{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T13:26:52Z","timestamp":1789046812665,"version":"build-2803163510"},"reference-count":78,"publisher":"American Chemical Society (ACS)","issue":"36","license":[{"start":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T00:00:00Z","timestamp":1788134400000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-029"},{"start":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T00:00:00Z","timestamp":1788134400000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-037"},{"start":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T00:00:00Z","timestamp":1788134400000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-045"}],"funder":[{"name":"Shenzhen City","award":["C10120180043"],"award-info":[{"award-number":["C10120180043"]}]},{"name":"Longgang District","award":["LGKCSDPT2024001"],"award-info":[{"award-number":["LGKCSDPT2024001"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,9,10]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Human CYP2E1 oxidizes both eicosapentaenoic acid (EPA, an \u03c9\u20133 polyunsaturated fatty acid [PUFA]) and arachidonic acid (AA, an \u03c9\u20136 PUFA) to bioactive lipid mediators, yet the mechanistic basis for its regio- and enantioselective preferences remains incompletely understood. Here, we use a combined molecular dynamics (MD) and hybrid quantum mechanics\/molecular mechanics (QM\/MM) strategy to compare the oxidation of EPA and AA by human CYP2E1 at atomistic resolution. MD simulations indicate that EPA and AA occupy essentially the same CYP2E1 cavity but are stabilized through distinct interaction patterns. Compared with AA, EPA more frequently forms a hydrogen bond with A108 at the channel entrance and exhibits more uniform sampling of near-attack geometries in the \u03c9\u20131, \u03c9\u20132, and \u03c9\u20133 regions. QM\/MM free energy profiles show that \u03c9\u20131S hydroxylation has the lowest barrier for both substrates, but that the barriers for the \u03c9\u20132\/\u03c9\u20133 epoxidation pathways are close to that for \u03c9\u20131S hydroxylation in EPA, rendering these pathways kinetically competitive. Energy decomposition analysis indicates that regioselectivity is largely determined by the QM energy term (\u0394EQM), whereas enantioselectivity at \u03c9\u20131 reflects small differences in packing and entropic cost between the pro-R and pro-S transition states in the confined active site. These results provide a coherent mechanistic picture of CYP2E1-catalyzed oxidation of \u03c9\u20136 and \u03c9\u20133 PUFAs and identify specific active-site residues as promising targets for tuning regio- and stereoselectivity in lipid oxidation.<\/jats:p>","DOI":"10.1021\/acs.jpcb.6c04304","type":"journal-article","created":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T01:03:31Z","timestamp":1788397411000},"page":"9084-9096","source":"Crossref","is-referenced-by-count":0,"title":["Regio- and Enantioselective\nOxidation of Eicosapentaenoic\nand Arachidonic Acids by Human CYP2E1: A Comparative Mechanistic Study"],"prefix":"10.1021","volume":"130","author":[{"given":"Honghui","family":"Zhang","sequence":"first","affiliation":[{"name":"The Chinese University of Hong Kong , , , ,","place":["Shenzhen, Guangdong, P. R. China, 518172"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8239-3471","authenticated-orcid":true,"given":"Hajime","family":"Hirao","sequence":"additional","affiliation":[{"name":"The Chinese University of Hong Kong , , , ,","place":["Shenzhen, Guangdong, P. R. China, 518172"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,8,31]]},"reference":[{"key":"2026091008084012600_cit1","doi-asserted-by":"publisher","first-page":"94","DOI":"10.3390\/jox11030007","article-title":"The Central Role of Cytochrome P450\nin Xenobiotic Metabolism\u2500a Brief Review on a Fascinating Enzyme\nFamily","volume":"11","author":"Esteves","year":"2021","journal-title":"J. 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Biophys."},{"key":"2026091008084012600_cit5","doi-asserted-by":"publisher","first-page":"2253","DOI":"10.1021\/cr0307143","article-title":"Structure\nand Chemistry of Cytochrome P450","volume":"105","author":"Denisov","year":"2005","journal-title":"Chem. Rev."},{"key":"2026091008084012600_cit6","doi-asserted-by":"publisher","first-page":"126","DOI":"10.1016\/j.cbpa.2014.02.001","article-title":"Expanding\nP450 Catalytic Reaction\nSpace through Evolution and Engineering","volume":"19","author":"McIntosh","year":"2014","journal-title":"Curr.\nOpin. Chem. 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Nutr."},{"key":"2026091008084012600_cit10","doi-asserted-by":"publisher","first-page":"4892","DOI":"10.1021\/acscatal.9b00907","article-title":"Mechanistic\nInsights into the Directing Effect of Thr303 in Ethanol Oxidation\nby Cytochrome P450 2E1","volume":"9","author":"Lu","year":"2019","journal-title":"ACS Catal."},{"key":"2026091008084012600_cit11","doi-asserted-by":"publisher","first-page":"109056","DOI":"10.1016\/j.cbi.2020.109056","article-title":"Cytochrome\nP450 2E1 and Its Roles in Disease","volume":"322","author":"Guengerich","year":"2020","journal-title":"Chem. Biol.\nInteract."},{"key":"2026091008084012600_cit12","doi-asserted-by":"publisher","first-page":"860","DOI":"10.1111\/bph.15336","article-title":"Omega-3 Polyunsaturated\nFatty Acids and Hypertension: A Review of Vasodilatory Mechanisms\nof Docosahexaenoic Acid and Eicosapentaenoic Acid","volume":"178","author":"Bercea","year":"2021","journal-title":"Br. J. Pharmacol."},{"key":"2026091008084012600_cit13","doi-asserted-by":"publisher","first-page":"74","DOI":"10.1016\/j.pharmthera.2018.07.004","article-title":"20-HETE in the Regulation of Vascular and Cardiac Function","volume":"192","author":"Rocic","year":"2018","journal-title":"Pharmacol. Ther."},{"key":"2026091008084012600_cit14","doi-asserted-by":"publisher","first-page":"550","DOI":"10.1016\/j.taap.2015.10.003","article-title":"19-Hydroxyeicosatetraenoic\nAcid and Isoniazid Protect\nagainst Angiotensin II-Induced Cardiac Hypertrophy","volume":"289","author":"Elkhatali","year":"2015","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"2026091008084012600_cit15","doi-asserted-by":"publisher","first-page":"52","DOI":"10.3390\/antiox10010052","article-title":"Cytochrome P450 CYP2E1\nSuppression\nAmeliorates Cerebral Ischemia Reperfusion Injury","volume":"10","author":"Yu","year":"2021","journal-title":"Antioxidants"},{"key":"2026091008084012600_cit16","doi-asserted-by":"publisher","first-page":"12912","DOI":"10.1016\/S0021-9258(18)31472-8","article-title":"Formation\nof 19(S)-, 19(R)-, and 18(R)-Hydroxyeicosatetraenoic Acids by Alcohol-Inducible Cytochrome\nP450 2E1","volume":"268","author":"Laethem","year":"1993","journal-title":"J. Biol. Chem."},{"key":"2026091008084012600_cit17","doi-asserted-by":"crossref","DOI":"10.5772\/intechopen.80430","article-title":"Fatty Acids: From\nMembrane Ingredients to Signaling Molecules.","volume-title":"Biochem. 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Invest."},{"key":"2026091008084012600_cit21","doi-asserted-by":"publisher","first-page":"404","DOI":"10.1017\/S0029665120007077","article-title":"N-3 PUFA\nand Inflammation: From Membrane to Nucleus and from Bench to Bedside","volume":"79","author":"Calder","year":"2020","journal-title":"Proc. Nutr. Soc."},{"key":"2026091008084012600_cit22","doi-asserted-by":"publisher","first-page":"99","DOI":"10.1016\/j.prostaglandins.2011.09.001","article-title":"CYP-Eicosanoids\u2500a\nNew Link\nbetween Omega-3 Fatty Acids and Cardiac Disease?","volume":"96","author":"Westphal","year":"2011","journal-title":"Prostaglandins Other Lipid Mediators"},{"key":"2026091008084012600_cit23","doi-asserted-by":"publisher","first-page":"1125","DOI":"10.1194\/jlr.M003061","article-title":"Stereoselective Epoxidation\nof the Last Double Bond of Polyunsaturated Fatty Acids by Human Cytochromes\nP450","volume":"51","author":"Lucas","year":"2010","journal-title":"J. Lipid Res."},{"key":"2026091008084012600_cit24","doi-asserted-by":"publisher","first-page":"32720","DOI":"10.1074\/jbc.M110.118406","article-title":"Arachidonic\nAcid-Metabolizing Cytochrome P450 Enzymes Are Targets of \u03c9-3 Fatty Acids","volume":"285","author":"Arnold","year":"2010","journal-title":"J. Biol. Chem."},{"key":"2026091008084012600_cit25","doi-asserted-by":"publisher","first-page":"837","DOI":"10.1021\/jacs.5b08737","article-title":"Molecular\nDynamics and QM\/MM Calculations\nPredict the Substrate-Induced Gating of Cytochrome P450 BM3 and the\nRegio- and Stereoselectivity of Fatty Acid Hydroxylation","volume":"138","author":"Dubey","year":"2016","journal-title":"J. Am. Chem. Soc."},{"key":"2026091008084012600_cit26","doi-asserted-by":"publisher","first-page":"6786","DOI":"10.1021\/jacs.6b01716","article-title":"Emergence\nof Function in P450-Proteins: A Combined Quantum Mechanical\/Molecular\nMechanical and Molecular Dynamics Study of the Reactive Species in\nthe H2O2-Dependent Cytochrome P450SP\u03b1 and Its Regio- and Enantioselective Hydroxylation\nof Fatty Acids","volume":"138","author":"Ramanan","year":"2016","journal-title":"J. Am. Chem. Soc."},{"key":"2026091008084012600_cit27","doi-asserted-by":"publisher","first-page":"2080","DOI":"10.1021\/acs.jcim.5c00115","article-title":"Mechanism of Regio-\nand Enantioselective Hydroxylation of Arachidonic\nAcid Catalyzed by Human CYP2E1: A Combined Molecular Dynamics and\nQuantum Mechanics\/Molecular Mechanics Study","volume":"65","author":"Zhang","year":"2025","journal-title":"J. Chem. Inf. Model."},{"key":"2026091008084012600_cit28","doi-asserted-by":"publisher","first-page":"2379","DOI":"10.1194\/jlr.M800199-JLR200","article-title":"Cytochromes P450 from\nFamily 4 Are the Main Omega Hydroxylating Enzymes in Humans: CYP4F3B\nIs the Prominent Player in PUFA Metabolism","volume":"49","author":"Fer","year":"2008","journal-title":"J. Lipid Res."},{"key":"2026091008084012600_cit29","doi-asserted-by":"publisher","first-page":"26952","DOI":"10.1016\/S0021-9258(19)61465-1","article-title":"Molecular\nBasis for the \u03c9-Regiospecificity of the CYP4A2\nand CYP4A3 Fatty Acid Hydroxylases","volume":"275","author":"Hoch","year":"2000","journal-title":"J. Biol.\nChem."},{"key":"2026091008084012600_cit30","doi-asserted-by":"publisher","first-page":"1445","DOI":"10.1016\/j.bcp.2003.12.023","article-title":"Arachidonic and Eicosapentaenoic\nAcid Metabolism by Human CYP1A1: Highly Stereoselective Formation\nof 17(R),18(S)-Epoxyeicosatetraenoic\nAcid","volume":"67","author":"Schwarz","year":"2004","journal-title":"Biochem. Pharmacol."},{"key":"2026091008084012600_cit31","doi-asserted-by":"publisher","first-page":"3217","DOI":"10.1021\/ci2004016","article-title":"A Negative Cooperativity\nMechanism of Human CYP2E1 Inferred from Molecular Dynamics Simulations\nand Free Energy Calculations","volume":"51","author":"Li","year":"2011","journal-title":"J. Chem. Inf.\nModel."},{"key":"2026091008084012600_cit32","doi-asserted-by":"publisher","first-page":"22282","DOI":"10.1074\/jbc.M110.109017","article-title":"Human Cytochrome\nP450 2E1 Structures\nwith Fatty Acid Analogs Reveal a Previously Unobserved Binding Mode","volume":"285","author":"Porubsky","year":"2010","journal-title":"J. Biol. Chem."},{"key":"2026091008084012600_cit33","doi-asserted-by":"publisher","first-page":"8362","DOI":"10.1021\/ja048528h","article-title":"A Predictive Pattern of Computed Barriers for C\u2013H Hydroxylation\nby Compound I of Cytochrome P450","volume":"126","author":"de Visser","year":"2004","journal-title":"J. Am. Chem.\nSoc."},{"key":"2026091008084012600_cit34","doi-asserted-by":"publisher","first-page":"10128","DOI":"10.1021\/ja8019615","article-title":"A Valence\nBond Modeling of Trends\nin Hydrogen Abstraction Barriers and Transition States of Hydroxylation\nReactions Catalyzed by Cytochrome P450 Enzymes","volume":"130","author":"Shaik","year":"2008","journal-title":"J. Am. Chem. Soc."},{"key":"2026091008084012600_cit35","doi-asserted-by":"publisher","first-page":"30117","DOI":"10.1021\/jacs.4c07937","article-title":"Hydrogen-Bond-Assisted Catalysis:\nHydroxylation of Paclitaxel by Human CYP2C8","volume":"146","author":"Yue","year":"2024","journal-title":"J. Am. Chem. 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