{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,11]],"date-time":"2025-11-11T13:32:53Z","timestamp":1762867973657,"version":"build-2065373602"},"reference-count":62,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2019,11,9]],"date-time":"2019-11-09T00:00:00Z","timestamp":1573257600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81872782","81761128016"],"award-info":[{"award-number":["81872782","81761128016"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100012906","name":"Department of Education of Shandong Province","doi-asserted-by":"publisher","award":["J17KA260"],"award-info":[{"award-number":["J17KA260"]}],"id":[{"id":"10.13039\/100012906","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100008853","name":"Jining Medical University","doi-asserted-by":"publisher","award":["JYP2018KJ18"],"award-info":[{"award-number":["JYP2018KJ18"]}],"id":[{"id":"10.13039\/501100008853","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Human carboxylesterase 1 (hCES1) is a major carboxylesterase in the human body and plays important roles in the metabolism of a wide variety of substances, including lipids and drugs, and therefore is attracting more and more attention from areas including lipid metabolism, pharmacokinetics, drug\u2013drug interactions, and prodrug activation. In this work, we studied the catalytic hydrolysis mechanism of hCES1 by the quantum mechanics computation method, using cocaine as a model substrate. Our results support the four-step theory of the esterase catalytic hydrolysis mechanism, in which both the acylation stage and the deacylation stage include two transition states and a tetrahedral intermediate. The roles and cooperation of the catalytic triad, S221, H468, and E354, were also analyzed in this study. Moreover, orthoester intermediates were found in hCES1-catalyzed cocaine hydrolysis reaction, which significantly elevate the free energy barrier and slow down the reaction. Based on this finding, we propose that hCES1 substrates with \u03b2-aminocarboxylester structure might form orthoester intermediates in hCES1-catalyzed hydrolysis, and therefore prolong their in vivo half-life. Thus, this study helps to clarify the catalytic mechanism of hCES1 and elucidates important details of its catalytic process, and furthermore, provides important insights into the metabolism of hCES1 substrates and drug designing.<\/jats:p>","DOI":"10.3390\/molecules24224057","type":"journal-article","created":{"date-parts":[[2019,11,12]],"date-time":"2019-11-12T04:07:07Z","timestamp":1573531627000},"page":"4057","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Catalytic Hydrolysis Mechanism of Cocaine by Human Carboxylesterase 1: An Orthoester Intermediate Slows Down the Reaction"],"prefix":"10.3390","volume":"24","author":[{"given":"Maocai","family":"Yan","sequence":"first","affiliation":[{"name":"School of Pharmacy, Jining Medical University, Rizhao 276800, China"},{"name":"Beijing Key Laboratory of Antimicrobial Agents, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhen","family":"Zhang","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Jining Medical University, Rizhao 276800, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhaoming","family":"Liu","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Jining Medical University, Rizhao 276800, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chunyan","family":"Zhang","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Jining Medical University, Rizhao 276800, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jingchang","family":"Zhang","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Jining Medical University, Rizhao 276800, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shuai","family":"Fan","sequence":"additional","affiliation":[{"name":"Beijing Key Laboratory of Antimicrobial Agents, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China"},{"name":"Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhaoyong","family":"Yang","sequence":"additional","affiliation":[{"name":"Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2019,11,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1243","DOI":"10.1016\/0006-2952(84)90176-X","article-title":"Hydrolysis of ester- and amide-type drugs by the purified isoenzymes of nonspecific carboxylesterase from rat liver","volume":"33","author":"Mentlein","year":"1984","journal-title":"Biochem. 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