission Tomography (PET) in Rhesus Monkey....Pages 331-334
Effect of 6R-Tetrahydrobiopterin on the Central Muscarinic Cholinergic Receptor as Evaluated by Positron Emission Tomography Studies Using Rhesus Monkey....Pages 335-338
Increase of Tetrahydropterins in Cell-Free Retinal Extracts in Response to Light Exposure....Pages 339-342
Effect of Triamterene on the Electroretinogram of Long Evans Rats....Pages 343-345
Immunoenzymatic Labeling of Biopterin and Neopterin in the Pigment Epithelium of Bovine Retina....Pages 347-350
Reduced Pterins as Scavengers for Reactive Oxygen Species....Pages 351-354
Chemistry and Biology of the Molybdenum Cofactors....Pages 355-362
Studies on the Molybdenum Coactor. Synthesis of (±)-Form B (Dephospho)....Pages 363-367
Molybdenum-Pterin Complexes: A Functional and Structural Model for the Binding Site in the Enzyme Dimethyl Sulfoxide Reductase....Pages 369-372
Human Molybdenum Cofactor Deficiency....Pages 373-378
Molybdopterin Biosynthesis in Man. Properties of the Converting Factor in Liver Tissue from a Molybdenum Cofactor Deficient Patient....Pages 379-382
Cloning of a Eukaryotic Molybdenum Cofactor Gene....Pages 383-386
Design and Synthesis of Inhibitors of Folate Dependent Enzymes as Antitumor Agents....Pages 387-408
Synthesis and Antitumor Activity of LY288601, the 5,6-Dihydro Analog of LY231514....Pages 409-412
Synthesis and Preliminary Biological Evaluation of Analogues of 5,8-Dideazaisofolic Acid and its 2-Desamino-2-Methyl Derivative Containing Fluorine at Position Five....Pages 413-415
Synthesis and Biological Evaluation of Analogues of 5,8-Dideazaisofolic Acid (IAHQ) Modified at Positions 2, 4 and 9....Pages 417-420
New Thiophene Substituted 10-Deazaaminopterins: Synthesis and Biological Evaluation....Pages 421-424
Evaluation of the Anti-Arthritic Activity and an Alternate Synthesis of a Thiophene-Substituted 10-Deazaaminopterin....Pages 425-428
Lipophilic Antifolates as Candidates against Opportunistic Infections....Pages 429-433
Analogues of Classical Antifolates Bearing Naphthoyl in Place of Benzoyl....Pages 435-439
Synthesis and Biological Activity of Tricyclic, Conformationally Restricted Analogs of Lipophilic Pyrido[2,3- d ]-Pyrimidine Antifolates....Pages 441-444
Novel 2,4-Diamino-5-Substituted Furo[2,3- d ]-Pymmidines as Potential Antifolates....Pages 445-448
Bicyclic Conformationally Restricted Analogs of Nonclassical Pyrido[2,3- d ] Pyrevddines as Potential Inhibitors of Dihydrofolate Reductases....Pages 449-452
Synthesis, Structural and Biochemical Characterization of Cytostatic Methotrexate-γ-Glutamyl-Glutathione Conjugates....Pages 453-456
Activation by Peptidases and Cytotoxicity of 2-(L-α-Aminoacyl) Prodrugs of Methotrexate....Pages 457-460
Effect of a Novel Antifolate, N α -(4-Amino-4-Deoxypteroyl)-N δ -Hemiphthaloyl-L-Ornithbsfe (PT523), On Growth of H35 Rat Hepatoma and HEPG2 Human Hepatoma Cells....Pages 461-464
Tubulin Binding Properties of Two Chiral Isomers with 1-Deaza-7, 8-Dihydropteridine Structure....Pages 465-468
Effects of Folic Acid on Pyrimethamine Teratogenesis in Rats....Pages 469-472
Mutations of Human Dihydrofolate Reductase Causing Decreased Inhibition by Methotrexate....Pages 473-479
Conformational Analysis of Human Dihydrofolate Reductase Inhibitor Complexes: Crystal Structure Determination of Wild Type and F31 Mutant Binary and Ternary Inhibitor Complexes....Pages 481-486
Computer-Aided Design of Mechanism-Based Pterin Analogues and MD/FEP Simulations of Their Binding to Dihydrofolate Reductase....Pages 487-492
Does R67 Dihydrofolate Reductase Possess a Proton Donor?....Pages 493-498
Laser-Sensitized Tautomers in Dihydrofolate Reductase....Pages 499-502
Methotrexate-Insensitive Mutants of Human Dihydrofolate Reductase (hDHFR) Constructed by Site Directed Mutagenesis at Phenylalanine 34....Pages 503-505
Kinetic Investigation of Methotrexate Resistant Human Dihydrofolate Reductase (hDHFR) Mutants at PHE 31 ....Pages 507-510
The Effect of Codon 31 on the Relative Affinities for the Binding of Designed 8-Alkyl-Pterins to Dihydrofolate Reductase: A Statistical Perturbation Theory and Molecular Dynamics Simulation Study....Pages 511-514
Effect of Codon 22 Mutations on Substrate and Inhibitor Binding for Human Dihydrofolate Reductase....Pages 515-519
Thermodynamic Study of Folate Analogue Binding to Dihydrofolate Reductases from Different Species....Pages 521-524
Comparison of Binding and Activity of 8-Alkyl-Pterins and 8-Alkyl-N5-Deaza-Pterins with Dihydrofolate Reductase....Pages 525-528
Development of a Spectrofluorimetric Method for Determining the p K a of Pterin-Analogue Ligands Bound to DHFR....Pages 529-532
Selective Inhibition of Dihydrofolate Reductase from Problem Human Pathogens....Pages 533-536
Translational Regulation of the Synthesis of Dihydrofolate Reductase....Pages 537-540
Expression of the Trimethoprim Resistant Dihydrofolate Reductase Encoded by Transposon TN4003 in a Soluble Form and Its Subsequent Purification to Homogeneity....Pages 541-544
Effect of Genomic Position on Amplification of the DFR 1 Gene in Saccharomyces Cerevisiae ....Pages 545-550
Dihydrofolate Reductase is not the Target of Trimethoprim in Saccharomyces Cerevisiae ....Pages 551-554
Point Mutations in the Dihydropteroate Synthase Gene Causing Sulfonamide Resistance....Pages 555-558
Frequent Amplification of a Short Chain Dehydrogenase Gene in Methotrexate Resistant Leishmania ....Pages 559-562
Enzyme Interactions Involving T4 Phage-Coded Thymidylate Synthase and Deoxycytidylate Hydroxymethylase....Pages 563-570
Isolation of Cdnas Encoding Thymidylate Synthase from Soybean Seedlings and Expression of the Protein in E . Coli ....Pages 571-573
Use of 10-Propargyl-5,8-Dídeazafolate and Directed Mutagenesis to Probe the Catalytic Mechanism of Thymidylate Synthase....Pages 575-578
γ-Linked Dipeptide Analogues of 2-Desamino-2-Methyl-N 10 -Propargyl-5,8-Dideazafolate as Antitumour Agents....Pages 579-584
Substituted-2-Desamino-2-Methyl-Quinazolinones. A Series of Novel Antitumour Agents....Pages 585-588
Use of Murine L5178Y Lymphoma Thymidine Kinase Mutants for in Vitro and in Vivo Antitumour Efficacy Evaluation of Novel Thymidylate Synthase Inhibitors....Pages 589-592
Quinazoline Antifolates Inhibiting Thymidylate Synthase: Synthesis of γ-Linked Peptide and Amide Analogues of 2-Desamino-2-Methyl-N 10 -Propargyl-5,8-Dideazafolic Acid (ICI 198583) 10 -Propargyl-5,8-Dideazafolic Acid (ICI 198583)....Pages 593-596
The Duration of the Inhibition of Thymidylate Synthase in Intact L1210 Cells Exposed to Two Different Classes of Quinazoline Analogues....Pages 597-600
The Toxicity of ICI D1694 in Man and Mouse....Pages 601-604
Evaluation of Immunohistochemical Staining and Activity of Thymidylate Synthase in Cell Lines....Pages 605-608
The Interval Between Methotrexate and Leucovorin Determines the Efficacy of 5-Fluorouracil Modulation in Vitro and in Vivo ....Pages 609-612
Potentiation of 5-Fluorouracil Induced Inhibition of Thymidylate Synthase in Human Colon Tumors by Leucovorin is Dose Dependent....Pages 613-616
Interaction with 2(4)-Thio-5-Fluoro-dUMP of Thymidylate Synthases with Differing Sensitivities to 5-Fluoro-dUMP....Pages 617-620
Mechanism of Thymidylate Synthase Inhibition by N 4 -Hydroxy-(N 4 -Hydroxy-5-Fluoro)-dCMP in View of the Structure and Conformation of N 4 -Hydroxy-(N 4 Hydroxy-5-Fluoro)-Cytosine Calculated by the Ab Initio Quantum Mechanical Methods....Pages 621-624
Sulphonamide Antifolates Inhibiting Thymidylate Synthase. Synthesis, Enzyme Inhibition and Cytotoxicity....Pages 625-628
Folylpoly-γ-Glutamate Synthetase....Pages 629-634
Increased Activity of γ-Glutamyl Hydrolase in Human Sarcoma Cell Lines: A Novel Mechanism of Intrinsic Resistance to Methotrexate (MTX)....Pages 635-638
Mechanism-Based Approaches to Inhibition of the Synthesis and Degradation of Folate and Antifolate Polyglutamates....Pages 639-643
Polyglutamate Product Formation by Lactobacillus Casei Folylpolyglutamate Synthetase in Vitro and in Vivo in Recombinant Escherichia Coli ....Pages 645-650
Development of a Simple Folylpolyglutamate Synthetase Assay in Tissues and Cell Lines....Pages 651-654
Two Novel HPLC Methods which Rapidly Detect the Substrates and Cleavage Products of γ-Glutamyl Hydrolase....Pages 655-658
Purification and General Properties of Human Folylpolyglutamate Synthetase....Pages 659-662
Antitumor Efficacy of Classical Non-Polyglutamylatable Antifolates that Inhibit Dihydrofolate Reductase....Pages 663-666
Studies on the Cross-Resistance of Folylpolyglutamate Synthetase-Deficient, Methotrexate-Resistant CCRF-CEM Human Leukemia Sublines....Pages 667-670
Variable Pharmacodynamics of Antifolates in Squamous Cell Carcinoma of the Head and Neck....Pages 671-674
Metabolism of Folate Glutamates in Aspergillus Nidulans ....Pages 675-677
Evidence that 5-Formyltetrahydropteroylglutamate has a Metabolic Role in One-Carbon Metabolism....Pages 679-685
Cobalamin-Dependent and Cobalamin-Independent Methionine Synthases in Escherichia coli : Two Solutions to the Same Chemical Problem....Pages 687-692
Folate Metabolites as Modulators of Antitumor Drug Activity....Pages 693-698
MTX Does Not Affect Enhanced Biosynthesis and Metabolism of S-Adenosylmethionine in Testosterone-Induced Hypertrophic Mouse Kidney....Pages 699-702
Thermolability of Residual Methylenetetrahydrofolate Reductase (MR) Activity, Methionine Synthase Activity and Methyl-Cobalamin Levels in Cultured Fibroblasts from Patients with MR Deficiency....Pages 703-706
Enzymes For Synthesis of 10-Formyltetrahydrofolate in Plants: Characterization of a Monofunctional 10-Formyltetrahydrofolate Synthetase and Copurification of 5,10-Methylenetetrahydrofolate Dehydrogenase and 5,10-Methenyltetrahydrofolate Cyclohydrolase Activities....Pages 707-710
Cloning of the Genes Encoding the Serine Hydroxymethyltransferases from Saccharomyces Cerevisiae ....Pages 711-714
Serine Hydroxymethyltransferase: Role of the Active Site Lysine in the Mechanism of the Enzyme....Pages 715-718
Purification of Neurospora Crassa Cytosolic Serine Hydroxymethyltransferase....Pages 719-722
Purification and Properties of Rabbit Liver 5,10-Methenyltetrahydrofolate Synthetase....Pages 723-726
Folate Metabolism in Pregnancy....Pages 727-732
Influence of Gestation and Lactation on the Levels of Plasma Folates in Sows....Pages 733-736
Identification of Endogenous Tetrahydrofolate and 10-Formyltetrahydrofolate as Major Folates in Rat Bile....Pages 737-740
Development of a Sensitive Assay for Detection of Uracil in DNA....Pages 741-744
5-Methyltetrahydrofolate Urinary Excretion: Modeling by Cultured Human Kidney Cells....Pages 745-748
Contribution of Plasma Protein Binding to the Stability of Tetrahydrofolate in Pig Plasma....Pages 749-752
Ligand Induced Conformation Change in Folate Binding Protein....Pages 753-756
The High-Affinity Folate Binding Protein in Normal and Malignant Mammary Gland Tissue....Pages 757-760
Detergent-Insolubility During the Biosynthesis of Membrane Folate Receptor-2....Pages 761-765
The Reduced Folate/Methotrexate Carrier and a Membrane-Associated Folate Binding Protein as Transport Routes for Novel Antifolates: Structure-Activity Relationships....Pages 767-770
Identification of a Reduced Folate/Methotrexate Carrier in Human KB-Cells Expressing High Levels of Membrane Associated Folate Binding Protein....Pages 771-774
Altered Transport of Folic Acid and Antifolates Through the Carrier Mediated Reduced Folate Transport System in a Human Leukemia Cell Line Resistant to (6R) 5,10-Dideazatetrahydrofolic Acid (DDATHF)....Pages 775-778
Transformation of an L-Cell Line with the DNA Coding for the Reduced-Folate/Methotrexate Transporter Protein from a CCRF-CEM Human Leukemia Cell Line....Pages 779-782
Determinants of the Disparate Antitumor Effects of (6R)5,10-Dideaza-5,6,7,8-Tetrahydrofolate and Methotrexate Toward Methotrexate Resistant CCRF-CEM Cells, Characterized by Severely Impaired Antifolate Membrane Transport....Pages 783-786
Up-Regulated Transport of Methotrexate and 5-Methyltetrahydrofolate in a Human Breast Cancer Cell Line....Pages 787-790
Back Matter....Pages 791-801