This book has been developed from its earlier and far less formal presentment as the proceedings of a symposium entitled The Biochemistry of S-Adenosylmethionine as a Basis for Drug Design that was held at the Solstrand Fjord Hotel in Bergen, Norway on June 30-July 4, 1985. The purpose of the symposium was to bring together scientists from various disciplines (biochemistry, pharmacology, virology, immunology, chemistry, medicine, and so on) to discuss the recent advances that have been made in our understanding of the biological roles of S­ adenosylmethionine (AdoMet) and to discuss the feasibility of utilizing AdoMet-dependent enzymes as targets for drug design. Thus the information provided herein will be of value not only to basic scientists involved in elucidating the role of AdoMet in biology, but also to medicinal chemists who are using this basic knowledge in the process of drug design. The volume should also be of interest to pharmacologists and clinicians involved in biological evaluation of potential therapeutic agents arising from the efforts of the biochemists and medicinal chemists. Each plenary speaker at the symposium was requested to submit a chapter reviewing recent contributions of their discipline to our base of knowledge about the biological role of AdoMet. Topics covered in this volume include protein and phospholipid methylations (Section A), nucleic acid methyl­ ations (Section B), the regulation of AdoMet, S-adenosylhomocysteine, and methylthioadenosine metabolism (Section C), clinical aspects of AdoMet (Section D), and the design, synthesis, and biological evaluation of trans­ methylation inhibitors (Section E).

Inhalt

Preface.- Tributes.- Acknowledgments.- Contributors.- A. Protein and Phospholipid Methylations.- Protein Methylation at Abnormal Aspartyl Residues.- Enzymology of Protein Methylation: Recent Developments.- Is There a Function for Protein Carboxymethylation in the Nervous System?.- Methyl-Accepting Chemotaxis Proteins in Bacteria.- Biochemistry of Methylated Phospholipids.- Phospholipid Methylation and Cellular Differentiation.- Methylation of Phosphatidylethanolamine: Enzyme Characterization, Regulation, and Physiological function.- Regulation of Phospholipid Methylation by Reversible Phosphorylation.- Brain Phosphatidylcholine Pools as Possible Sources of Free Choline for Acetylcholine Synthesis.- B. Nucleic Acid Methylations.- DNA Methylation: Overview and Prospectives.- Tissue-Specific DNA Methylation Patterns: Biochemistry of Formation and Possible Role.- Regulation of Gene Expression by Site-Specific Promoter Methylation.- Carcinogenesis and DNA Hypomethylation in Methyl-Deficient Animals.- The Role of Coenzymes and tRNA Modifications in Metabolic Control of Gene Expression.- Relationship Between Methylation and Maturation of Ribosomal RNA in Prokaryotic and Eukaiyotic Cells.- Distribution of m6A in RNA and Its Possible Biological Role.- C. Regulation of S-Adenosylmethionine, S-Adenosylhomocysteine, and Methylthioadenosine Metabolism.- Regulation of S-Adenosylmethionine Synthesis in Human Lymphocytes.- Cancer, Methionine, and Transmethylation.- The Centrality of S-Adenosylhomocysteinase in the Regulation of the Biological Utilization of S-Adenosyhnethionine.- S-Adenosylhomocysteine Hydrolase.- Probes for Examining the Structure and Function of Human S-Adenosylhomocysteine Hydrolase, and for Isolation of cDNA.- Disposition of Endogenous S-Adenosylhomocysteine and Homocysteine Following Exposure to Nucleoside Analogs and Methotrexate.- Regulation of S-Adenosylmethionine and Methylthioadenosine Metabolism in Methylthioadenosine Phosphorylase-Deficient Malignant Cells.- Purification and Properties of Mammalian S'-Methylthioadenosine Phosphorylase and Bacterial 5'-Methylthioadenosine Nucleosidase: Pharmacological Implications and Perspectives.- Uncoupling of Granulopoietic Cell Proliferation and Differentiation by Methylthioadenosine.- D. Clinical Aspects of S-Adenosylmethionine.- AdoMet as a Drug: Pharmacokinetic and Pharmacological Aspects.- A Biochemical Study of Depressed Patients Receiving S-Adenosyl -L-methionine (SAM).- Noradrenergic and Cardiovascular Effects ofChronic S-Adenosyl-methionine in Healthy Volunteers.- Role of the One-Carbon Cycle in Neuropsychiatry.- Double-Blind Study of S-Adenosylmethionine Versus Placebo in Hip and Knee Arthrosis.- E. Design, Synthesis, and Biological Evaluation of Transmethylation Inhibitors.- Methionine Analog Inhibitors of S-Adenosylmethionine Biosynthesis as Potential Antitumor Agents.- Metabolism and Mechanism of Action of Neplanocin A-A Potent Inhibitor of S-Adenosylhomocysteine Hydrolase.- Biological Consequences of S-Adenosyl-L-homocysteinase Inhibition by Acyclic Adenosine Analogs.- Nucleoside Analogs as Antiviral Agents.- Studies Concerning the Mechanism of Action of 3-Deazaadenosine in Leukocytes.- Mechanism-Based Inhibitors of Alkyltransferase.- Sinefungin and Derivatives: Synthesis, Biosynthesis, and Molecular Target Studies in Leishmania.