ENZYME MECHANISMS AND ENZYME INHIBITORS

酶机制和酶抑制剂

基本信息

批准号：
2020644
负责人：
ROBERT H ABELES
金额：
$ 34.78万
依托单位：
BRANDEIS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1977
资助国家：
美国
起止时间：
1977-12-01 至 1997-11-30
项目状态：
已结题

项目摘要

Inhibitors bases on fluoromethyl ketones. The mechanism of inhibitions of serine proteases (initially chymotrypsin) by peptidyl-fluoreomethyl ketones will be investigated. Questions of interest are: 1) Do all peptidyl-fluoromethyl ketones form adducts with the active site serine? 2) If they do, is the hydroxyl group of the resulting hemiacetal ionized? 3) What kind of interactions occur between amino-acid components of the inhibitor and the active site. These investigations will involve kinetic studies and x-ray crystallography of inhibitor enzyme complexes. This information will be used to develop strategies for the design of improved inhibitors for other serine proteases. Of primary interest is human leucocyte elastase. A new kind of active site directed inhibitor will be synthesized based on fluoromethyl ketones; targets: carboxypeptidase and angiotensin converting enzyme. Inhibitors of enzyme which utilize Schiff bases will also be synthesized, as well as inhibitors for acyl-transfer enzymes. A methionine salvage pathway. We shall continue our investigation of the pathway whereby 5'-S-methyl adenosine is converted to methionine. Intermediates and enzymes involved will be characterized. Lactyl-CoA dehydratase. An enzyme has been isolated from C1. propionicum which converts lactyl-CoA to acrylyl-CoA. The mechanism of this unusual reaction will be investigated, to determine whether a radical process is involved and what the role, if any, is of the cofactors (flavin, Fe/S centers). The composition and metabolic role of the multi-enzyme complex, of which the dehydratase is a part, will be examined.

抑制剂碱基上的荧光甲基酮。机制通过抑制丝氨酸蛋白酶（最初是胰凝乳蛋白酶）的抑制作用将研究肽基氟甲基酮。问题兴趣是：1）使所有肽基氟甲基酮形成加合物与活动地点丝氨酸？ 2）如果这样做，则是羟基由此产生的半骨离子化？ 3）什么样的互动发生在抑制剂的氨基酸成分和活性之间地点。这些研究将涉及动力学研究和X射线抑制剂酶复合物的晶体学。此信息将用于制定改进设计的策略其他丝氨酸蛋白酶的抑制剂。主要感兴趣的是人白细胞弹性酶。一种新型的主动网站抑制剂将根据荧光甲基酮合成；靶点：羧肽酶和血管紧张素转化酶。利用Schiff基地的酶抑制剂也将是合成的，以及酰基转移酶的抑制剂。蛋氨酸打捞途径。我们将继续调查 5'-S-甲基腺苷转换为5'-S-甲基腺苷的途径蛋氨酸。涉及的中间体和酶将是特征。乳糖氧基脱水酶。从C1分离出酶。丙酰丙糖蛋白转化为丙烯酰-COA。这将研究这种异常反应的机制，确定是否涉及激进过程以及角色如果有的话，是辅助因子（Flavin，Fe/S中心）。这多酶复合物的组成和代谢作用，脱水酶是一部分，将被检查。