A highly efficient cocaine-detoxifying enzyme obtained by computational design

Fang Zheng, Liu Xue, Shurong Hou, Junjun Liu, Max Zhan, Wenchao Yang and Chang-Guo Zhan ()
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Fang Zheng: College of Pharmacy, University of Kentucky
Liu Xue: College of Pharmacy, University of Kentucky
Shurong Hou: College of Pharmacy, University of Kentucky
Junjun Liu: College of Pharmacy, University of Kentucky
Max Zhan: College of Pharmacy, University of Kentucky
Wenchao Yang: College of Pharmacy, University of Kentucky
Chang-Guo Zhan: College of Pharmacy, University of Kentucky

Nature Communications, 2014, vol. 5, issue 1, 1-8

Abstract: Abstract Compared with naturally occurring enzymes, computationally designed enzymes are usually much less efficient, with their catalytic activities being more than six orders of magnitude below the diffusion limit. Here we use a two-step computational design approach, combined with experimental work, to design a highly efficient cocaine hydrolysing enzyme. We engineer E30-6 from human butyrylcholinesterase (BChE), which is specific for cocaine hydrolysis, and obtain a much higher catalytic efficiency for cocaine conversion than for conversion of the natural BChE substrate, acetylcholine (ACh). The catalytic efficiency of E30-6 for cocaine hydrolysis is comparable to that of the most efficient known naturally occurring hydrolytic enzyme, acetylcholinesterase, the catalytic activity of which approaches the diffusion limit. We further show that E30-6 can protect mice from a subsequently administered lethal dose of cocaine, suggesting the enzyme may have therapeutic potential in the setting of cocaine detoxification or cocaine abuse.

Date: 2014
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DOI: 10.1038/ncomms4457

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