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: 3300558
• 负责人: RICHARD David GANDOUR
• 金额: $ 6.98万
• 依托单位: LOUISIANA STATE UNIV A&M COL BATON ROUGE
• 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 1992-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3300558
• 关键词: acyl coA; carnitine; chemical reaction; chemical structure function; chemical synthesis; chloramphenicol acetyltransferase; cis trans isomerization; conformation; diabetes mellitus; diabetes mellitus therapy; drug metabolism; enzyme inhibitors; enzyme mechanism; gluconeogenesis; laboratory rat; liver cells; membrane permeability; morpholine; stereoisomer

We are designing, preparing, and assaying conformationally rigid inhibitors of carnitine octanoyltransferase (CAT), carnitine octanoyltransferase (COT), and carnitine palmitoyltransferase (CPT), enzymes that catalyze acyl transfer between carnitine and coenzyme A (CoA). The primary aim of the proposed work is to identify the topographical arrangement of the four key recognition sites on these enzymes by comparing inhibition constants (Ki's) of a series of rigid, cyclic analogs. Our long-range goal is to map the pattern of molecular recognition in these enzymes. Identifying the molecular interactions will lead to a better understanding of the physiological chemistry and, more specifically, regulation of the enzymes. Carnitine has critical functions in the overall oxidation of fatty acids for the generation of energy. Specifically it is required for the transport of long-chain fatty acids across the inner mitochondrial membrane. Because of this, our inhibitors have potential therapeutic value in diabetes, ischemia, and drug delivery. Insulin deficiency leads to ketosis. CPT is the rate-limiting enzyme in ketogenesis and thus CPT inhibitors are anti-ketotics in diabetes. Ischemia causes an increase in acylcarnitines, which alter the activity of sodium, potassium ATPase and calcium ATPase. CPT inhibitors can alter metabolic dysfunction to improve myocardial function in the ischemic heart. Acylcarnitines enhance membrane permeability for a variety of poorly absorbing drugs. The proposed molecules or isomers of acylarnitines, could function as drug absorption enhancing agents. Preliminary results show that our meso-2,6(biscarboxymethyl)-4,4- dimethylmorpholinium bromide inhibits gluconeogenesis in rat hepatocytes. As such, it may be useful as a hypoglycemic agent in the treatment of diabetes. These results bode well for the pharmacological potential of our proposed inhibitors.

我们正在设计，准备和分析构象上的刚性抑制剂 carnitine octanoyltransferase（CAT），carnitine octanoyltransferase酶 （COT）和肉碱棕榈酰转移酶（CPT），催化的酶 肉碱和辅酶A（COA）之间的酰基转移。主要目的 拟议的工作是确定四个的地形布置 通过比较抑制常数，这些酶的关键识别位点 一系列刚性的循环类似物的（ki）。 我们的远程目标是映射 这些酶中分子识别的模式。 识别 分子相互作用将使人们更好地理解 生理化学，更具体地说，是对酶的调节。 肉碱在脂肪酸的总氧化中具有关键功能 为了产生能量。 具体而言，这是必需的 长链脂肪酸在内部线粒体上运输 膜。 因此，我们的抑制剂具有潜在的治疗价值 在糖尿病，缺血和药物输送中。 胰岛素缺乏导致 酮症。 CPT是生酮发生中的限速酶，因此CPT 抑制剂是糖尿病中的抗酮类药物。 缺血导致增加 改变钠，钾ATPase和 钙ATPase。 CPT抑制剂可以改变代谢功能障碍以改善 缺血性心脏的心肌功能。 酰基肉碱增强膜 多种吸收药物的渗透性。 提议 酰基苯胺的分子或异构体可以充当药物吸收 增强代理。 初步结果表明，我们的Meso-2,6（双羧甲基）-4,4-- 二甲基极酚溴化物抑制大鼠肝细胞中的糖异生。 因此，它在治疗中可能是降血糖剂 糖尿病。 这些结果bode良好，我们的药理潜力 提出的抑制剂。