Zurich, Switzerland, September 3-8, 1989

389,95 €
inkl. 7% MwSt. und
ggf. zzgl. Versand

Frontmatter -- Preface -- Adrien Albert -- Alois Niederwieser -- Tetsuo Shiota -- Contents -- I CHEMISTRY OF PTERINS AND FOLATES -- Recent progress in pteridine chemistry -- Synthesis of pteridines for immunoassay of biopterin and neopterin isomers -- Design of new mechanism-based substrates for dihydrofolate reductase -- New methods for the synthesis of quinazoline antifolates and poly-y-glutamyl metabolites of folates and antifolates -- The decay of quinoid- and 7,8-dihydropterins -- Synthesis of 6-acetyl-2,4-diamino-7,8-dihydro-9//-pyrimido-[4,5-b][l,4]- diazepine, an amino analog of 6-acetyldihydrohomopterin -- Synthetic approaches to methanopterin -- Synthesis and properties of tetrahydropterins coupled to 1,4-dihydropyridines -- A new synthesis of biopterin and some analogues from epoxyaldehydes -- Synthetic studies on the molybdenum cofactor -- A new regiospecific synthesis of anapterin and primapterin -- A novel and efficient synthesis of folylpolyglutamates -- Reaction of acidic anhydride and pyridine with folic acid and classical antifolates -- Quinazoline antifolate thymidylate synthase inhibitors: Synthesis of analogues containing heterocyclic isosteres of the para-aminobenzoate unit -- Synthesis of tetrahydro-8-deazabiopterin -- Synthesis and enzymic properties of new mechanism based substrates for dihydrofolate reductase of the 8-substituted pterin class. -- Imidazolines as carbon-transfer vehicles: models of the tetrahydrofolate (and other) coenzymes -- 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 -- Synthesis and biological evaluation of a fluorescent analogue of folic acid -- Metal complexes of tetrahydroneopterin -- Syntheses of lipophilic analogues of 2-desamino-2-CH3-NIO-propargyl- 5,8-dideazafolate targeted at the enzyme thymidylate synthase (TS). -- Studies in models of folate cofactors: oxidation of 5-methyltetrahydropterin revisited. -- New strategy in the synthesis of neopterin phosphates -- First regiospecific synthesis of 7-iso-D-neopterin and 7-iso-D-neopterin- 3 '-monophosphate -- II. ANALYSIS OF PTERINS AND FOLATES -- Detection of pterins in biological material using mass spectrometry -- Mass spectrometric methods for the structural determination of pteridines and folic acid derivatives -- Structural characterization of underivatized pteridines by laser desorption fourier transform mass spectrometry -- New immunoassays for determination of biopterin and neopterin in body fluids -- A new immunoassay for neopterin and biopterin -- Enzyme immunoassay for urinary neopterin -- A competitive enzyme linked ligand sorbent assay (ELLSA) for quantitation of erythrocyte folates -- Preparation of a bovine serum albumin based chiral matrix for resolution of (6R,S)-N5-formyltetrahydrofolate. -- Rp-HPLC methods for the isolation and chemical identification of pterins from monocytic blood cells -- Cyclodextrin based HPLC separation of 6-S and 6-R diastereomers of 5,10-dideaza and 5-deazatetrahydrofolates. -- Analysis of folate and antifolate metabolites by mass spectrometry -- A critical assessment of methods for measuring folate in human serum and red blood cells. -- HPLC analysis of intracellular folate compounds after enzymic conversion to the corresponding pteroates -- III. BIOSYNTHESIS AND BIOCHEMISTRY OF PTERINS -- The Gowland Hopkins Lecture: Biosynthesis of H4biopterin and related compounds -- The structure ofq-Bh2 - chemistry and biochemistry -- Pteridines in riboflavin biosynthesis -- Pteridine mimicking antibodies -- 6-Pyruvoyl-tetrahydropterin reductases -- Analysis of 6-pyruvoyl tetrahydropterin synthase, a target gene product of su(s) suppressor in Drosophila -- Synthesis of fluorinated 8-ribityllumazines as "F NMR probes and potential inhibitors of the light riboflavin synthase of Bacillus subtilis -- Studies on the oxidation state and biosynthesis of molybdopterin -- Molybdenum cofactor genes in Drosophila -- DNA photolyase: role of pterin in DNA repair. -- 7-Substituted pterins, a new class of mammalian pteridines -- Methanopterin: A structural and functional folic acid analogon in the biochemistry of methanogenic bacteria. -- Biosynthesis of methanopterin -- Tetrahydrobiopterin is required for the oxidation of arginine to nitric oxide by macrophages. -- Biosynthesis of 7-hydroxybiopterin -- GTP cyclohydrolase I from Escherichia coli. Molecular cloning and crystallization -- Molecular characterization of the GTP cyclohydrolase I gene of Drosophila: analysis of cDNA clones -- Inhibitors of bovine adrenal medullary sepiapterin reductase -- Catalytic implication of the reductase and isomerase activity of sepiapterin reductase in the biosynthesis of tetrahydrobiopterin -- Purification and characterization of sepiapterin reductase from human liver -- Biosynthesis of methanopterin and deazaflavin in Methanobacterium thermoautotrophicum -- Studies on riboflavin synthases of Bacillus subtilis. Amino acid sequence of the a subunit -- Structure of the lumazine synthase/riboflavin synthase complex of Bacillus subtilis: crystallization of hollow reconstitutß60, capsids. -- Biosynthesis of 6,7-dimethyl-8-ribityllumazine. Purification and properties of 3,4-dihydroxy-2-butanone 4-phosphate synthase -- High resolution electron microscopy on crystals of the icosahedral lumazine synthase/riboflavin synthase complex. -- Differential synthesis of LDH A-like proteins and of phosphoproteins in response to the modified deazaguanine-derivative queuine -- Metabolic control in HeLa-cells mediated by the deazaguanine-derivative queuine -- On the biosynthesis of the deazaguanine-derivative queuine: structure of the tgt gene of E. coli -- Changes in the level of biopterin and of queuine-containing tRNA during erythroid differentiation of murine erythroleukemia cells -- Brain contents of biopterins and monoamines after intraperitoneal injections of SUN0588, active 6R-tetrahydrobiopterin, during ontogeny in rats -- The effect of 2,4-diamino-6-hydroxypyrimidine on tetrahydrobiopterin and serotonin in the gastrointestinal tract of mice. -- Differential metabolism of tetrahydrobiopterin in central and peripheral monoamine neurons maintained in culture -- IV. TETRAHYDROBIOPTERIN DEFICIENCY -- Inborn errors in tetrahydrobiopterin metabolism -- Molecular defects in dihydropteridine reductase deficiency -- Screening and treatment of tetrahydrobiopterin deficiency -- Tetrahydrobiopterin deficient phenylketonuria detected by neonatal screening in Taiwan -- Prenatal diagnosis of 6-pyruvoyl tetrahydropterin synthase deficiency in East Asia. -- Heterogeneity of tetrahydrobiopterin deficiency: combined phenylalaninetetrahydrobiopterin loading test -- Unusual case of atypical PKU: peripheral or central form of PPH4S deficiency -- Development of vision in BH4, deficiency -- Fetal guinea-pig model of tetrahydrobiopterin deficiency -- Unexpected favorable clinical results of therapy in late diagnosed DHPR deficiency -- Systematic investigation for biopterin defects in hyperphenylalaninemic patients -- Neuroradiological improvement after one year of therapy in a case of DHPR deficiency -- V. PTERINS VARIOUS -- Lumazine protein and the bioluminescence of photobacterium -- Binding of pteridine derivatives to lumazine apoprotein -- Hormonal imbalance by pteridine treatment in diapausing Pieridae induces mutations in the progeny of treated Drosophila melanogaster -- N-acetyltransferase activity in Pieris brassicae -- VI. BIOLOGY OF PTERINS -- Pteridines and the immune response. -- Neopterin elevation and interferon induction in viral diseases -- Tetrahydrobiopterin in human T cells: control of its biosynthesis by interferon-y and interleukin 2 - modulator function in interleukin 2 perception -- Effects of BH4 on the synthesis of serotonin in brain slices and synaptosomes: implications for the use of BH4 as a therapeutic agent -- Regulation of cellular proliferation by tetrahydrobiopterin -- Characterisation of the mutation in dihydropteridine reductase deficiency -- Urinary excretion of total pteridines in cancer -- Alterations of interferon-gamma-induced monocyte activation by immunomodulating compounds determined by neopterin production -- Levels of neopterin, biopterin, 5-hydroxyindoleacetic acid, and homovanillic acid in cerebrospinal fluid of sick neonates and infants -- Urinary neopterin levels in healthy children -- Urinary neopterin factor in viral and bacteriological children infections -- Urinary neopterin levels in liver transplant -- The effect of IL-2, neopterin and immunomodulators on neopterin release from macrophages and PBMC -- Membrane transport of unconjugated pteridines. The model of human erythrocytes. -- Encephalopathy and abnormal cerebrospinal fluid pteridine profile. Fact or artefact ? -- Informativity of pteridine measurements in the survey of organ transplantations -- Effect of triamteren on urinary excretion of pterins in different rat strains -- Pteridines and retinal degenerations in rats and humans -- Pterins in bovine, rat, quail and human retina -- Comparison of urinary biopterin in rats with various housing and enviromental conditions -- Differences in the quantity and distribution of urinary pterins in various species of mammals -- Total biopterin levels in the ventricular CSF of Parkinson's disease and essential tremor -- Urinary xanthopterin and derivatives as indicators of liver disease -- Genetic control of dihydropterin oxidase activity in Drosophila melanogaster -- A controlled system for supplementation experiments in Drosophila melanogaster -- New eye-color mutants affecting the biosynthesis of pteridines and ommochromes in Drosophila melanogaster -- Search for 6- and 7-biopterins in human saliva -- VII. TETRAHYDROBIOPTERIN-DEPENDENT MONOOXYGENASES -- Regulation of the aromatic amino acid hydroxylases -- Expression of rat liver dihydropteridine reductase in Escherichia coli -- Escherichia coli dihydropteridine reductase is a trifunctional enzyme with dihydrofolate reductase activity. -- Rat liver preparations with glyceryl etherase activity -- Purification and characterization of a membrane associated folate binding protein from human leukemic CCRF-CEM cells -- On the effects of high protein diet and of starvation on phenylalanine hydroxylase activities in rats. -- Effects of experimental diabetes on phenylalanine hydroxylase activities in rats -- Molecular defects of PKU in Italy differ from those of other European countries -- The oxidation of tetrahydropteridines by phenylalanine hydroxylase -- Interaction of catecholamines and tetrahydropterins with bovine liver phenylalanine hydroxylase -- Studies of tetrahydrobiopterin uptake in rat brain synaptosomes -- The influence of cofactor side-chain chirality on the activity and regulation of phenylalanine and tyrosine and hydroxylases -- Limited denaturation stimulates tetrahydrobiopterin-dependent activity of rat liver phenylalanine hydroxylase -- Effect of limited proteolysis on structure and activity of phenylalanine hydroxylase -- Tetrahydropterin as a possible natural cofactor in the Drosophila phenylalanine hydroxylation system -- Interaction of substrate analog inhibitors with rat liver dihydropteridine reductase -- Simultaneous purification of phenylalanine hydroxylase, phenylalanine hydroxylase stimulator protein, and dihydropteridine reductase from rat liver -- VIII. FOLATES -- A. DIHYDROFOLATE REDUCTASE -- NMR and mutagenesis studies of dihydrofolate reductase -- Spectroscopic studies of the interaction of ligands with dihydrofolate reductase -- Comparison between human and bacterial dihydrofolate reductase structures -- Mutagenesis of human dihydrofolate reductase structure as a probe of enzyme function -- Folate and dihydrofolate reduction by mouse dihydrofolate reductase -- Kinetic mechanism of recombinant human dihydrofolate reductase -- The kinetic mechanism of the reaction catalyzed by an R-plasmid (R-67) dihydrofolate reductase from E.coli. -- Mechanism based inhibitors of dihydrofolate reductase. -- Trimetrexate resistant L. casei and S. faecium -- Second site revertants of E. coli dihydrofolate reductase -- Structural and energetic aspects of the reaction pathway and transition state for hydride-ion transfer in dihydrofolate reductase -- Cloning of trimethoprim-resistant dihydrofolate reductase from multiresistant staphylococci and expression in E. coli -- Role of TRP-24 in binding and catalysis for human dihydrofolate reductase (DHFR) -- Mutation at hydrophobic residues in dihydrofolate reductase -- Determination of the functional role of phenylalanine-31 of recombinant human dihydrofolate reductase by site-directed mutagenesis -- Molecular modeling studies and crystal structure determination of pteridine antifolate-DHFR enzyme interactions -- Allelic variants of Chinese hamster dihydrofolate reductase -- B: THYMIDYLATE SYNTHASE -- Thymidylate synthase - structural and functional considerations -- Defining the catalytic role of specific amino acids in thymidylate synthase by site-specific mutagenesis -- Studies of the effects of mutagenesis on a conserved active site arginine residue in thymidylate synthase -- 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. -- Interaction of N4-hydroxy-dCMP and N4-hydroxy-5-FdCMP with L1210 thymidylate synthase differing in sensitivity towards 5- FdUMP Inhibition -- Mechanism of thymidylate synthase inhibition by N4-Hydroxy-dCMP -- Thymidylate synthase activity in bronchoalveolar lavage cells as a possible marker in lung cancer diagnosis -- Purification and properties of Hymenolepis diminuta and regenerating rat liver thymidylate synthases -- Influence of FdUMP on the binding of methotrexate to thymidylate synthase -- Efficient expression of mammalian thymidylate synthase in Escherichia coli -- Catalytic role of histidine-147 in Escherichia coli thymidylate synthase -- Variation among human thymidylate synthase enzymes in folate affinity -- Evaluation of in vivo inhibition of thymidylate synthase in patients with colorectal cancer treated with 5-fluorouracil -- Effect of leucovorin on 5-fluorouracil induced inhibition of thymidylate synthase in murine colon cancer -- Feedback inhibition of thymidylate synthase by dihydrofolate polyglutamates cannot account for partial depletion of tetrahydrofolate cofactors by antifolates -- Kinetic studies on thymidylate synthase from Lactobacillus casei -- C. METHIONINE SYNTHASE -- Studies on the cobalamin-dependent methionine synthase from Escherichia coli K12 -- Foimyl phosphate as an intermediate in the N10-formyltetrahydrofolate synthetase reaction. -- Enzymes of homocysteine remethylation and transsulfuration in methionine or cholesterol induced atherosclerosis in rabbits -- Biochemical changes in porcine neural tissue after inactivation of methionine synthase by nitrous oxide. -- Increased synthesis of AdoMet but not of methionine during testosterone stimulation of polyamine biosynthesis in mouse kidney -- D. ENZYMOLOGY AND METABOLISM -- Role of folylpolyglutamate synthetase in the regulation of folate and antifolate metabolism. -- NAD-dependent methylenetetrahydrofolate dehydrogenase-cyclohydrolase present in transformed mammalian cells -- Gammaglutamyl hydrolases -- Human methenyltetrahydrofolate synthetase -- Folate catabolism in man and the rat -- Effects of growth rate on y-glutamyl hydrolase in Ehrlich ascites carcinoma cells -- Folylpolyglutamate synthesis in Neurospora crassa. Wild type FPGS activity and transformation of polyglutamate deficient mutants using cosmid vectors containing the met-6 gene -- Cloning and expression of the gene encoding Lactobacillus casei folylpolyglutamate synthetase in Escherichia coli -- Effect of treatments with different anticonvulsant drugs on folate pattern in rat liver. -- A sensitive new microassay useful for measurement and purification of mammalian folylpolyglutamate synthetase -- Tissue differences in N5 formyltetrahydrofolate metabolism -- E. FOLATES IN ENDOGENOUS PURINE METABOLISM -- Glycinamide ribonucleotide transformylase from E. coli: characterization and inhibition. -- Estimation of the flux control coefficient of glycineamide ribonucleotide transformylase for purine biosynthesis de novo -- Monocyclic 5-deazatetrahydrofolate analogues as inhibitors of de novo purine biosynthesis -- Inhibition of glycinamide ribonucleotide transformylase, methotrexate transport, and the growth of MCF-7 cells by 5,8-dideazafolates -- F. FOLATES, VARIOUS -- Formation of methylcobamide from methyltetrahydrofolate by acetogenic bacteria: enzymology and redox chemistry. -- Incorporation of the ring carbon of histidine into coenzymes of folylpolyglutamates. -- In vivo effect of folic acid on fragile-site expression -- IX. ANTIFOLATES -- A. DEAZADERIVATIVES -- New synthetic studies on deazafolates -- Molecular modeling studies on deazatetrahydrofolates -- Biochemical pharmacology of deazatetrahydrofolates -- Synthesis and evaluation of l-deaza-7,8-dihydropteridines and ring analogues -- In vitro and in vivo activity of the GAR transformylase inhibitor 5-deazacyclotetrahydrofolate -- vitro and in vivo studies with 2-desamino-2-CH3-N10-propargyl-5,8- dideazafolate (ICI 198583), an inhibitor of thymidylate synthase -- 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. -- Transport of 5,10-dideazatetrahydrofolic acid (DDATHF) in CCRF-CEM sensitive and methotrexate resistant cell lines -- Synthesis and structure-activity relationship studies of 5,10- dideazatetrahydrofolic acid (DDATHF) -- Synthesis and antifolate properties of 5-alkyl-5-deazaaminopterin analogues modified in the 10-position -- Synthesis and biological evaluation of 2-desamino-2-methyl-5,10- dideazatetrahydrofolate -- Quinazoline antifolate thymidylate synthase inhibitors: potent cytotoxic agents containing heterocyclic isosteres of the para-amino benzoate unit -- Antifungal activity of some 2,4-diamino-5-methyl-6-alkyl quinazoline -- Membrane transport characteristics of the thymidylate synthase inhibitor 2-desamino-2-methyl-N10-propargyl-5,8-dideazafolic acid. -- Synthesis and potential antitumor activity of 5-deaza analogs of 5,10- methylenetetrahydrofolic acid -- Theoretical studies of the structures and conformations of triazine antifolates -- In vitro and in vivo metabolism of 5-DACTHF, an acyclic tetrahydrofolate analog -- Measurement of retained thymidylate synthase (TS) inhibition by antifolates in whole cells in vitro -- Substitution on the benzene ring of quinazoline antifolates that inhibit thymidylate synthase -- Inhibition of de novo purine synthesis by deazatetrahydrofolates -- B.Methotrexates -- Resistance to methotrexate in experimental models and in patients -- Methotrexate peptides as cancer chemotherapeutic agents -- Biochemical determinants of methotrexate selectivity -- Mechanisms underlying methotrexate inactivity in human head and neck cancer xenografts -- Design and synthesis of novel methotrexate derivatives for antibody directed drug targeting -- 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 -- Folate enhancement of antifolate synergism in lymphoma cells -- Amino acid oxidation and dihydrofolate reductase inactivation photosensitized by a diaminopteridine -- Synchronisation of U937 and SW626 cancer cell lines of human origin using methotrexate -- New inhibitors of plasmodial folate synthesis - comparison of cell-free, whole cell and in vivo activities for single drugs and drug combinations -- Effect of vincristine on methotrexate cytotoxicity and accumulation in MCF-7 cells, a human breast cancer cell line -- The y-tetrazole analog of methotrexate: design, synthesis and biological activity -- Effect of intravenous 24 hr infusions of methotrexate on unconjugated pteridine metabolism -- Covalent labeling of dihydrofolate reductase and folate transport proteins by fluorescein methotrexate -- Study of methotrexate polyglutamate formation in cultured leukemic cells -- C. Various Antifolates -- Folyl polyglutamates in metabolism and chemotherapy -- Biological determination of selective antitumor action of 4-amino-folate analogs -- Inhibition of the thymidylate synthase cycle of leukemia cells by antifolates: The usefulness of the cellular tritium release assay -- Fluoroglutamate-containing folates and antifols: probing the role of polyglutamylation in vitro -- Therapeutic strategies for 5-fluorouracil-leucovorin based upon cellular metabolic characteristics in human colon adenocarcinoma xenografts -- The lack of response of human colonic tumor cell lines to biochemical modulation by folinic acid. -- Folinic acid as a source of intracellular 5,10-methylenetetrahydrofolate in human carcinoma cells -- Structure activity relationships of multidrug resistance -- Enhancement of the cytotoxicity of fluoropyrimidines to human carcinoma cell lines by leucovorin -- D. Transport And Absorption Of Folates And Antifolates -- Methotrexate transport via the high-affinity folate binding protein of L1210 cells. -- Combined affinity and ion pair liquid chromatographies for direct analysis of tissue folate composition -- Tumor cell sensitivity and resistance to folate analogues: the role of carrierand receptor-mediated transport systems -- Lysosomal permeability to methotrexate polyglutamates -- Folic acid metabolism in placental cells associated with neural tube defects -- Homologous membrane folate binding proteins in human placenta -- A high-affinity folate binding protein in human amniotic fluid -- Interaction of N-hydroxy(sulfo)succinimide active esters with the reduced folate/methotrexate transport system from human CCRF-CEM leukemia cells -- Renal uptake and metabolism of 5-methyltetrahydrofolate in the rat -- Methotrexate- and folate-lipid conjugates of defined chemical structures as new antifolate analogs and transport probes -- Characterization of receptor-mediated (anti)folate uptake in human CCRF-CEM cells -- Author Index -- Subject Index -- List of Participants -- Backmatter