{"gene":"CES1","run_date":"2026-06-09T22:57:18","timeline":{"discoveries":[{"year":2004,"finding":"CES1A1 (CES1) is the major enzyme responsible for the stereoselective hydrolysis of both d- and l-enantiomers of methylphenidate, with higher catalytic efficiency for l-methylphenidate (kcat/Km = 7.7 mM⁻¹ min⁻¹) than d-methylphenidate (kcat/Km = 1.3–2.1 mM⁻¹ min⁻¹); CES2 and CES3 showed no detectable activity toward either enantiomer.","method":"In vitro kinetic assay with purified recombinant CES1A1, CES2, and CES3 expressed in Sf9 cells; LC/MS assay; 3D active-site modeling","journal":"The Journal of pharmacology and experimental therapeutics","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with purified enzymes, kinetic parameters determined, structural modeling, replicated in clinical pharmacokinetics context","pmids":["15082749"],"is_preprint":false},{"year":2004,"finding":"CES1A1 hydrolyzes irinotecan (CPT-11) and its oxidative metabolites NPC and APC to the active metabolite SN-38; catalytic efficiency of CES1A1 for CPT-11 is intermediate between CES2 (highest) and CES3 (lowest). CES2 > CES1A1 >> CES3 for all three substrates.","method":"In vitro hydrolysis assay with purified recombinant CES1A1, CES2, and CES3; kinetic parameter determination","journal":"Drug metabolism and disposition: the biological fate of chemicals","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with purified recombinant enzymes, quantitative kinetics, multiple substrates tested","pmids":["15100172"],"is_preprint":false},{"year":2008,"finding":"Two CES1 coding mutations — p.Gly143Glu (exon 4) and p.Asp260fs (exon 6 frameshift) — substantially impair catalytic function: p.Gly143Glu retains only 21.4% catalytic efficiency (Vmax/Km) and p.Asp260fs retains only 0.6% relative to wild-type using p-nitrophenyl acetate as substrate; both mutations result in complete loss of hydrolytic activity toward methylphenidate.","method":"In vitro functional assay of recombinant wild-type and mutant CES1 proteins expressed in cell lines; DNA sequencing; enzymatic kinetics","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 1 / Strong — active-site mutagenesis with in vitro enzymatic assay, multiple substrates, quantitative kinetic parameters","pmids":["18485328"],"is_preprint":false},{"year":2008,"finding":"CES1A1 transcription is regulated by Sp1 and C/EBPalpha binding to responsive elements in its promoter; CES1A2 promoter lacks functional Sp1/C/EBP binding sites, explaining the much higher CES1A1 mRNA expression in liver and lung compared to CES1A2.","method":"Reporter gene assay; electrophoretic mobility shift assay (EMSA) in transfected cells","journal":"Drug metabolism and pharmacokinetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — EMSA and reporter gene assay, single lab, two orthogonal methods","pmids":["18305377"],"is_preprint":false},{"year":2008,"finding":"A minor haplotype in the CES1A2 promoter (positions -62 to -32) contains two Sp1 binding sites absent in the major haplotype, and the minor haplotype drives higher transcriptional and Sp1 binding activity in vitro, establishing Sp1 binding site variation as a functional determinant of CES1A2 expression.","method":"Promoter re-sequencing; reporter gene assay; EMSA; linkage disequilibrium analysis","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — EMSA and reporter gene assay, single lab, two orthogonal methods","pmids":["18328811"],"is_preprint":false},{"year":2016,"finding":"Sacubitril (prodrug) is selectively activated by CES1 in human liver; CES2 does not activate sacubitril. The CES1 G143E variant (rs71647871) is a loss-of-function variant for sacubitril activation, significantly impairing hydrolysis in liver samples carrying G143E.","method":"Incubation with human liver/intestine/kidney S9 fractions; CES1 inhibitor (bis-p-nitrophenyl phosphate) studies; recombinant CES1 and CES2 incubation; transfected cell lines expressing wild-type CES1 vs. G143E variant","journal":"Drug metabolism and disposition: the biological fate of chemicals","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with recombinant enzymes, inhibitor studies, human liver tissue validation, multiple orthogonal methods","pmids":["26817948"],"is_preprint":false},{"year":2015,"finding":"CES1 selectively activates multiple ACEI prodrugs (enalapril, ramipril, perindopril, moexipril, fosinopril) in human liver; the G143E variant reduces enalapril activation in human livers carrying the variant to approximately one-third of wild-type activity.","method":"Incubation of human liver/intestine/kidney S9 fractions with ACEI prodrugs; transfected cell lines expressing wild-type CES1 and G143E variant; activity assays in 102 human liver samples","journal":"The pharmacogenomics journal","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro enzymatic assay with recombinant proteins, human liver tissue confirmation, multiple substrates, single lab","pmids":["26076923"],"is_preprint":false},{"year":2009,"finding":"Mouse Es-x/Ces1 (ortholog of human CES1) prevents triacylglycerol accumulation in hepatocytes by reducing partitioning of exogenous fatty acids into TG and increasing beta-oxidation, rather than by increasing TG turnover; this effect persists in the presence of esterase/lipase inhibitor E600, indicating the mechanism is independent of direct TG hydrolysis.","method":"Stable transfection of McArdle-RH7777 hepatocytes with Es-x cDNA; TG quantification; acid-soluble metabolite measurement (beta-oxidation indicator); esterase inhibitor (E600) treatment; glycerol supplementation experiments","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function and gain-of-function in cell culture, multiple metabolic readouts, inhibitor dissection, single lab","pmids":["19651238"],"is_preprint":false},{"year":2017,"finding":"Global inactivation of mouse Ces1/Ces1g reduces plasma cholesterol and TG levels and protects against atherosclerosis in Ldlr⁻/⁻ mice by inhibiting intestinal cholesterol and fat absorption, reducing Niemann-Pick C1-like 1 expression, and increasing macrophage cholesterol efflux via ABCA1 and ABCG1 upregulation; Ces1g⁻/⁻ also promotes M2 macrophage polarization and induces hepatic cholesterol 7α-hydroxylase and sterol 12α-hydroxylase expression.","method":"Ces1g⁻/⁻ mouse generation; Ces1g⁻/⁻ Ldlr⁻/⁻ double knockout on Western diet; hepatic Ces1/Ces1g knockdown in Apoe⁻/⁻ mice; plasma lipid measurement; atherosclerotic lesion quantification; gene expression analysis","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean knockout with defined metabolic phenotypes, multiple mechanistic readouts, single lab","pmids":["29259301"],"is_preprint":false},{"year":2018,"finding":"The CES1 G143E variant (p.Gly143Glu) exhibits only ~20% of wild-type lipolytic activity; humanized CES1G143E-expressing mice on high-fat diet have reduced liver and plasma TG levels due to decreased VLDL secretion, decreased hepatic lipogenic gene expression, and increased fatty acid oxidation (elevated plasma ketone bodies and hepatic mitochondrial electron transport chain proteins).","method":"Humanized mouse model expressing CES1WT, CES1G143E, or catalytically dead CES1S221A in liver; high-fat diet challenge; lipidomics; plasma/liver TG measurement; VLDL secretion assay; gene expression; plasma ketone measurement; protein abundance analysis","journal":"Biochimica et biophysica acta. Molecular and cell biology of lipids","confidence":"High","confidence_rationale":"Tier 1 / Strong — humanized mouse model with catalytic dead control, multiple orthogonal metabolic readouts, mechanistic dissection of lipolytic vs lipogenic pathway","pmids":["29631096"],"is_preprint":false},{"year":2015,"finding":"Fluoxetine reduces CES1 expression and hydrolytic activity in HepG2 cells by decreasing pregnane X receptor (PXR), which positively regulates CES1; overexpression of PXR attenuates fluoxetine-induced CES1 decrease, while PXR knockdown abolishes the fluoxetine effect, placing PXR upstream of CES1 transcription. DEC1 upregulation by fluoxetine contributes to PXR repression.","method":"PXR overexpression and knockdown in HepG2 cells; DEC1 knockdown; CES1 expression and enzymatic activity measurement; western blot","journal":"Xenobiotica; the fate of foreign compounds in biological systems","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis via overexpression/knockdown, two orthogonal interventions, single lab","pmids":["26340669"],"is_preprint":false},{"year":2019,"finding":"CES1 expression is upregulated by Nrf2 activation; vitamin E treatment upregulates Nrf2 and CES1 in NAFLD mouse liver, and the Nrf2 inhibitor ML385 reverses CES1 upregulation and the protective lipid-lowering effect, placing CES1 downstream of Nrf2 in lipid metabolism.","method":"NAFLD mouse model (fructose-fed); vitamin E treatment in vivo and in vitro; Nrf2 inhibitor (ML385) treatment; histopathology; western blot for Nrf2 and CES1","journal":"Digestive diseases and sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological epistasis with specific inhibitor, in vivo and in vitro confirmation, single lab","pmids":["31076985"],"is_preprint":false},{"year":2020,"finding":"CES1 in human monocytic THP-1 cells hydrolyzes prostaglandin D2-glyceryl ester (PGD2-G), accounting for ~50% of its hydrolytic metabolism; CES1 knockdown stabilizes PGD2-G and enhances its anti-inflammatory effects (greater attenuation of IL-6 and TNFα), while PGE2-G pro-inflammatory effects are attenuated by CES1-dependent hydrolysis to PGE2. PGD2-G activates PPARγ.","method":"CES1 knockdown (CES1KD) in THP-1 cells; small-molecule CES1 inhibitors (CPO, WWL229, WWL113); LC-MS/MS quantification of PGD2-G and PGD2; cytokine measurement (IL-6, TNFα); PPARγ activation assay","journal":"ACS omega","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockdown confirmed by pharmacological inhibitors, LC-MS/MS quantification, multiple functional readouts, single lab","pmids":["33225149"],"is_preprint":false},{"year":2022,"finding":"TMAO (trimethylamine N-oxide) increases Ces1 protein expression and activity in mouse liver and CES1 levels in HepG2 cells through the NOX-dependent ROS/Nrf2/CES1 pathway, leading to increased clopidogrel hydrolysis and impaired platelet response; co-treatment with ROS scavenger N-acetyl-L-cysteine or Nrf2 inhibitor ML385 reverses TMAO-induced Ces1 upregulation and restores clopidogrel activity.","method":"TMAO/choline feeding in mice; HepG2 cell treatment; ROS measurement; Nrf2 nuclear translocation; Ces1 protein expression; clopidogrel metabolite quantification; platelet aggregation assay; pharmacological pathway inhibitors","journal":"Journal of thrombosis and haemostasis : JTH","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo and in vitro confirmation, multiple pathway inhibitors, functional platelet readout, single lab","pmids":["36695375"],"is_preprint":false},{"year":2023,"finding":"G9a (Ehmt2-encoded histone methyltransferase) suppresses Ces1 transcription by binding to Ces1 promoter regions; G9a and farnesoid X receptor (FXR) competitively bind the same Ces1 promoter regions. Renal tubular G9a knockout increases Ces1 expression, reduces lipid accumulation, and alleviates AKI; pharmacological Ces1 inhibition reverses these beneficial effects.","method":"Renal tubular-specific G9a knockout mice (Ehmt2Ksp); pharmacological G9a inhibition; Ces1 pharmacological inhibition; ChIP-like promoter binding competition assays; lipid quantification; AKI model (I/R injury, cisplatin); Ces1 expression in patient kidneys","journal":"EMBO reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — tissue-specific knockout with defined phenotype, competitive promoter binding, pharmacological validation, single lab","pmids":["37042626"],"is_preprint":false},{"year":2021,"finding":"Melatonin treatment restores CES1 expression in CRPC through epigenetic modification of the CES1 gene; restored CES1 expression reduces lipid droplet accumulation, induces apoptosis by increasing ER stress, and reduces de novo intratumoral androgen synthesis. Ces1-knockout (Ces1⁻/⁻) mice confirmed the role of endogenous Ces1 in prostate cancer progression.","method":"Animal CRPC models; melatonin treatment; PCa cell lines; Ces1-knockout mice; lipid droplet quantification; ER stress markers; androgen synthesis measurement; mechanistic investigations of CES1 epigenetic regulation","journal":"Clinical and translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockout with phenotypic readout, pharmacological intervention, multiple mechanistic readouts, single lab","pmids":["34185414"],"is_preprint":false},{"year":2023,"finding":"CES1 inhibition in hepatocellular carcinoma (HCC) cells alters lipid profiles by dramatically reducing polyunsaturated fatty acids (PUFAs), which activate PPARα/γ; reduced PPARα/γ activation downregulates SCD (a lipogenic/chemoresistance gene), sensitizing HCC cells to cisplatin. CES1 acts upstream of PPARα/γ-SCD axis.","method":"Pharmacological and genetic CES1 blockade in HCC cells; lipidomic analyses; PPARα/γ activity measurement; SCD expression analysis; HCC xenograft mouse model with cisplatin co-treatment","journal":"JCI insight","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic and pharmacological CES1 inhibition, lipidomics, in vivo xenograft confirmation, single lab","pmids":["36472914"],"is_preprint":false},{"year":2021,"finding":"The CES1 G143E variant significantly impairs enalapril activation in a multi-dose steady-state clinical study: G143E carriers had 30.9% lower enalaprilat Cmax, 27.5% lower AUCo-∞, and 32.3% lower enalaprilat-to-enalapril AUC ratio compared to non-carriers; non-carriers showed significant systolic BP reduction while G143E carriers did not.","method":"Prospective multi-dose clinical pharmacokinetic/pharmacodynamic study; LC-MS/MS plasma concentration measurement; genotyping for G143E","journal":"British journal of clinical pharmacology","confidence":"High","confidence_rationale":"Tier 2 / Strong — prospective human PK/PD study, replicated in vitro finding confirmed clinically, quantitative endpoints","pmids":["33963573"],"is_preprint":false},{"year":2016,"finding":"Hepatic CES1 protein abundance increases approximately 5-fold from neonates to adults in human liver microsomes; CES1 protein abundance in pediatric liver microsomes correlates with oseltamivir carboxylase activity, establishing a direct relationship between CES1 expression level and enzymatic function during ontogeny.","method":"LC-MS/MS targeted proteomics with purified protein standards; hepatic microsomal and cytosolic fractionation from 136 pediatric and 35 adult donors; oseltamivir carboxylase activity assay; PBPK modeling","journal":"Drug metabolism and disposition: the biological fate of chemicals","confidence":"High","confidence_rationale":"Tier 2 / Strong — quantitative proteomics with calibrators, large sample size, direct correlation to enzymatic activity, two independent labs","pmids":["27895113"],"is_preprint":false},{"year":2022,"finding":"Crystal structure of mouse Ces2c shows that the core domain adopts an α/β hydrolase-fold with S230, E347, and H459 forming a catalytic triad; conserved gate (M417) and switch (F418) residues are proposed to function in product release, similar to human CES1; the protein is a monomer in solution.","method":"X-ray crystallography (2.12 Å resolution); biophysical characterization; structural comparison to human CES1","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — crystal structure of ortholog (mouse Ces2c, not human CES1), structural comparisons to hCES1, single study","pmids":["36361897"],"is_preprint":false},{"year":2014,"finding":"Recombinant human CES1 expressed in E. coli and refolded from inclusion bodies retains its biological hydrolytic activity after refolding in Tris-HCl pH 7.5 with 1% glycerol and 2 mM β-mercaptoethanol; other additive combinations (trehalose, sorbitol, sucrose) failed to recover functional protein.","method":"Recombinant CES1 expression in E. coli; in vitro refolding; immobilized-metal affinity purification; enzymatic activity assay","journal":"Protein expression and purification","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro reconstitution of enzymatic activity, single lab, single method","pmids":["25462813"],"is_preprint":false},{"year":2018,"finding":"MiR-155 upregulates CEH (CES1) expression in THP-1 macrophages in a dose- and time-dependent manner; CEH upregulation by miR-155 inhibits foam cell formation, reduces intracellular cholesterol ester accumulation, and enhances cholesterol efflux. Knockdown of CEH (siCEH) reverses these anti-foam cell effects. Tim-3 overexpression attenuates miR-155-mediated CEH induction.","method":"miR-155 mimic transfection in THP-1 macrophages; siRNA knockdown of CEH; foam cell formation assay; cholesterol ester and free cholesterol measurement; Tim-3 overexpression","journal":"Biomedicine & pharmacotherapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain-of-function and loss-of-function with functional readouts, epistasis via Tim-3, single lab","pmids":["29803178"],"is_preprint":false},{"year":2024,"finding":"CHRNA5 and CES1 physically interact in HNSC cells (co-immunoprecipitation); nicotine-induced CHRNA5 activation upregulates CES1 expression via the MEK/ERK pathway; CHRNA5 knockdown reduces CES1 mRNA and protein levels, p-MEK/MEK, and p-ERK/ERK, effects reversible by nicotine.","method":"Co-immunoprecipitation; molecular docking; immunofluorescence; CHRNA5 knockdown and overexpression; western blot for MEK/ERK phosphorylation; transcriptomics pathway enrichment; in vivo tumor formation in nude mice","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-immunoprecipitation, molecular docking, knockdown/overexpression with pathway validation, single lab","pmids":["39472448"],"is_preprint":false}],"current_model":"Human CES1 (carboxylesterase 1) is a serine hydrolase with a catalytic triad that mediates the stereoselective hydrolysis of ester, amide, carbamate, and thioester bonds in a wide range of drugs (methylphenidate, enalapril, sacubitril, clopidogrel, irinotecan, oseltamivir) and endogenous lipid mediators (prostaglandin glyceryl esters, triglycerides); its activity is governed by coding variants (notably G143E, which reduces catalytic efficiency to ~20% of wild-type) and transcriptionally regulated by Sp1/C/EBPα, PXR, Nrf2, G9a, and miR-155, while it plays roles in hepatic lipid metabolism (VLDL secretion, fatty acid oxidation), macrophage cholesterol efflux, and anti-inflammatory lipid mediator catabolism."},"narrative":{"mechanistic_narrative":"CES1 is a serine hydrolase of the α/β-hydrolase fold whose catalytic triad mediates the stereoselective hydrolysis of ester and related bonds in a broad range of xenobiotics and endogenous lipids [PMID:15082749, PMID:25462813]. It is the principal enzyme for activating or clearing numerous drugs, including methylphenidate [PMID:15082749], the anticancer prodrug irinotecan (CPT-11) to SN-38 [PMID:15100172], the prodrugs sacubitril [PMID:26817948] and multiple ACE-inhibitors such as enalapril [PMID:26076923, PMID:33963573], and oseltamivir [PMID:27895113]. Catalytic competence is strongly governed by coding variation: the p.Gly143Glu (G143E) variant retains only ~20% of wild-type efficiency and the p.Asp260fs frameshift abolishes activity, with G143E producing clinically measurable reductions in prodrug activation and blunted pharmacodynamic responses [PMID:18485328, PMID:26817948, PMID:26076923, PMID:33963573]. Beyond drug metabolism, CES1 shapes hepatic lipid homeostasis—limiting triacylglycerol accumulation by redirecting fatty acids toward β-oxidation and modulating VLDL secretion and lipogenic gene expression [PMID:19651238, PMID:29631096]—and influences whole-body cholesterol balance, atherosclerosis, and macrophage foam-cell formation/cholesterol efflux [PMID:29259301, PMID:29803178]. In immune cells it catabolizes anti-inflammatory prostaglandin glyceryl esters such as PGD2-G, tuning inflammatory cytokine output and PPARγ signaling [PMID:33225149]. CES1 expression is transcriptionally controlled by Sp1/C/EBPα [PMID:18305377, PMID:18328811], PXR [PMID:26340669], Nrf2 [PMID:31076985, PMID:36695375], the histone methyltransferase G9a in competition with FXR [PMID:37042626], and miR-155 [PMID:29803178], and its dysregulation contributes to lipid-driven phenotypes in kidney injury and several cancers [PMID:37042626, PMID:34185414, PMID:36472914, PMID:39472448].","teleology":[{"year":2004,"claim":"Established CES1 as the specific carboxylesterase isoform responsible for metabolizing key clinical substrates, distinguishing it functionally from CES2 and CES3.","evidence":"In vitro kinetics with purified recombinant CES1A1, CES2, CES3 on methylphenidate enantiomers and on irinotecan/metabolites","pmids":["15082749","15100172"],"confidence":"High","gaps":["Did not address regulation of CES1 levels in vivo","Substrate range limited to the tested drugs"]},{"year":2008,"claim":"Defined the molecular basis of interindividual variation by showing specific coding mutations cripple catalytic function, and identified promoter elements driving CES1 expression.","evidence":"Mutagenesis and enzymatic kinetics of G143E and Asp260fs; reporter/EMSA assays of Sp1/C/EBPα promoter elements","pmids":["18485328","18305377","18328811"],"confidence":"High","gaps":["Functional consequence of G143E shown only for limited substrates at the time","Promoter regulation tested in vitro, not in native chromatin"]},{"year":2009,"claim":"Demonstrated a metabolic role beyond xenobiotic clearance—limiting hepatic triacylglycerol accumulation by shifting fatty acids toward β-oxidation rather than via direct TG hydrolysis.","evidence":"Gain-of-function in McArdle-RH7777 hepatocytes with esterase-inhibitor dissection of mouse ortholog Es-x/Ces1","pmids":["19651238"],"confidence":"Medium","gaps":["Mechanism by which non-hydrolytic activity drives β-oxidation unclear","Mouse ortholog rather than human CES1"]},{"year":2015,"claim":"Mapped upstream transcriptional control of CES1 to nuclear receptor PXR and broadened its prodrug-activation portfolio to ACE-inhibitors.","evidence":"PXR overexpression/knockdown in HepG2; ACEI prodrug activation in human liver S9 and recombinant CES1 with G143E comparison","pmids":["26340669","26076923"],"confidence":"Medium","gaps":["PXR-CES1 link shown in a single cell model","Direct PXR binding to CES1 promoter not resolved"]},{"year":2016,"claim":"Confirmed CES1-selective activation of sacubitril and quantified developmental scaling of CES1 abundance with enzymatic activity.","evidence":"Human liver/intestine/kidney S9 and recombinant enzyme assays for sacubitril; targeted proteomics across pediatric/adult livers correlated to oseltamivir carboxylase activity","pmids":["26817948","27895113"],"confidence":"High","gaps":["Ontogenic regulators of the ~5-fold abundance increase not identified"]},{"year":2018,"claim":"Causally tied the G143E variant to altered systemic lipid metabolism and linked CES1 to macrophage cholesterol handling and atheroprotection.","evidence":"Humanized CES1WT/G143E/S221A mice on high-fat diet; Ces1g knockout in Ldlr-/- mice; miR-155-driven CEH induction in THP-1 macrophages","pmids":["29631096","29259301","29803178"],"confidence":"Medium","gaps":["Human relevance of mouse Ces1g knockout phenotypes uncertain","miR-155–CES1 axis shown in a single macrophage model"]},{"year":2020,"claim":"Identified CES1 as a regulator of bioactive lipid signaling by hydrolyzing prostaglandin glyceryl esters and thereby modulating inflammation.","evidence":"CES1 knockdown plus small-molecule inhibitors in THP-1 cells with LC-MS/MS of PGD2-G/PGE2-G and cytokine readouts","pmids":["33225149"],"confidence":"Medium","gaps":["In vivo relevance of PG-glyceryl ester catabolism not established","Single cell-line system"]},{"year":2022,"claim":"Resolved the catalytic architecture of the carboxylesterase fold and connected gut-microbial TMAO signaling to CES1-dependent drug response.","evidence":"X-ray structure of mouse Ces2c with comparison to human CES1; TMAO feeding/HepG2 studies dissecting NOX-ROS/Nrf2/CES1 control of clopidogrel activation and platelet function","pmids":["36361897","36695375"],"confidence":"Medium","gaps":["Structure is of an ortholog, not human CES1","Direct Nrf2 binding to CES1 promoter not shown"]},{"year":2023,"claim":"Placed CES1 within epigenetic and lipid-signaling circuits driving disease, including G9a/FXR-controlled expression in kidney injury and PPAR-SCD–linked chemoresistance in cancer.","evidence":"Renal G9a knockout with competitive promoter-binding assays and AKI models; genetic/pharmacological CES1 blockade in HCC with lipidomics and xenografts","pmids":["37042626","36472914"],"confidence":"Medium","gaps":["G9a/FXR competition characterized by promoter-binding surrogates","Causal lipid species mediating chemoresistance not definitively isolated"]},{"year":2024,"claim":"Confirmed CES1 clinical pharmacogenetics and uncovered receptor-driven control via CHRNA5/MEK-ERK signaling.","evidence":"Prospective enalapril PK/PD study genotyped for G143E; co-IP and CHRNA5 knockdown/overexpression with MEK/ERK phosphorylation analysis in HNSC cells","pmids":["33963573","39472448"],"confidence":"Medium","gaps":["CHRNA5-CES1 interaction from single-lab co-IP/docking, no reciprocal structural validation","Direct vs indirect nature of physical interaction unresolved"]},{"year":null,"claim":"How the diverse upstream regulators (PXR, Nrf2, G9a/FXR, Sp1/C/EBPα, miR-155, CHRNA5) are integrated to set tissue- and disease-specific CES1 levels, and how its non-hydrolytic lipid-partitioning role is mechanistically achieved, remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking transcriptional inputs to context-specific CES1 output","Mechanism coupling CES1 activity to fatty acid β-oxidation undefined","No experimental structure of human CES1 in the corpus"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[0,1,2,5,6,9,12,18,20]},{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,5,6]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[7,9,12]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[18]}],"pathway":[{"term_id":"R-HSA-9748784","term_label":"Drug ADME","supporting_discovery_ids":[0,1,5,6,17,18]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[7,8,9,12,21]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[3,4,10,11,14]}],"complexes":[],"partners":["CHRNA5"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P02795","full_name":"Metallothionein-2","aliases":["Metallothionein-2A","Metallothionein-II","MT-II"],"length_aa":61,"mass_kda":6.0,"function":"Metallothioneins have a high content of cysteine residues that bind various heavy metals; these proteins are transcriptionally regulated by both heavy metals and glucocorticoids","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/P02795/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CES1","classification":"Not Classified","n_dependent_lines":4,"n_total_lines":1208,"dependency_fraction":0.0033112582781456954},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CES1","total_profiled":1310},"omim":[{"mim_id":"618678","title":"CARBOXYLESTERASE 5A; CES5A","url":"https://www.omim.org/entry/618678"},{"mim_id":"618057","title":"DRUG METABOLISM, ALTERED, CES1-RELATED","url":"https://www.omim.org/entry/618057"},{"mim_id":"605279","title":"CARBOXYLESTERASE 3; CES3","url":"https://www.omim.org/entry/605279"},{"mim_id":"605278","title":"CARBOXYLESTERASE 2; CES2","url":"https://www.omim.org/entry/605278"},{"mim_id":"602150","title":"SNAIL FAMILY TRANSCRIPTIONAL REPRESSOR 2; SNAI2","url":"https://www.omim.org/entry/602150"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Endoplasmic reticulum","reliability":"Supported"}],"tissue_specificity":"Tissue 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toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/30801959","citation_count":17,"is_preprint":false},{"pmid":"11747075","id":"PMC_11747075","title":"The Caenorhabditis elegans distal-less ortholog ceh-43 is required for development of the anterior hypodermis.","date":"2001","source":"Developmental dynamics : an official publication of the American Association of Anatomists","url":"https://pubmed.ncbi.nlm.nih.gov/11747075","citation_count":17,"is_preprint":false},{"pmid":"36695375","id":"PMC_36695375","title":"Choline and trimethylamine N-oxide impair metabolic activation of and platelet response to clopidogrel through activation of the NOX/ROS/Nrf2/CES1 pathway.","date":"2022","source":"Journal of thrombosis and haemostasis : JTH","url":"https://pubmed.ncbi.nlm.nih.gov/36695375","citation_count":16,"is_preprint":false},{"pmid":"12711598","id":"PMC_12711598","title":"Sequence-specific binding to telomeric DNA by CEH-37, a homeodomain protein in the nematode Caenorhabditis elegans.","date":"2003","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12711598","citation_count":16,"is_preprint":false},{"pmid":"14738885","id":"PMC_14738885","title":"An early pharyngeal muscle enhancer from the Caenorhabditis elegans ceh-22 gene is targeted by the Forkhead factor PHA-4.","date":"2004","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/14738885","citation_count":16,"is_preprint":false},{"pmid":"19458622","id":"PMC_19458622","title":"Exploring the diabetogenicity of the HLA-B18-DR3 CEH: independent association with T1D genetic risk close to HLA-DOA.","date":"2009","source":"Genes and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/19458622","citation_count":16,"is_preprint":false},{"pmid":"31675356","id":"PMC_31675356","title":"CEH-60/PBX regulates vitellogenesis and cuticle permeability through intestinal interaction with UNC-62/MEIS in Caenorhabditis elegans.","date":"2019","source":"PLoS biology","url":"https://pubmed.ncbi.nlm.nih.gov/31675356","citation_count":15,"is_preprint":false},{"pmid":"32946434","id":"PMC_32946434","title":"PIG-1 MELK-dependent phosphorylation of nonmuscle myosin II promotes apoptosis through CES-1 Snail partitioning.","date":"2020","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/32946434","citation_count":15,"is_preprint":false},{"pmid":"32466188","id":"PMC_32466188","title":"Genetic Analysis Reveals a Significant Contribution of CES1 to Prostate Cancer Progression in Taiwanese Men.","date":"2020","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/32466188","citation_count":15,"is_preprint":false},{"pmid":"11783006","id":"PMC_11783006","title":"Multiple enhancers contribute to expression of the NK-2 homeobox gene ceh-22 in C. elegans pharyngeal muscle.","date":"2001","source":"Genesis (New York, N.Y. : 2000)","url":"https://pubmed.ncbi.nlm.nih.gov/11783006","citation_count":14,"is_preprint":false},{"pmid":"37083231","id":"PMC_37083231","title":"CES1-Triggered Liver-Specific Cargo Release of CRISPR/Cas9 Elements by Cationic Triadic Copolymeric Nanoparticles Targeting Gene Editing of PCSK9 for Hyperlipidemia Amelioration.","date":"2023","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/37083231","citation_count":14,"is_preprint":false},{"pmid":"22237548","id":"PMC_22237548","title":"A discriminative analytical method for detection of CES1A1 and CES1A2/CES1A3 genetic variants.","date":"2012","source":"Pharmacogenetics and genomics","url":"https://pubmed.ncbi.nlm.nih.gov/22237548","citation_count":13,"is_preprint":false},{"pmid":"35500030","id":"PMC_35500030","title":"The anterior Hox gene ceh-13 and elt-1/GATA activate the posterior Hox genes nob-1 and php-3 to specify posterior lineages in the C. elegans embryo.","date":"2022","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/35500030","citation_count":13,"is_preprint":false},{"pmid":"33963573","id":"PMC_33963573","title":"Effect of CES1 genetic variation on enalapril steady-state pharmacokinetics and pharmacodynamics in healthy subjects.","date":"2021","source":"British journal of clinical pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/33963573","citation_count":13,"is_preprint":false},{"pmid":"18161854","id":"PMC_18161854","title":"Behavioral and synaptic defects in C. elegans lacking the NK-2 homeobox gene ceh-28.","date":"2008","source":"Developmental neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/18161854","citation_count":13,"is_preprint":false},{"pmid":"18316179","id":"PMC_18316179","title":"Mesodermal expression of the C. elegans HMX homolog mls-2 requires the PBC homolog CEH-20.","date":"2008","source":"Mechanisms of development","url":"https://pubmed.ncbi.nlm.nih.gov/18316179","citation_count":13,"is_preprint":false},{"pmid":"25474681","id":"PMC_25474681","title":"Regulation of C. elegans neuronal differentiation by the ZEB-family factor ZAG-1 and the NK-2 homeodomain factor CEH-28.","date":"2014","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/25474681","citation_count":13,"is_preprint":false},{"pmid":"25462813","id":"PMC_25462813","title":"Efficient in vitro refolding and functional characterization of recombinant human liver carboxylesterase (CES1) expressed in E. coli.","date":"2014","source":"Protein expression and purification","url":"https://pubmed.ncbi.nlm.nih.gov/25462813","citation_count":13,"is_preprint":false},{"pmid":"23862020","id":"PMC_23862020","title":"CEH-20/Pbx and UNC-62/Meis function upstream of rnt-1/Runx to regulate asymmetric divisions of the C. elegans stem-like seam cells.","date":"2013","source":"Biology open","url":"https://pubmed.ncbi.nlm.nih.gov/23862020","citation_count":13,"is_preprint":false},{"pmid":"36361897","id":"PMC_36361897","title":"The Crystal Structure of Mouse Ces2c, a Potential Ortholog of Human CES2, Shows Structural Similarities in Substrate Regulation and Product Release to Human CES1.","date":"2022","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/36361897","citation_count":13,"is_preprint":false},{"pmid":"32601060","id":"PMC_32601060","title":"cnd-1/NeuroD1 Functions with the Homeobox Gene ceh-5/Vax2 and Hox Gene ceh-13/labial To Specify Aspects of RME and DD Neuron Fate in Caenorhabditis elegans.","date":"2020","source":"G3 (Bethesda, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/32601060","citation_count":12,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":51301,"output_tokens":6370,"usd":0.124727,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":15285,"output_tokens":3678,"usd":0.084187,"stage2_stop_reason":"end_turn"},"total_usd":0.208914,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2004,\n      \"finding\": \"CES1A1 (CES1) is the major enzyme responsible for the stereoselective hydrolysis of both d- and l-enantiomers of methylphenidate, with higher catalytic efficiency for l-methylphenidate (kcat/Km = 7.7 mM⁻¹ min⁻¹) than d-methylphenidate (kcat/Km = 1.3–2.1 mM⁻¹ min⁻¹); CES2 and CES3 showed no detectable activity toward either enantiomer.\",\n      \"method\": \"In vitro kinetic assay with purified recombinant CES1A1, CES2, and CES3 expressed in Sf9 cells; LC/MS assay; 3D active-site modeling\",\n      \"journal\": \"The Journal of pharmacology and experimental therapeutics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with purified enzymes, kinetic parameters determined, structural modeling, replicated in clinical pharmacokinetics context\",\n      \"pmids\": [\"15082749\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"CES1A1 hydrolyzes irinotecan (CPT-11) and its oxidative metabolites NPC and APC to the active metabolite SN-38; catalytic efficiency of CES1A1 for CPT-11 is intermediate between CES2 (highest) and CES3 (lowest). CES2 > CES1A1 >> CES3 for all three substrates.\",\n      \"method\": \"In vitro hydrolysis assay with purified recombinant CES1A1, CES2, and CES3; kinetic parameter determination\",\n      \"journal\": \"Drug metabolism and disposition: the biological fate of chemicals\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with purified recombinant enzymes, quantitative kinetics, multiple substrates tested\",\n      \"pmids\": [\"15100172\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Two CES1 coding mutations — p.Gly143Glu (exon 4) and p.Asp260fs (exon 6 frameshift) — substantially impair catalytic function: p.Gly143Glu retains only 21.4% catalytic efficiency (Vmax/Km) and p.Asp260fs retains only 0.6% relative to wild-type using p-nitrophenyl acetate as substrate; both mutations result in complete loss of hydrolytic activity toward methylphenidate.\",\n      \"method\": \"In vitro functional assay of recombinant wild-type and mutant CES1 proteins expressed in cell lines; DNA sequencing; enzymatic kinetics\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — active-site mutagenesis with in vitro enzymatic assay, multiple substrates, quantitative kinetic parameters\",\n      \"pmids\": [\"18485328\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"CES1A1 transcription is regulated by Sp1 and C/EBPalpha binding to responsive elements in its promoter; CES1A2 promoter lacks functional Sp1/C/EBP binding sites, explaining the much higher CES1A1 mRNA expression in liver and lung compared to CES1A2.\",\n      \"method\": \"Reporter gene assay; electrophoretic mobility shift assay (EMSA) in transfected cells\",\n      \"journal\": \"Drug metabolism and pharmacokinetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — EMSA and reporter gene assay, single lab, two orthogonal methods\",\n      \"pmids\": [\"18305377\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"A minor haplotype in the CES1A2 promoter (positions -62 to -32) contains two Sp1 binding sites absent in the major haplotype, and the minor haplotype drives higher transcriptional and Sp1 binding activity in vitro, establishing Sp1 binding site variation as a functional determinant of CES1A2 expression.\",\n      \"method\": \"Promoter re-sequencing; reporter gene assay; EMSA; linkage disequilibrium analysis\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — EMSA and reporter gene assay, single lab, two orthogonal methods\",\n      \"pmids\": [\"18328811\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Sacubitril (prodrug) is selectively activated by CES1 in human liver; CES2 does not activate sacubitril. The CES1 G143E variant (rs71647871) is a loss-of-function variant for sacubitril activation, significantly impairing hydrolysis in liver samples carrying G143E.\",\n      \"method\": \"Incubation with human liver/intestine/kidney S9 fractions; CES1 inhibitor (bis-p-nitrophenyl phosphate) studies; recombinant CES1 and CES2 incubation; transfected cell lines expressing wild-type CES1 vs. G143E variant\",\n      \"journal\": \"Drug metabolism and disposition: the biological fate of chemicals\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with recombinant enzymes, inhibitor studies, human liver tissue validation, multiple orthogonal methods\",\n      \"pmids\": [\"26817948\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CES1 selectively activates multiple ACEI prodrugs (enalapril, ramipril, perindopril, moexipril, fosinopril) in human liver; the G143E variant reduces enalapril activation in human livers carrying the variant to approximately one-third of wild-type activity.\",\n      \"method\": \"Incubation of human liver/intestine/kidney S9 fractions with ACEI prodrugs; transfected cell lines expressing wild-type CES1 and G143E variant; activity assays in 102 human liver samples\",\n      \"journal\": \"The pharmacogenomics journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro enzymatic assay with recombinant proteins, human liver tissue confirmation, multiple substrates, single lab\",\n      \"pmids\": [\"26076923\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Mouse Es-x/Ces1 (ortholog of human CES1) prevents triacylglycerol accumulation in hepatocytes by reducing partitioning of exogenous fatty acids into TG and increasing beta-oxidation, rather than by increasing TG turnover; this effect persists in the presence of esterase/lipase inhibitor E600, indicating the mechanism is independent of direct TG hydrolysis.\",\n      \"method\": \"Stable transfection of McArdle-RH7777 hepatocytes with Es-x cDNA; TG quantification; acid-soluble metabolite measurement (beta-oxidation indicator); esterase inhibitor (E600) treatment; glycerol supplementation experiments\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function and gain-of-function in cell culture, multiple metabolic readouts, inhibitor dissection, single lab\",\n      \"pmids\": [\"19651238\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Global inactivation of mouse Ces1/Ces1g reduces plasma cholesterol and TG levels and protects against atherosclerosis in Ldlr⁻/⁻ mice by inhibiting intestinal cholesterol and fat absorption, reducing Niemann-Pick C1-like 1 expression, and increasing macrophage cholesterol efflux via ABCA1 and ABCG1 upregulation; Ces1g⁻/⁻ also promotes M2 macrophage polarization and induces hepatic cholesterol 7α-hydroxylase and sterol 12α-hydroxylase expression.\",\n      \"method\": \"Ces1g⁻/⁻ mouse generation; Ces1g⁻/⁻ Ldlr⁻/⁻ double knockout on Western diet; hepatic Ces1/Ces1g knockdown in Apoe⁻/⁻ mice; plasma lipid measurement; atherosclerotic lesion quantification; gene expression analysis\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean knockout with defined metabolic phenotypes, multiple mechanistic readouts, single lab\",\n      \"pmids\": [\"29259301\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"The CES1 G143E variant (p.Gly143Glu) exhibits only ~20% of wild-type lipolytic activity; humanized CES1G143E-expressing mice on high-fat diet have reduced liver and plasma TG levels due to decreased VLDL secretion, decreased hepatic lipogenic gene expression, and increased fatty acid oxidation (elevated plasma ketone bodies and hepatic mitochondrial electron transport chain proteins).\",\n      \"method\": \"Humanized mouse model expressing CES1WT, CES1G143E, or catalytically dead CES1S221A in liver; high-fat diet challenge; lipidomics; plasma/liver TG measurement; VLDL secretion assay; gene expression; plasma ketone measurement; protein abundance analysis\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular and cell biology of lipids\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — humanized mouse model with catalytic dead control, multiple orthogonal metabolic readouts, mechanistic dissection of lipolytic vs lipogenic pathway\",\n      \"pmids\": [\"29631096\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Fluoxetine reduces CES1 expression and hydrolytic activity in HepG2 cells by decreasing pregnane X receptor (PXR), which positively regulates CES1; overexpression of PXR attenuates fluoxetine-induced CES1 decrease, while PXR knockdown abolishes the fluoxetine effect, placing PXR upstream of CES1 transcription. DEC1 upregulation by fluoxetine contributes to PXR repression.\",\n      \"method\": \"PXR overexpression and knockdown in HepG2 cells; DEC1 knockdown; CES1 expression and enzymatic activity measurement; western blot\",\n      \"journal\": \"Xenobiotica; the fate of foreign compounds in biological systems\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis via overexpression/knockdown, two orthogonal interventions, single lab\",\n      \"pmids\": [\"26340669\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CES1 expression is upregulated by Nrf2 activation; vitamin E treatment upregulates Nrf2 and CES1 in NAFLD mouse liver, and the Nrf2 inhibitor ML385 reverses CES1 upregulation and the protective lipid-lowering effect, placing CES1 downstream of Nrf2 in lipid metabolism.\",\n      \"method\": \"NAFLD mouse model (fructose-fed); vitamin E treatment in vivo and in vitro; Nrf2 inhibitor (ML385) treatment; histopathology; western blot for Nrf2 and CES1\",\n      \"journal\": \"Digestive diseases and sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological epistasis with specific inhibitor, in vivo and in vitro confirmation, single lab\",\n      \"pmids\": [\"31076985\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CES1 in human monocytic THP-1 cells hydrolyzes prostaglandin D2-glyceryl ester (PGD2-G), accounting for ~50% of its hydrolytic metabolism; CES1 knockdown stabilizes PGD2-G and enhances its anti-inflammatory effects (greater attenuation of IL-6 and TNFα), while PGE2-G pro-inflammatory effects are attenuated by CES1-dependent hydrolysis to PGE2. PGD2-G activates PPARγ.\",\n      \"method\": \"CES1 knockdown (CES1KD) in THP-1 cells; small-molecule CES1 inhibitors (CPO, WWL229, WWL113); LC-MS/MS quantification of PGD2-G and PGD2; cytokine measurement (IL-6, TNFα); PPARγ activation assay\",\n      \"journal\": \"ACS omega\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockdown confirmed by pharmacological inhibitors, LC-MS/MS quantification, multiple functional readouts, single lab\",\n      \"pmids\": [\"33225149\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TMAO (trimethylamine N-oxide) increases Ces1 protein expression and activity in mouse liver and CES1 levels in HepG2 cells through the NOX-dependent ROS/Nrf2/CES1 pathway, leading to increased clopidogrel hydrolysis and impaired platelet response; co-treatment with ROS scavenger N-acetyl-L-cysteine or Nrf2 inhibitor ML385 reverses TMAO-induced Ces1 upregulation and restores clopidogrel activity.\",\n      \"method\": \"TMAO/choline feeding in mice; HepG2 cell treatment; ROS measurement; Nrf2 nuclear translocation; Ces1 protein expression; clopidogrel metabolite quantification; platelet aggregation assay; pharmacological pathway inhibitors\",\n      \"journal\": \"Journal of thrombosis and haemostasis : JTH\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo and in vitro confirmation, multiple pathway inhibitors, functional platelet readout, single lab\",\n      \"pmids\": [\"36695375\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"G9a (Ehmt2-encoded histone methyltransferase) suppresses Ces1 transcription by binding to Ces1 promoter regions; G9a and farnesoid X receptor (FXR) competitively bind the same Ces1 promoter regions. Renal tubular G9a knockout increases Ces1 expression, reduces lipid accumulation, and alleviates AKI; pharmacological Ces1 inhibition reverses these beneficial effects.\",\n      \"method\": \"Renal tubular-specific G9a knockout mice (Ehmt2Ksp); pharmacological G9a inhibition; Ces1 pharmacological inhibition; ChIP-like promoter binding competition assays; lipid quantification; AKI model (I/R injury, cisplatin); Ces1 expression in patient kidneys\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — tissue-specific knockout with defined phenotype, competitive promoter binding, pharmacological validation, single lab\",\n      \"pmids\": [\"37042626\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Melatonin treatment restores CES1 expression in CRPC through epigenetic modification of the CES1 gene; restored CES1 expression reduces lipid droplet accumulation, induces apoptosis by increasing ER stress, and reduces de novo intratumoral androgen synthesis. Ces1-knockout (Ces1⁻/⁻) mice confirmed the role of endogenous Ces1 in prostate cancer progression.\",\n      \"method\": \"Animal CRPC models; melatonin treatment; PCa cell lines; Ces1-knockout mice; lipid droplet quantification; ER stress markers; androgen synthesis measurement; mechanistic investigations of CES1 epigenetic regulation\",\n      \"journal\": \"Clinical and translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout with phenotypic readout, pharmacological intervention, multiple mechanistic readouts, single lab\",\n      \"pmids\": [\"34185414\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CES1 inhibition in hepatocellular carcinoma (HCC) cells alters lipid profiles by dramatically reducing polyunsaturated fatty acids (PUFAs), which activate PPARα/γ; reduced PPARα/γ activation downregulates SCD (a lipogenic/chemoresistance gene), sensitizing HCC cells to cisplatin. CES1 acts upstream of PPARα/γ-SCD axis.\",\n      \"method\": \"Pharmacological and genetic CES1 blockade in HCC cells; lipidomic analyses; PPARα/γ activity measurement; SCD expression analysis; HCC xenograft mouse model with cisplatin co-treatment\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic and pharmacological CES1 inhibition, lipidomics, in vivo xenograft confirmation, single lab\",\n      \"pmids\": [\"36472914\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"The CES1 G143E variant significantly impairs enalapril activation in a multi-dose steady-state clinical study: G143E carriers had 30.9% lower enalaprilat Cmax, 27.5% lower AUCo-∞, and 32.3% lower enalaprilat-to-enalapril AUC ratio compared to non-carriers; non-carriers showed significant systolic BP reduction while G143E carriers did not.\",\n      \"method\": \"Prospective multi-dose clinical pharmacokinetic/pharmacodynamic study; LC-MS/MS plasma concentration measurement; genotyping for G143E\",\n      \"journal\": \"British journal of clinical pharmacology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — prospective human PK/PD study, replicated in vitro finding confirmed clinically, quantitative endpoints\",\n      \"pmids\": [\"33963573\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Hepatic CES1 protein abundance increases approximately 5-fold from neonates to adults in human liver microsomes; CES1 protein abundance in pediatric liver microsomes correlates with oseltamivir carboxylase activity, establishing a direct relationship between CES1 expression level and enzymatic function during ontogeny.\",\n      \"method\": \"LC-MS/MS targeted proteomics with purified protein standards; hepatic microsomal and cytosolic fractionation from 136 pediatric and 35 adult donors; oseltamivir carboxylase activity assay; PBPK modeling\",\n      \"journal\": \"Drug metabolism and disposition: the biological fate of chemicals\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — quantitative proteomics with calibrators, large sample size, direct correlation to enzymatic activity, two independent labs\",\n      \"pmids\": [\"27895113\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Crystal structure of mouse Ces2c shows that the core domain adopts an α/β hydrolase-fold with S230, E347, and H459 forming a catalytic triad; conserved gate (M417) and switch (F418) residues are proposed to function in product release, similar to human CES1; the protein is a monomer in solution.\",\n      \"method\": \"X-ray crystallography (2.12 Å resolution); biophysical characterization; structural comparison to human CES1\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — crystal structure of ortholog (mouse Ces2c, not human CES1), structural comparisons to hCES1, single study\",\n      \"pmids\": [\"36361897\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Recombinant human CES1 expressed in E. coli and refolded from inclusion bodies retains its biological hydrolytic activity after refolding in Tris-HCl pH 7.5 with 1% glycerol and 2 mM β-mercaptoethanol; other additive combinations (trehalose, sorbitol, sucrose) failed to recover functional protein.\",\n      \"method\": \"Recombinant CES1 expression in E. coli; in vitro refolding; immobilized-metal affinity purification; enzymatic activity assay\",\n      \"journal\": \"Protein expression and purification\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro reconstitution of enzymatic activity, single lab, single method\",\n      \"pmids\": [\"25462813\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"MiR-155 upregulates CEH (CES1) expression in THP-1 macrophages in a dose- and time-dependent manner; CEH upregulation by miR-155 inhibits foam cell formation, reduces intracellular cholesterol ester accumulation, and enhances cholesterol efflux. Knockdown of CEH (siCEH) reverses these anti-foam cell effects. Tim-3 overexpression attenuates miR-155-mediated CEH induction.\",\n      \"method\": \"miR-155 mimic transfection in THP-1 macrophages; siRNA knockdown of CEH; foam cell formation assay; cholesterol ester and free cholesterol measurement; Tim-3 overexpression\",\n      \"journal\": \"Biomedicine & pharmacotherapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain-of-function and loss-of-function with functional readouts, epistasis via Tim-3, single lab\",\n      \"pmids\": [\"29803178\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CHRNA5 and CES1 physically interact in HNSC cells (co-immunoprecipitation); nicotine-induced CHRNA5 activation upregulates CES1 expression via the MEK/ERK pathway; CHRNA5 knockdown reduces CES1 mRNA and protein levels, p-MEK/MEK, and p-ERK/ERK, effects reversible by nicotine.\",\n      \"method\": \"Co-immunoprecipitation; molecular docking; immunofluorescence; CHRNA5 knockdown and overexpression; western blot for MEK/ERK phosphorylation; transcriptomics pathway enrichment; in vivo tumor formation in nude mice\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-immunoprecipitation, molecular docking, knockdown/overexpression with pathway validation, single lab\",\n      \"pmids\": [\"39472448\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"Human CES1 (carboxylesterase 1) is a serine hydrolase with a catalytic triad that mediates the stereoselective hydrolysis of ester, amide, carbamate, and thioester bonds in a wide range of drugs (methylphenidate, enalapril, sacubitril, clopidogrel, irinotecan, oseltamivir) and endogenous lipid mediators (prostaglandin glyceryl esters, triglycerides); its activity is governed by coding variants (notably G143E, which reduces catalytic efficiency to ~20% of wild-type) and transcriptionally regulated by Sp1/C/EBPα, PXR, Nrf2, G9a, and miR-155, while it plays roles in hepatic lipid metabolism (VLDL secretion, fatty acid oxidation), macrophage cholesterol efflux, and anti-inflammatory lipid mediator catabolism.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CES1 is a serine hydrolase of the α/β-hydrolase fold whose catalytic triad mediates the stereoselective hydrolysis of ester and related bonds in a broad range of xenobiotics and endogenous lipids [#0, #20]. It is the principal enzyme for activating or clearing numerous drugs, including methylphenidate [#0], the anticancer prodrug irinotecan (CPT-11) to SN-38 [#1], the prodrugs sacubitril [#5] and multiple ACE-inhibitors such as enalapril [#6, #17], and oseltamivir [#18]. Catalytic competence is strongly governed by coding variation: the p.Gly143Glu (G143E) variant retains only ~20% of wild-type efficiency and the p.Asp260fs frameshift abolishes activity, with G143E producing clinically measurable reductions in prodrug activation and blunted pharmacodynamic responses [#2, #5, #6, #17]. Beyond drug metabolism, CES1 shapes hepatic lipid homeostasis—limiting triacylglycerol accumulation by redirecting fatty acids toward β-oxidation and modulating VLDL secretion and lipogenic gene expression [#7, #9]—and influences whole-body cholesterol balance, atherosclerosis, and macrophage foam-cell formation/cholesterol efflux [#8, #21]. In immune cells it catabolizes anti-inflammatory prostaglandin glyceryl esters such as PGD2-G, tuning inflammatory cytokine output and PPARγ signaling [#12]. CES1 expression is transcriptionally controlled by Sp1/C/EBPα [#3, #4], PXR [#10], Nrf2 [#11, #13], the histone methyltransferase G9a in competition with FXR [#14], and miR-155 [#21], and its dysregulation contributes to lipid-driven phenotypes in kidney injury and several cancers [#14, #15, #16, #22].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Established CES1 as the specific carboxylesterase isoform responsible for metabolizing key clinical substrates, distinguishing it functionally from CES2 and CES3.\",\n      \"evidence\": \"In vitro kinetics with purified recombinant CES1A1, CES2, CES3 on methylphenidate enantiomers and on irinotecan/metabolites\",\n      \"pmids\": [\"15082749\", \"15100172\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not address regulation of CES1 levels in vivo\", \"Substrate range limited to the tested drugs\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Defined the molecular basis of interindividual variation by showing specific coding mutations cripple catalytic function, and identified promoter elements driving CES1 expression.\",\n      \"evidence\": \"Mutagenesis and enzymatic kinetics of G143E and Asp260fs; reporter/EMSA assays of Sp1/C/EBPα promoter elements\",\n      \"pmids\": [\"18485328\", \"18305377\", \"18328811\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of G143E shown only for limited substrates at the time\", \"Promoter regulation tested in vitro, not in native chromatin\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Demonstrated a metabolic role beyond xenobiotic clearance—limiting hepatic triacylglycerol accumulation by shifting fatty acids toward β-oxidation rather than via direct TG hydrolysis.\",\n      \"evidence\": \"Gain-of-function in McArdle-RH7777 hepatocytes with esterase-inhibitor dissection of mouse ortholog Es-x/Ces1\",\n      \"pmids\": [\"19651238\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which non-hydrolytic activity drives β-oxidation unclear\", \"Mouse ortholog rather than human CES1\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Mapped upstream transcriptional control of CES1 to nuclear receptor PXR and broadened its prodrug-activation portfolio to ACE-inhibitors.\",\n      \"evidence\": \"PXR overexpression/knockdown in HepG2; ACEI prodrug activation in human liver S9 and recombinant CES1 with G143E comparison\",\n      \"pmids\": [\"26340669\", \"26076923\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"PXR-CES1 link shown in a single cell model\", \"Direct PXR binding to CES1 promoter not resolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Confirmed CES1-selective activation of sacubitril and quantified developmental scaling of CES1 abundance with enzymatic activity.\",\n      \"evidence\": \"Human liver/intestine/kidney S9 and recombinant enzyme assays for sacubitril; targeted proteomics across pediatric/adult livers correlated to oseltamivir carboxylase activity\",\n      \"pmids\": [\"26817948\", \"27895113\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Ontogenic regulators of the ~5-fold abundance increase not identified\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Causally tied the G143E variant to altered systemic lipid metabolism and linked CES1 to macrophage cholesterol handling and atheroprotection.\",\n      \"evidence\": \"Humanized CES1WT/G143E/S221A mice on high-fat diet; Ces1g knockout in Ldlr-/- mice; miR-155-driven CEH induction in THP-1 macrophages\",\n      \"pmids\": [\"29631096\", \"29259301\", \"29803178\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Human relevance of mouse Ces1g knockout phenotypes uncertain\", \"miR-155–CES1 axis shown in a single macrophage model\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identified CES1 as a regulator of bioactive lipid signaling by hydrolyzing prostaglandin glyceryl esters and thereby modulating inflammation.\",\n      \"evidence\": \"CES1 knockdown plus small-molecule inhibitors in THP-1 cells with LC-MS/MS of PGD2-G/PGE2-G and cytokine readouts\",\n      \"pmids\": [\"33225149\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo relevance of PG-glyceryl ester catabolism not established\", \"Single cell-line system\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Resolved the catalytic architecture of the carboxylesterase fold and connected gut-microbial TMAO signaling to CES1-dependent drug response.\",\n      \"evidence\": \"X-ray structure of mouse Ces2c with comparison to human CES1; TMAO feeding/HepG2 studies dissecting NOX-ROS/Nrf2/CES1 control of clopidogrel activation and platelet function\",\n      \"pmids\": [\"36361897\", \"36695375\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structure is of an ortholog, not human CES1\", \"Direct Nrf2 binding to CES1 promoter not shown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Placed CES1 within epigenetic and lipid-signaling circuits driving disease, including G9a/FXR-controlled expression in kidney injury and PPAR-SCD–linked chemoresistance in cancer.\",\n      \"evidence\": \"Renal G9a knockout with competitive promoter-binding assays and AKI models; genetic/pharmacological CES1 blockade in HCC with lipidomics and xenografts\",\n      \"pmids\": [\"37042626\", \"36472914\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"G9a/FXR competition characterized by promoter-binding surrogates\", \"Causal lipid species mediating chemoresistance not definitively isolated\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Confirmed CES1 clinical pharmacogenetics and uncovered receptor-driven control via CHRNA5/MEK-ERK signaling.\",\n      \"evidence\": \"Prospective enalapril PK/PD study genotyped for G143E; co-IP and CHRNA5 knockdown/overexpression with MEK/ERK phosphorylation analysis in HNSC cells\",\n      \"pmids\": [\"33963573\", \"39472448\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"CHRNA5-CES1 interaction from single-lab co-IP/docking, no reciprocal structural validation\", \"Direct vs indirect nature of physical interaction unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the diverse upstream regulators (PXR, Nrf2, G9a/FXR, Sp1/C/EBPα, miR-155, CHRNA5) are integrated to set tissue- and disease-specific CES1 levels, and how its non-hydrolytic lipid-partitioning role is mechanistically achieved, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking transcriptional inputs to context-specific CES1 output\", \"Mechanism coupling CES1 activity to fatty acid β-oxidation undefined\", \"No experimental structure of human CES1 in the corpus\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [0, 1, 2, 5, 6, 9, 12, 18, 20]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 5, 6]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [7, 9, 12]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [18]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9748784\", \"supporting_discovery_ids\": [0, 1, 5, 6, 17, 18]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [7, 8, 9, 12, 21]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [3, 4, 10, 11, 14]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"CHRNA5\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}