近日，美国和以色列科学家用计算机设计出一种含锌酶，可以对具有与神经药剂沙林类似结构的分子进行降解，相关论文发表在《自然—化学生物学》（Nature Chemical Biology）上。
近年来，蛋白质合理设计取得重要进展，科学家可以通过新蛋白质折叠和新酶活性进行蛋白质测序。但是，很少有人注意到将金属与之相结合的尝试。而在该项研究中，这种加入金属后得到的酶具有针对各种特殊反应的催化能力，从而极大地为蛋白质设计中各种可能的反应拓宽道路。
David Baker和同事检验了大量已知含锌酶，从中筛选出12种形状可被重新设计以便于研究的酶。他们发现，其中一种酶具有分解有机磷分子的活性。通过进一步设计并以新酶的晶体结构为部分依据，研究小组成功得到了这种新型酶。（生物谷Bioon.com）
doi:10.1038/nchembio.777
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Computational redesign of a mononuclear zinc metalloenzyme for organophosphate hydrolysis
Sagar D Khare, Yakov Kipnis, Per Jr Greisen, Ryo Takeuchi, Yacov Ashani, Moshe Goldsmith, Yifan Song, Jasmine L Gallaher, Israel Silman, Haim Leader, Joel L Sussman, Barry L Stoddard, Dan S Tawfik & David Baker
The ability to redesign enzymes to catalyze noncognate chemical transformations would have wide-ranging applications. We developed a computational method for repurposing the reactivity of metalloenzyme active site functional groups to catalyze new reactions. Using this method, we engineered a zinc-containing mouse adenosine deaminase to catalyze the hydrolysis of a model organophosphate with a catalytic efficiency (kcat/Km) of ～104 M?1 s?1 after directed evolution. In the high-resolution crystal structure of the enzyme, all but one of the designed residues adopt the designed conformation. The designed enzyme efficiently catalyzes the hydrolysis of the RP isomer of a coumarinyl analog of the nerve agent cyclosarin, and it shows marked substrate selectivity for coumarinyl leaving groups. Computational redesign of native enzyme active sites complements directed evolution methods and offers a general approach for exploring their untapped catalytic potential for new reactivities.
