N- versus C-domain selectivity of catalytic inactivation of human angiotensin converting enzyme by lisinopril-coupled transition metal chelates.
N- versus C-domain selectivity of catalytic inactivation of human angiotensin converting enzyme by lisinopril-coupled transition metal chelates.
复制标题
DOI：
10.1021/jm4009345
复制
发表时间：
2013-12-27
影响因子：
7.3
通讯作者：
Cowan JA
中科院分区：
文献类型：
--
作者：
Hocharoen L;Joyner JC;Cowan JA
人类体细胞血管紧张素转换酶(SACE-1)的N-末端和C-末端结构域具有不同的生理功能，因此开发针对特定治疗应用的结构域选择性抑制剂引起了人们的兴趣。在此，我们测试了赖诺普利偶联的过渡金属络合物对SACE-1的可逆结合和不可逆催化失活的活性。C/N结构域结合选择性比从1到350，而N-结构域和C-结构域的不可逆催化失活速率对于N-结构域明显更大，这表明M-螯合赖诺普利络合物在SACE-1的N-结构域的活性中心内具有更优的取向。最后，对每个催化剂的结合选择性和失活选择性的综合效应(双过滤选择性因子)进行了评估，发现有几种催化剂会导致区域选择性催化失活。这项研究的结果表明，通过结合和取向因子(双过滤效应)，能够优化催化金属多肽的目标选择性。
The N- and C-terminal domains of human somatic Angiotensin I Converting Enzyme (sACE-1) demonstrate distinct physiological functions, with resulting interest in the development of domain-selective inhibitors for specific therapeutic applications. Herein, the activity of lisinopril-coupled transition metal chelates were tested for both reversible binding and irreversible catalytic inactivation of sACE-1. C/N domain binding selectivity ratios ranged from 1 to 350, while rates of irreversible catalytic inactivation of the N- and C-domains were found to be significantly greater for the N-domain, suggesting a more optimal orientation of the M-chelate-lisinopril complexes within the active site of the N-domain of sACE-1. Finally, the combined effect of binding selectivity and inactivation selectivity was assessed for each catalyst (double-filter selectivity factors), and several catalysts were found to cause domain-selective catalytic inactivation. The results of this study demonstrate the ability to optimize the target selectivity of catalytic metallopeptides through both binding and orientation factors (double-filter effect).
登录
查看更多内容
影响因子：
14.9
作者：
Cer RZ;Mudunuri U;Stephens R;Lebeda FJ
通讯作者：
Lebeda FJ
影响因子：
4.3
作者：
Hocharoen, Lalintip;Cowan, James A.
通讯作者：
Cowan, James A.
影响因子：
14.8
作者：
Carmona, Adriana K.;Schwager, Sylva L.;Sturrock, Edward D.
通讯作者：
Sturrock, Edward D.
影响因子：
1.8
作者：
Cowan, James A.
通讯作者：
Cowan, James A.
影响因子：
2.9
作者：
Araujo, MC;Melo, RL;Carmona, AK
通讯作者：
Carmona, AK