Li Yinghao, Cheng Mingpan, Hao Jingya, Wang Changhao, Jia Guoqing, Li Can
State Key Laboratory of Catalysis , Dalian Institute of Chemical Physics , Chinese Academy of Sciences , Dalian 116023 , China . Email:
University of Chinese Academy of Sciences , No. 19A Yuquan Road , Beijing , 100049 , China.
Chem Sci. 2015 Oct 1;6(10):5578-5585. doi: 10.1039/c5sc01381j. Epub 2015 Jun 24.
The cofactors commonly involved in natural enzymes have provided the inspiration for numerous advances in the creation of artificial metalloenzymes. Nevertheless, to design an appropriate cofactor for a given biomolecular scaffold or remains a challenge in developing efficient catalysts in biochemistry. Herein, we extend the idea of G-quadruplex-targeting anticancer drug design to construct a G-quadruplex DNA metalloenzyme. We found that a series of terpyridine-Cu(ii) complexes (CuL) can serve as excellent cofactors to dock with human telemetric G-quadruplex DNA. The resulting G-quadruplex DNA metalloenzyme utilising CuL1 catalyzes an enantioselective Diels-Alder reaction with enantioselectivity of >99% enantiomeric excess and about 73-fold rate acceleration compared to CuL1 alone. The terpyridine-Cu(ii) complex cofactors demonstrate dual functions, both as an active site to perform catalysis and as a structural regulator to promote the folding of human telemetric G-quadruplex DNA towards excellent catalysts.
天然酶中常见的辅助因子为人工金属酶的众多进展提供了灵感。然而，为给定的生物分子支架设计合适的辅助因子或在生物化学中开发高效催化剂仍然是一项挑战。在此，我们扩展了靶向G-四链体的抗癌药物设计理念，构建了一种G-四链体DNA金属酶。我们发现一系列三联吡啶-Cu（II）配合物（CuL）可以作为优异的辅助因子与人类端粒G-四链体DNA对接。所得利用CuL1的G-四链体DNA金属酶催化对映选择性狄尔斯-阿尔德反应，对映选择性大于99%对映体过量，与单独的CuL1相比，反应速率加快约73倍。三联吡啶-Cu（II）配合物辅助因子具有双重功能，既是进行催化的活性位点，又是促进人类端粒G-四链体DNA折叠成为优异催化剂的结构调节剂。
