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ACTIVE SITE CHARACTERIZATION OF ACROSIN

顶体素活性位点表征

基本信息

批准号：
3311089
负责人：
KENNETH L POLAKOSKI
金额：
$ 13.67万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1978
资助国家：
美国
起止时间：
1978-12-01 至 1985-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/3311089
关键词：
acrosin acrosome analytical method chemical structure function drug design /synthesis /production enzyme structure female antifertility drug fertilization human tissue in vitro fertilization isozymes membrane model protease inhibitor radiotracer reproductive system pharmacology spermicide

项目摘要

Acrosin (E.N. 3.4.21.10) is a unique trypsin-like enzyme in mammalian sperm acrosomes and is used by sperm to penetrate the ovum, a prerequisite to fertilization. This project is designed to continue the characterization of acrosin, including the definition of the topography (structure) of acrosin's active site, so that specific affinity labeling (irreversible) acrosin inhibitors can be synthesized which may be used to inhibit fertilization. Particular emphasis will be placed on determining the mechanism of acrosin's unique catalytic properties in order to define reagents that specifically bind to acrosin and not trypsin (the enzyme most similar to acrosin). Agents that specifically bind to acrosin will be modified to become affinity labeling inhibitors. These inhibitors will be tested for their specificity to acrosin and the functional amino acid residues which participate in the binding will be determined. Since acrosin is a membrane bound proteinase, artifical membranes in the form of phospholipid micelles (liposomes) will be utilized as a model system to study various parameters of membrane bound acrosin which may affect the design of the inhibitors. The biological effectiveness (inhibition of sperm bound acrosin) will be ascertained. Finally, the most significant experiments will be repeated with human acrosin and sperm to permit an accurate evaluation of the possible contraceptive usefulness of these inhibitors.

顶体酶(E.N.3.4.21.10)是哺乳动物精子中一种独特的类胰酶顶体，精子用来穿透卵子，这是受精。这个项目的目的是继续描述顶体酶，包括顶体酶的形态(结构)定义顶体酶的活性部位，使特异性亲和标记(不可逆) 可以合成顶体酶抑制剂，它可以用来抑制受精。将特别强调确定顶体酶独特催化性质的作用机理与顶体酶而不是胰酶(最常见的酶)特异结合的试剂类似于顶体酶)。与顶体酶特异结合的药物将是经修饰后成为亲和标记抑制剂。这些抑制剂将是测试它们对顶体酶和功能性氨基酸的特异性将确定参与结合的残基。自.以来顶体酶是一种膜结合的蛋白水解酶，人工膜的形式磷脂胶束(脂质体)将作为模型系统用于研究膜结合顶体酶的各种参数对酶活性的影响。抑制剂的设计。生物有效性(抑制精子结合顶体酶)将被确定。最后，最重要的对人类顶体酶和精子的实验将重复进行，以允许准确评估这些药物可能的避孕效用抑制剂。