STRUCTURAL ANALOGS OF S-ADENOSYLMETHIONINE

S-腺苷甲硫氨酸的结构类似物

• 批准号: 3276876
• 负责人: Ronald T Borchardt
• 金额: $ 12.28万
• 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 1985-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3276876
• 关键词: L cell; RNA; S adenosylmethionine; aminoacid analog; aminohydrolases; antiviral agents; bacteria; catecholamines; chemical synthesis; chemotaxis; drug screening /evaluation; enzyme structure; homocysteine; leukocytes; liver; messenger RNA; neuroblastoma; neurotransmitter metabolism; neurotransmitters; oncogenic virus; radiotracer; spleen; synaptosomes; transfer RNA; transmethylation; virus replication

This program has as its primary objective the design and synthesis of inhibitors of S-adenosylmethionine (AdoMet)-dependent methylations as potential experimental or chemotherapeutic agents. Two approaches will be taken to accomplish this objective: (1) the design of S-adenosylhomocysteine (AdoHcy9 analogs that will selectively bind to specific methyltransferases; and (2) the design of adenosine analogs that will inhibit AdoHcy hydrolase, thereby raising the intracellular level of this natural methylase inhibitor. The AdoHcy analogs will be evaluated as inhibitors of a series of purified small molecule methyltransferases (e.g., catechol-O-methyltransferase, phenylethanolamine N-methyltransferase, histamine N-methyltransferase, hydroxyindole O-methyltransferase, aminopropyltransferases etc.) and a series of purified macrmolecule methyltransferases (e.g., t-RNA methylases, mRNA methylases, protein methylases, phospholipid methylases, etc.). The adenosine analogs will be evaluated on purified bovine AdoHcy hydrolase. Both the AdoHcy and adenosine analogs will be evaluated for their ability to inhibit catecholamine metabolism in neuroblastoma cells, vaccinia virus replication in L-cells, leucocyte chemotaxis and secretion from hypothalamic synaptosomes and isolated perfused cat spleen. Studies will also be carried out to determine the active site of histamine-N-methyltransferase and AdoHcy hydrolase using affinity labeling reagents and to determine their catalytic transition states using isotopic probes.

该计划的主要目标是抑制剂的设计和合成 S-腺苷甲硫氨酸 (AdoMet) 依赖性甲基化作为潜在的 实验剂或化疗剂。 将采取两种方法 实现这一目标：（1）S-腺苷高半胱氨酸（AdoHcy9 选择性结合特定甲基转移酶的类似物；和（2） 设计抑制 AdoHcy 水解酶的腺苷类似物，从而提高 这种天然甲基化酶抑制剂的细胞内水平。 AdoHcy 类似物 将被评估为一系列纯化小分子的抑制剂 甲基转移酶（例如儿茶酚-O-甲基转移酶、苯乙醇胺 N-甲基转移酶、组胺N-甲基转移酶、羟基吲哚 O-甲基转移酶、氨丙基转移酶等）等一系列纯化 大分子甲基转移酶（例如 t-RNA 甲基化酶、mRNA 甲基化酶、 蛋白质甲基化酶、磷脂甲基化酶等）。 腺苷类似物将 对纯化的牛 AdoHcy 水解酶进行评估。 AdoHcy 和腺苷 将评估类似物抑制儿茶酚胺代谢的能力 在神经母细胞瘤细胞中，痘苗病毒在 L 细胞、白细胞中复制 下丘脑突触体的趋化性和分泌以及分离灌注 猫的脾脏。 还将进行研究以确定其活性位点 使用亲和标记的组胺-N-甲基转移酶和 AdoHcy 水解酶 试剂并使用同位素测定其催化过渡态 探针。