ArticleThe Biochemical journal2014
Kinetic characterization of high-activity mutants of human butyrylcholinesterase for the cocaine metabolite norcocaine.
Article in The Biochemical journal, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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22 citing papers in PubMed, 43 citations in OpenAlex.
- In vitro and in vivo stability of a highly efficient long-acting cocaine hydrolase.Scientific reports · 2024Article
- Long-lasting blocking of interoceptive effects of cocaine by a highly efficient cocaine hydrolase in rats.Scientific reports · 2024Article
- Catalytic activities of a highly efficient cocaine hydrolase for hydrolysis of biologically active cocaine metabolites norcocaine and benzoylecgonine.Scientific reports · 2023Article
- Gender differences in cocaine-induced hyperactivity and dopamine transporter trafficking to the plasma membrane.Addiction biology · 2022Article
- Cocaine hydrolase blocks cocaine-induced dopamine transporter trafficking to the plasma membrane.Addiction biology · 2022Article
- Effects of alcohol on metabolism and toxicity of cocaine in rats.Toxicology reports · 2022Article
- Clinical potential of a rationally engineered enzyme for treatment of cocaine dependence: Long-lasting blocking of the psychostimulant, discriminative stimulus, and reinforcing effects of cocaine.Neuropharmacology · 2020Article
- Structure-Based Design and Discovery of a Long-Acting Cocaine Hydrolase Mutant with Improved Binding Affinity to Neonatal Fc Receptor for Treatment of Cocaine Abuse.The AAPS journal · 2020Article
- Catalytic activities of cocaine hydrolases against the most toxic cocaine metabolite norcocaethylene.Organic & biomolecular chemistry · 2020Article
- Reengineering of Albumin-Fused Cocaine Hydrolase CocH1 (TV-1380) to Prolong Its Biological Half-Life.The AAPS journal · 2019Article
- In vivo characterization of toxicity of norcocaethylene and norcocaine identified as the most toxic cocaine metabolites in male mice.Drug and alcohol dependence · 2019Article
- Catalytic Reaction Mechanism for Drug Metabolism in Human Carboxylesterase-1: Cocaine Hydrolysis Pathway.Molecular pharmaceutics · 2018Article
- Phenylethynyl-substituted Heterocycles Inhibit Cyclin D1 and Induce the Expression of Cyclin-dependent Kinase Inhibitor p21MedChemComm · 2018Article
- Effectiveness of a Cocaine Hydrolase for Cocaine Toxicity Treatment in Male and Female Rats.The AAPS journal · 2017Article
- Plant-expressed cocaine hydrolase variants of butyrylcholinesterase exhibit altered allosteric effects of cholinesterase activity and increased inhibitor sensitivity.Scientific reports · 2017Article
- A quantitative LC-MS/MS method for simultaneous determination of cocaine and its metabolites in whole blood.Journal of pharmaceutical and biomedical analysis · 2017Article
- Effects of a cocaine hydrolase engineered from human butyrylcholinesterase on metabolic profile of cocaine in rats.Chemico-biological interactions · 2016Article
- Potential anti-obesity effects of a long-acting cocaine hydrolase.Chemico-biological interactions · 2016Article
- Metabolic Enzymes of Cocaine Metabolite Benzoylecgonine.ACS chemical biology · 2016Article
- Reply to Curry and Coombs: Benzoic acid is formed predominantly from the benzoyl ester hydrolysis in the presence of cocaine hydrolase.Proceedings of the National Academy of Sciences of the United States of America · 2016Article
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4 authors at 1 institution in 1 country.
Funding
Abstract
It has been known that cocaine produces its toxic and physiological effects through not only cocaine itself, but also norcocaine formed from cocaine oxidation catalysed by microsomal CYP (cytochrome P450) 3A4 in the human liver. The catalytic parameters (kcat and Km) of human BChE (butyrylcholinesterase) and its three mutants (i.e. A199S/S287G/A328W/Y332G, A199S/F227A/S287G/A328W/E441D and A199S/F227A/S287G/A328W/Y332G) for norcocaine have been characterized in the present study for the first time and compared with those for cocaine. On the basis of the obtained kinetic data, wild-type human BChE has a significantly lower catalytic activity for norcocaine (kcat=2.8 min(-1), Km=15 μM and kcat/Km=1.87 × 10(5) M(-1)·min(-1)) compared with its catalytic activity for (-)-cocaine. The BChE mutants examined in the present study have considerably improved catalytic activities against both cocaine and norcocaine compared with the wild-type enzyme. Within the enzymes examined in the present study, the A199S/F227A/S287G/A328W/Y332G mutant (CocH3) is identified as the most efficient enzyme for hydrolysing both cocaine and norcocaine. CocH3 has a 1080-fold improved catalytic efficiency for norcocaine (kcat=2610 min(-1), Km=13 μM and kcat/Km=2.01 × 10(8) M(-1)·min(-1)) and a 2020-fold improved catalytic efficiency for cocaine. It has been demonstrated that CocH3 as an exogenous enzyme can rapidly metabolize norcocaine, in addition to cocaine, in rats. Further kinetic modelling has suggested that CocH3 with an identical concentration with that of the endogenous BChE in human plasma can effectively eliminate both cocaine and norcocaine in a simplified kinetic model of cocaine abuse.
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