抗癌前药CPT - 11与加州电鳐乙酰胆碱酯酶的三维结构揭示了其对乙酰胆碱酯酶的抑制作用以及被丁酰胆碱酯酶和羧酸酯酶水解的机制。

The 3D structure of the anticancer prodrug CPT-11 with Torpedo californica acetylcholinesterase rationalizes its inhibitory action on AChE and its hydrolysis by butyrylcholinesterase and carboxylesterase.

作者信息

Harel Michal, Hyatt Janice L, Brumshtein Boris, Morton Christopher L, Wadkins Randy M, Silman Israel, Sussman Joel L, Potter Philip M

机构信息

Department of Structural Biology, Weizmann Institute of Science, Rehovot 76100, Israel.

出版信息

Chem Biol Interact. 2005 Dec 15;157-158:153-7. doi: 10.1016/j.cbi.2005.10.016. Epub 2005 Nov 14.

DOI:10.1016/j.cbi.2005.10.016

PMID:16289500

Abstract

The anticancer prodrug CPT-11 is a highly effective camptothecin analog that has been approved for the treatment of colon cancer. The 2.6 angstroms resolution crystal structure of its complex with Torpedo californica acetylcholinesterase (TcAChE) demonstrates that CPT-11 binds to TcAChE and spans its gorge similarly to the Alzheimer drug, Aricept. The crystal structure clearly reveals the interactions, which contribute to the inhibitory action of CPT-11. Modeling of the complexes of CPT-11 with mammalian butyrylcholinesterase and carboxylesterase, both of which are known to hydrolyze the drug, shows how binding to either of the two enzymes yields a productive substrate-enzyme complex.

摘要

抗癌前药CPT-11是一种高效的喜树碱类似物，已被批准用于治疗结肠癌。其与加州电鳐乙酰胆碱酯酶（TcAChE）复合物的2.6埃分辨率晶体结构表明，CPT-11与TcAChE结合，并与治疗阿尔茨海默病的药物安理申类似地跨越其峡谷。晶体结构清楚地揭示了这些相互作用，这些相互作用有助于CPT-11的抑制作用。CPT-11与哺乳动物丁酰胆碱酯酶和羧酸酯酶复合物的模型显示，这两种酶都已知会水解该药物，该模型展示了与这两种酶中的任何一种结合如何产生有效的底物-酶复合物。