REACTION INTERMEDIATE ANALOGS OF CARNITINE ACYL TRANSFER

肉碱酰基转移的反应中间体类似物

• 批准号: 3568407
• 负责人: RICHARD David GANDOUR
• 金额: $ 9.21万
• 依托单位: VIRGINIA POLYTECHNIC INST AND ST UNIV
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-01-01 至 1996-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3568407
• 关键词: active sites; acyl coA; acyltransferase; carnitine; chemical structure function; conformation; drug design /synthesis /production; enzyme inhibitors; enzyme mechanism; enzyme structure; enzyme substrate analog; morpholine; receptor binding; stereoisomer

We are designing, preparing, and assaying conformationally constrained inhibitors of carnitine acetyltransferase (CAT), carnitine octanoyltransferase (COT), and carnitine palmitoyltransferase (CPT). The primary aim is to identify the topographical arrangement of the key recognition sites on these enzymes by comparing inhibition constants (K- i's) of a series of cyclic analogues. Our long-range goal is to elucidate the structure of the molecular interactions between carnitine and the active site in these enzymes. Identifying these molecular interactions will lead to a better understanding of the physiological chemistry and, more specifically, of the regulation of the enzymes. Beyond the academic interest, these compounds have commercial value. Hemiacylcarnitiniums and morpholiniums show strong binding to carnitine acyltransferases. These inhibitors mimic the putative reaction intermediate in the acyl transfer from carnitine to Coenzyme A. These compounds also mimic carnitine and acylcamitines. They might compete with these natural substrates for other carnitine and acylcarnitine receptors in cells. As such, our compounds have potential for pharmaceutical value in many areas -- hypoglycemic agents, protectors in myocardial ischemia, spermicides, etc. Hemicholinium lipids inhibit protein kinase C and cell- cell aggregation. These compounds inactivate sperm and HIV. Modifications in the design will lead to more selective spermicides and anti-HIV agents. Every eukaryotic cell contains carnitine. Energy production in the cell from fatty acid metabolism depends on carnitine. As carnitine is not synthesized in every cell, proteins transport it across the plasma membrane. More recently, researchers have found a carnitine receptor and a carnitine palmitoyltransferase on erythrocytes, which are cells that lack mitochondria. Our compounds should bind to both of these proteins.

我们正在设计，准备和分析构象约束 肉碱乙酰转移酶（CAT），肉碱的抑制剂 八氧基转移酶（COT）和肉碱棕榈酰转移酶（CPT）。这 主要目的是确定钥匙的地形布置 通过比较抑制常数（k-）在这些酶上的识别位点（k-） 一系列循环类似物的i。我们的远程目标是阐明 肉碱与分子相互作用的结构 这些酶的活性位点。识别这些分子相互作用 将使人们更好地了解生理化学，并且 更具体地说，是对酶的调节。超越学术 兴趣，这些化合物具有商业价值。 半基因基硝基属和形态表现出与肉碱的较强结合 酰基转移酶。这些抑制剂模仿了假定的反应 酰基从肉碱到辅酶A的中间体中间。 化合物还模仿肉碱和酰基胺。他们可能与 这些天然底物用于其他肉碱和酰基肉碱受体 在细胞中。因此，我们的化合物具有药物价值的潜力 在许多领域 - 降血糖药物，心肌缺血的保护者， 杀精子剂等。脂质脂质抑制蛋白激酶C和细胞 - 细胞聚集。这些化合物使精子和艾滋病毒失活。修改 在设计中，将导致更具选择性的杀精子剂和抗HIV剂。 每个真核细胞都含有肉碱。细胞中的能源生产 来自脂肪酸的代谢取决于肉碱。因为肉碱不是 蛋白质在每个细胞中合成，将其转运到血浆中 膜。最近，研究人员发现了肉碱受体和 红细胞上的肉碱棕榈转移酶，这是细胞的细胞 缺乏线粒体。我们的化合物应与这两种蛋白质结合。