权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Mechanism of toxification induced by involvement of a medium chain acyl-CoA synthetase

中链酰基辅酶A合成酶参与诱导的毒性机制

基本信息

批准号：
10672099
负责人：
KASUYA Fumiyo
金额：
$ 1.92万
依托单位：
Kobegakuin University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1998
资助国家：
日本
起止时间：
1998 至 2000
项目状态：
已结题

项目摘要

The mechanism of toxification induced by involvement of a medium chain acyl-CoA synthetases catalyzing the amino acid conjugation has been investigated. However, little information is available about the medium chain acyl-CoA synthetases. Therefore, each medium chain acyl-CoA synthetase was purified from liver and kidney mitochondria of mouse, rat and bovine, and characterized (the substrate specificity, the pH optimum and the inhibition, etc). The further findings are as follows :1.There was the slight difference in the substrate specificity between three species.2.The relative expression of the medium chain acyl-CoA synthetases differed between liver and kidney.3.All substrates activated by this enzyme contain a flat hydrophobic region coplanar to the carboxylate group and have negative values for the charge on the carbon atom in the β-position of carboxylic acids.4.The activities of this enzyme were inhibited competitively by the nonsteroidal anti-inflammatory drugs and the quinolone antimicrobial drugs having the hydroxy or ketone groups at the β-position of carboxylic acids. Then, the inhibition of this enzyme might be one of some possible mechanisms for the development of Reye's syndrome.5.The combination of enoxacine and felbinac inhibited strongly this enzyme, suggesting that it might be one of some mechanisms for the induction of convulsion by NQs-NSAIDs.6.This enzyme may be predominantly responsible for incorporation of benzoic acids having the large alkyl or alkoxyl groups into triacylglycerides.7.The formation rates and the stability of acyl-CoAs were the factors that determine the metabolic fate (either detoxification or toxification) of xenobiotics containing a carboxylic group.

研究了中链酰基辅酶A合成酶催化氨基酸结合引起的蛋白质变性的机制。然而，关于中链酰基辅酶A合成酶的信息很少。因此，从小鼠、大鼠和牛的肝和肾线粒体中纯化了每种中链酰基辅酶A合成酶，并对其进行了表征（底物特异性、最适pH和抑制性等）。结果表明：1.中链酰基辅酶A合成酶的底物特异性在3种动物间略有差异; 2.中链酰基辅酶A合成酶在肝脏和肾脏中的相对表达量存在差异; 3.该酶激活的所有底物均含有与羧酸基团共面的平坦疏水区，且羧酸β位碳原子上的电荷为负值; 4.该酶的活性可被非甾体抗炎药和羧酸β位带有羟基或酮基的喹诺酮类抗菌药物竞争性抑制。5.依诺沙星和联苯乙酸联合应用对该酶有较强的抑制作用，这表明这可能是NQs诱导惊厥的机制之一-6.这种酶可能主要负责将具有大的烷基或烷氧基的苯甲酸掺入三酰甘油中。酰基辅酶A的形成速率和稳定性是决定含有羧基的异生物质的代谢命运（解毒或解毒）的因素。