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)."

In 1962, 30 years after the discovery by du Vigneaud have pathologic consequences. One potentially sig- of a new sulfur amino acid, homocysteine; Carson and nificant health outcome of such mild to moderate Neil reported two siblings with mental retardation in hyperhomocysteinemia is an increased risk of occlu- northern Ireland with elevated urinary homocystine. sive vascular disease. Homocysteine concentrations in Nearly simultaneously, Gerritsen and Waisman patients with vascular disease were, on average, 31 % greater than in normal controls. Prospective assess- identified increased homocystine in the urine of a mentally retarded infant in Wisconsin. Within two ment of vascular disease risk among men with higher years, Harvey Mudd, James Finkelstein, and their homocysteine concentrations indicated that plasma coworkers at the National Institutes of health (USA) homocysteine at only 12% above the upper limit of that the enzyme cystathionine ~- normal levels was associated with a 3. 4-fold increase had reported synthase was lacking in a liver biopsy specimen from in risk of acute myocardial infarction. Studies from another patient with homocystinuria. This was the original Framingham Heart Study cohort (USA) the first indication of a vitamin relationship to have shown strong, positive correlation between homocystinuria, because that enzyme has as its co- plasma homocysteine concentration and degree of factor vitamin B6 (pyridoxal phosphate). Thereafter, carotid stenosis.

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)."

In 1962, 30 years after the discovery by du Vigneaud have pathologic consequences. One potentially sig- of a new sulfur amino acid, homocysteine; Carson and nificant health outcome of such mild to moderate Neil reported two siblings with mental retardation in hyperhomocysteinemia is an increased risk of occlu- northern Ireland with elevated urinary homocystine. sive vascular disease. Homocysteine concentrations in Nearly simultaneously, Gerritsen and Waisman patients with vascular disease were, on average, 31 % greater than in normal controls. Prospective assess- identified increased homocystine in the urine of a mentally retarded infant in Wisconsin. Within two ment of vascular disease risk among men with higher years, Harvey Mudd, James Finkelstein, and their homocysteine concentrations indicated that plasma coworkers at the National Institutes of health (USA) homocysteine at only 12% above the upper limit of that the enzyme cystathionine ~- normal levels was associated with a 3. 4-fold increase had reported synthase was lacking in a liver biopsy specimen from in risk of acute myocardial infarction. Studies from another patient with homocystinuria. This was the original Framingham Heart Study cohort (USA) the first indication of a vitamin relationship to have shown strong, positive correlation between homocystinuria, because that enzyme has as its co- plasma homocysteine concentration and degree of factor vitamin B6 (pyridoxal phosphate). Thereafter, carotid stenosis.