Kinetic characterization of cholinesterases and a therapeutically valuable cocaine hydrolase for their catalytic activities against heroin and its metabolite 6-monoacetylmorphine

Kyungbo Kim, Jianzhuang Yao, Zhenyu Jin, Fang Zheng, Chang Guo Zhan

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

As the most popularly abused one of opioids, heroin is actually a prodrug. In the body, heroin is hydrolyzed/activated to 6-monoacetylmorphine (6-MAM) first and then to morphine to produce its toxic and physiological effects. It has been known that heroin hydrolysis to 6-MAM and morphine is accelerated by cholinesterases, including acetylcholinesterase (AChE) and/or butyrylcholinesterase (BChE). However, there has been controversy over the specific catalytic activities and functional significance of the cholinesterases, which requires for the more careful kinetic characterization under the same experimental conditions. Here we report the kinetic characterization of AChE, BChE, and a therapeutically promising cocaine hydrolase (CocH1) for heroin and 6-MAM hydrolyses under the same experimental conditions. It has been demonstrated that AChE and BChE have similar kcat values (2100 and 1840 min−1, respectively) against heroin, but with a large difference in KM (2170 and 120 μM, respectively). Both AChE and BChE can catalyze 6-MAM hydrolysis to morphine, with relatively lower catalytic efficiency compared to the heroin hydrolysis. CocH1 can also catalyze hydrolysis of heroin (kcat = 2150 min−1 and KM = 245 μM) and 6-MAM (kcat = 0.223 min−1 and KM = 292 μM), with relatively larger KM values and lower catalytic efficiency compared to BChE. Notably, the KM values of CocH1 against both heroin and 6-MAM are all much larger than previously reported maximum serum heroin and 6-MAM concentrations observed in heroin users, implying that the heroin use along with cocaine will not drastically affect the catalytic activity of CocH1 against cocaine in the CocH1-based enzyme therapy for cocaine abuse.

Original languageEnglish
Pages (from-to)107-114
Number of pages8
JournalChemico-Biological Interactions
Volume293
DOIs
StatePublished - Sep 25 2018

Bibliographical note

Funding Information:
This work was supported in part by the National Institutes of Health through the NIDA Translational Avant-Garde Award ( UH2/UH3 DA041115 ) and R01 grants ( R01 DA035552 , R01 DA032910 , R01 DA013930 , and R01 DA025100 ) and the National Science Foundation through grant CHE-1111761 . The authors also acknowledge the Computer Center at University of Kentucky for supercomputing time on a Dell X-series Cluster with 384 nodes or 4768 processors.

Funding Information:
This work was supported in part by the National Institutes of Health through the NIDA Translational Avant-Garde Award (UH2/UH3 DA041115) and R01 grants (R01 DA035552, R01 DA032910, R01 DA013930, and R01 DA025100) and the National Science Foundation through grant CHE-1111761. The authors also acknowledge the Computer Center at University of Kentucky for supercomputing time on a Dell X-series Cluster with 384 nodes or 4768 processors.

Publisher Copyright:
© 2018 Elsevier B.V.

ASJC Scopus subject areas

  • Toxicology

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