STRUCTURAL ANALOGS OF S-ADENOSYLMETHIONINE

S-腺苷甲硫氨酸的结构类似物

• 批准号: 3276879
• 负责人: Ronald T Borchardt
• 金额: $ 15.76万
• 依托单位: UNIVERSITY OF KANSAS LAWRENCE
• 依托单位国家: 美国
• 财政年份: 1980
• 资助国家: 美国
• 起止时间: 1980-12-01 至 1990-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3276879
• 关键词: L cell; RNA; S adenosylmethionine; aminoacid analog; aminohydrolases; antineoplastics; antiviral agents; bacteria; bacterial proteins; catecholamines; cats; chemical synthesis; chemotaxis; cow; drug design /synthesis /production; drug screening /evaluation; enzyme inhibitors; enzyme structure; homocysteine; hypothalamus; laboratory rabbit; laboratory rat; leukocytes; liver; messenger RNA; neuroblastoma; neurotransmitter metabolism; neurotransmitters; oncogenic virus; posttranslational modifications; protein biosynthesis; radiotracer; spleen; synaptosomes; transfer RNA; transmethylation; virus protein; virus replication

This program has as its primary objective the design, synthesis and biological evaluation of inhibitors of S-adenosylmethionine (AdoMet)-dependent macromolecular methylations (e.g., nucleic acid and protein). This objective will be accomplished through the design and synthesis of inhibitors of eukaryotic and prokaryotic S-adenosylhomocysteine (AdoHcy) hydrolase. AdoHcy hydrolase is the enzyme that regulates the cellular level of AdoHcy, which is the endogenous inhibitor of AdoMet-dependent methylations. To more rationally design inhibitors of AdoHcy hydrolase, we will study the structure of both the prokaryotic and eukaryotic enzymes, their mechanisms of catalysis, their mechanisms of interaction with inhibitors and the physiological mechanisms by which the activity of these enzymes are regulated in vivo. The biochemical mechanisms by which neplanocin A, a potent inhibitor of AdoHcy hydrolase, produces its antiviral and antibacterial effects will be elucidated. Analogs of neplanocin A will be synthesized and evaluated as inhibitors of eukaryotic (bovine liver) and prokaryotic (A. faecalis) AdoHcy hydrolase and as substrates for eukaryotic (murine L929 cells) and prokaryotic (A. faecalis, B. subtilis) adenosine kinase. The neplanocin analogs will be evaluated for their effects on AdoMet/AdoHcy metabolism in eukaryotes (murine L929, human colon carcinoma cell line HT-29, neuroblastoma N2a cells) and prokaryotes (A. faecalis, B. subtilis) and for their antiviral (vaccinia virus), antitumor (human colon carcinoma cell line HT-29) and antibacterial (A. faecalis, B. subtilis) effects. AdoHcy hydrolase inhibitors (e.g., neplanocin A) will be used to determine the chemical nature of protein carboxylmethylation (e.g., D-aspartyl residues, Beta-linked aspartyl residues) in neuroblastoma cells and to determine the physiological function of this type of post-translational modification in neuronal tissue.

该计划的主要目标是设计、综合和 S-腺苷甲硫氨酸抑制剂的生物学评价 (AdoMet) 依赖性大分子甲基化（例如核酸和 蛋白质）。 这一目标将通过设计和 真核和原核抑制剂的合成 S-腺苷高半胱氨酸（AdoHcy）水解酶。 AdoHcy水解酶是酶 调节 AdoHcy 的细胞水平，AdoHcy 是内源性的 AdoMet 依赖性甲基化抑制剂。 更合理的设计 AdoHcy 水解酶抑制剂，我们将研究两者的结构 原核生物和真核生物的酶、它们的催化机制、它们的作用 与抑制剂相互作用的机制和生理机制 这些酶的活性在体内受到调节。 这 Neplanocin A（AdoHcy 的有效抑制剂）的生化机制 水解酶，产生抗病毒和抗菌作用 阐明了。 neplanocin A 的类似物将被合成并评估为 真核生物（牛肝）和原核生物（粪曲霉）抑制剂 AdoHcy 水解酶和作为真核细胞（鼠 L929 细胞）和 原核生物（粪杆菌、枯草芽孢杆菌）腺苷激酶。 奈普拉诺星 将评估类似物对 AdoMet/AdoHcy 代谢的影响 真核生物（鼠L929、人结肠癌细胞系HT-29、 神经母细胞瘤 N2a 细胞）和原核生物（粪杆菌、枯草芽孢杆菌）以及 他们的抗病毒（痘苗病毒），抗肿瘤（人结肠癌细胞） 线 HT-29）和抗菌（粪杆菌、枯草芽孢杆菌）作用。 青春期 水解酶抑制剂（例如，neplanocin A）将用于确定 蛋白质羧甲基化的化学性质（例如，D-天冬氨酰残基， 神经母细胞瘤细胞中的β连接天冬氨酰残基）并确定 此类翻译后修饰的生理功能 神经元组织。