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Human Carboxylesterase 2 in Cocaine Metabolism
Open accessPublished version of a preprint
Abstract
Increased hydrolysis of cocaine to non-toxic compounds is a promising way to prevent cocaine-induced toxicity. However, the short half-life of cocaine in the blood and the rapid conversion in the body to the hydrolysis-resistant metabolite benzoylecgonine, limits the therapeutic potential of serum proteins. Therefore, hydrolysis by tissue-specific hydrolases that do not generate benzoylecgonine deserves further investigation. Here, we report for the first time, the mechanism of cocaine hydrolysis by the human Carboxylesterase 2. We have combined conventional and accelerated Molecular Dynamics, which allowed us to identify the structural motions of the α1 and α10’ helices that act as a putative lid. Quantum Mechanics/Molecular Mechanics calculations on the full cycle showed that the rate-limiting step is the formation of benzoic acid (deacylation step) with an ΔG of 18.3 kcal.mol-1 (a value in close conformity with the experimental value of 19.7 kcal.mol-1).
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Metadata
- Authors
- Figueiredo, P. R., González, R. D., & Carvalho, A. T. P.
- Affiliations
- University of Coimbra (PT)
- Almac (United Kingdom) (GB)
- Corresponding author
- Carvalho, Alexandra T.P.
- Venue
- Molecular Catalysis
- Publisher
- Elsevier BV
- Published
- 2021-10
- Volume
- 515
- Pages
- 111938
- ISSN
- 2468-8231 (ISSN-L)
- OpenAlex
- W3204987835
- Cited by
- 9
- References
- 61
- Citations by year
- 2025: 2 · 2024: 3 · 2023: 2 · 2022: 2
- FWCI
- 0.69
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (am, 378 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Molecular Catalysis (acceptedVersion)
- ChemRxiv (acceptedVersion, cc-by-nc-nd)
- Funders
- Fundação para a Ciência e a Tecnologia (IF/01272/2015, UIDB/04539/2020)
- European Regional Development Fund (01/SAICT/2016, 022153, CPCA/A2/4568/2020)
- Topics
- Physical Sciences › Chemistry › Organic Chemistry › Physical Organic Chemistry and Reaction Kinetics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Enzyme Catalysis and Immobilization
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Enzyme function and inhibition
- Keywords
- CE2, cocaine hydrolysis, cocaine metabolism, benzoylecgonine, cocaine toxicity, deacylation, enzyme mechanism, quantum mechanics/molecular mechanics, molecular dynamics, reaction free energy
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