{"gene":"ESD","run_date":"2026-06-09T23:54:43","timeline":{"discoveries":[{"year":2020,"finding":"ESD (Esterase D) functions as a nonclassical deacetylase that hydrolyzes serine/threonine acetyl groups. Specifically, ESD removes Thr89 acetylation from JAB1 (Jun activation domain binding protein 1), increasing JAB1 activity. Activated JAB1 then promotes ABCA1 (ATP-binding cassette transporter A1) expression to accelerate cholesterol efflux. The small-molecule activator FPD5 triggered ESD aggregation in lysosomes and its interaction with JAB1, reducing blood cholesterol in apoE-/- mice on a high-fat diet and inhibiting foam cell formation from oxLDL-treated cells.","method":"Co-immunoprecipitation (ESD–JAB1 interaction), in vitro/cell-based deacetylase assay (Thr89 acetylation of JAB1), lysosomal fractionation/localization, mouse model (apoE-/- high-fat diet), foam cell assay, pharmacological activation with FPD5","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — single lab, multiple orthogonal methods (Co-IP, acetylation assay, fractionation, in vivo mouse model, foam cell assay), but not independently replicated","pmids":["33615471"],"is_preprint":false},{"year":2011,"finding":"ESD exhibits serine hydrolase enzymatic activity detectable in human lung tissue by activity-based protein profiling (ABPP). ESD activity (but not expression level alone) was measurable and correlated with aggressive lung adenocarcinoma phenotype, confirming the protein's catalytic serine hydrolase function is active in human tissue.","method":"Activity-based protein profiling (ABPP) coupled to mass spectrometry on 40 paired fresh-frozen human lung adenocarcinoma and non-neoplastic tissue samples","journal":"Journal of proteomics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single activity-based method; establishes active serine hydrolase function in human tissue but no mechanistic pathway placement or mutagenesis","pmids":["21596165"],"is_preprint":false},{"year":2004,"finding":"The molecular basis of ESD allelic variants ESD*5 and ESD*7 was characterized: ESD*5 arises from ESD*1 via a G-to-A transition causing Gly257→Asp; ESD*7 arises from ESD*2 via an A-to-G transition causing Asp231→Gly. The common ESD*1/ESD*2 polymorphism involves Gly190→Glu. Haplotype analysis showed strong linkage disequilibrium across the ~25 kb, 10-exon ESD gene with little recombination.","method":"PCR amplification and DNA sequencing of all coding exons; intragenic SNP haplotype analysis in German and Japanese populations","journal":"Human biology","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — direct DNA sequencing with amino acid identification; single lab but definitive molecular characterization of coding variants","pmids":["15481680"],"is_preprint":false},{"year":2002,"finding":"A null allele ESD(*)Q0(yonago) was characterized at the molecular level: a C-to-T transition in codon 63 converts TCA (Ser) to TGA (stop codon), abolishing ESD protein production from this allele.","method":"PCR amplification and DNA sequencing of all eight coding exons from a paternity case sample","journal":"Forensic science international","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — direct sequencing identifying a premature stop codon; single case, single lab, but molecularly definitive","pmids":["12062949"],"is_preprint":false}],"current_model":"ESD (Esterase D) is a serine hydrolase that, beyond its classical esterase activity, functions as a nonclassical deacetylase capable of removing acetyl groups from serine/threonine residues; in the context of cholesterol metabolism, ESD localizes to lysosomes, interacts with and deacetylates JAB1 at Thr89 to increase its activity, which in turn promotes ABCA1-mediated cholesterol efflux, thereby reducing blood cholesterol levels."},"narrative":{"mechanistic_narrative":"ESD (Esterase D) is a catalytically active serine hydrolase whose enzymatic activity is detectable in human tissue and, beyond classical esterase function, extends to a nonclassical deacetylase activity acting on serine/threonine residues [PMID:33615471, PMID:21596165]. In the context of cholesterol homeostasis, ESD localizes to lysosomes, interacts with JAB1 (Jun activation domain binding protein 1), and removes the Thr89 acetyl mark from JAB1 to increase its activity; activated JAB1 in turn promotes ABCA1 expression to accelerate cholesterol efflux, an axis that lowers blood cholesterol and inhibits foam cell formation in apoE-/- mice and oxLDL-treated cells [PMID:33615471]. The coding sequence of ESD has been resolved at the variant level, including missense polymorphisms and a premature-stop null allele that abolishes protein production [PMID:15481680, PMID:12062949]. Beyond the JAB1–ABCA1 cholesterol-efflux axis and its catalytic activity in human tissue, no further mechanistic detail has been characterized in the available corpus.","teleology":[{"year":2002,"claim":"Establishing the molecular genetics of ESD: defining a null allele clarified that specific coding mutations can fully abolish ESD protein production, framing the gene's allelic landscape.","evidence":"PCR and DNA sequencing of all eight coding exons from a forensic paternity case identifying a C-to-T transition creating a premature stop at codon 63","pmids":["12062949"],"confidence":"Medium","gaps":["Does not address ESD protein function or biochemical activity","Single case observation"]},{"year":2004,"claim":"Characterizing common and rare ESD allelic variants at the amino-acid level mapped the polymorphic coding architecture of the gene across populations.","evidence":"PCR amplification, DNA sequencing, and intragenic SNP haplotype analysis in German and Japanese populations","pmids":["15481680"],"confidence":"Medium","gaps":["No functional consequence assigned to the identified amino-acid substitutions","Does not connect variants to enzymatic activity or disease"]},{"year":2011,"claim":"Demonstrating that ESD's serine hydrolase activity is catalytically active in human tissue established the protein as a functional enzyme in vivo rather than an inferred activity.","evidence":"Activity-based protein profiling coupled to mass spectrometry on 40 paired human lung adenocarcinoma and non-neoplastic tissue samples","pmids":["21596165"],"confidence":"Low","gaps":["Single activity-based method with no mutagenesis confirming the catalytic serine","No substrate identified","No mechanistic pathway placement"]},{"year":2020,"claim":"Identifying ESD as a nonclassical Ser/Thr deacetylase acting on JAB1 placed it in a defined signaling axis controlling cholesterol efflux, moving ESD from an enzyme of unknown physiological substrate to a regulator of lipid metabolism.","evidence":"Co-immunoprecipitation, cell-based deacetylase assay for JAB1 Thr89, lysosomal fractionation, apoE-/- high-fat-diet mouse model, foam cell assay, and pharmacological activation with FPD5","pmids":["33615471"],"confidence":"Medium","gaps":["Single lab without independent replication","Mechanism of ESD lysosomal aggregation and JAB1 recruitment not structurally defined","Direct enzymatic measurement of deacetylation kinetics on a purified substrate not established"]},{"year":null,"claim":"Whether the cataloged ESD coding variants alter its deacetylase/esterase activity or the JAB1–ABCA1 cholesterol-efflux axis remains unresolved, and the full substrate repertoire of ESD beyond JAB1 is unknown.","evidence":"No timeline discovery links the sequenced variants to functional or pathway-level consequences","pmids":[],"confidence":"Low","gaps":["No genotype-to-activity mapping for ESD variants","No substrate beyond JAB1 Thr89 characterized","No structural model of substrate engagement"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[0,1]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0]}],"complexes":[],"partners":["JAB1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P10768","full_name":"S-formylglutathione hydrolase","aliases":["Esterase D","Methylumbelliferyl-acetate deacetylase"],"length_aa":282,"mass_kda":31.5,"function":"Serine hydrolase involved in the detoxification of formaldehyde","subcellular_location":"Cytoplasm; Cytoplasmic vesicle","url":"https://www.uniprot.org/uniprotkb/P10768/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ESD","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000139684","cell_line_id":"CID000962","localizations":[{"compartment":"cytoplasmic","grade":3},{"compartment":"nucleoplasm","grade":3}],"interactors":[{"gene":"ACTR2","stoichiometry":0.2},{"gene":"ACADM","stoichiometry":0.2},{"gene":"HEATR3","stoichiometry":0.2},{"gene":"TRAP1","stoichiometry":0.2},{"gene":"NDUFA3","stoichiometry":0.2},{"gene":"DCTN1;DKFZP686E0752","stoichiometry":0.2},{"gene":"PIKFYVE","stoichiometry":0.2},{"gene":"DIAPH2","stoichiometry":0.2},{"gene":"UQCRB","stoichiometry":0.2},{"gene":"LONP1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000962","total_profiled":1310},"omim":[{"mim_id":"614041","title":"RB TRANSCRIPTIONAL COREPRESSOR 1; RB1","url":"https://www.omim.org/entry/614041"},{"mim_id":"613884","title":"CHROMOSOME 13q14 DELETION SYNDROME","url":"https://www.omim.org/entry/613884"},{"mim_id":"277900","title":"WILSON DISEASE; WND","url":"https://www.omim.org/entry/277900"},{"mim_id":"182135","title":"5-@HYDROXYTRYPTAMINE RECEPTOR 2A; HTR2A","url":"https://www.omim.org/entry/182135"},{"mim_id":"180200","title":"RETINOBLASTOMA; RB1","url":"https://www.omim.org/entry/180200"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Golgi apparatus","reliability":"Approved"},{"location":"Nucleoplasm","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ESD"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"P10768","domains":[{"cath_id":"3.40.50.1820","chopping":"3-280","consensus_level":"high","plddt":98.4175,"start":3,"end":280}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P10768","model_url":"https://alphafold.ebi.ac.uk/files/AF-P10768-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P10768-F1-predicted_aligned_error_v6.png","plddt_mean":98.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ESD","jax_strain_url":"https://www.jax.org/strain/search?query=ESD"},"sequence":{"accession":"P10768","fasta_url":"https://rest.uniprot.org/uniprotkb/P10768.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P10768/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P10768"}},"corpus_meta":[{"pmid":"22867446","id":"PMC_22867446","title":"Fabricated autologous epidermal cell sheets for the prevention of esophageal stricture after circumferential ESD in a porcine model.","date":"2012","source":"Gastrointestinal endoscopy","url":"https://pubmed.ncbi.nlm.nih.gov/22867446","citation_count":73,"is_preprint":false},{"pmid":"26135649","id":"PMC_26135649","title":"Efficacy of short period, low dose oral prednisolone for the prevention of stricture after circumferential endoscopic submucosal dissection (ESD) for esophageal cancer.","date":"2014","source":"Endoscopy international open","url":"https://pubmed.ncbi.nlm.nih.gov/26135649","citation_count":68,"is_preprint":false},{"pmid":"21596165","id":"PMC_21596165","title":"Activity-based proteomics: identification of ABHD11 and ESD activities as potential biomarkers for human lung adenocarcinoma.","date":"2011","source":"Journal of proteomics","url":"https://pubmed.ncbi.nlm.nih.gov/21596165","citation_count":50,"is_preprint":false},{"pmid":"6654325","id":"PMC_6654325","title":"Familial, EsD-linked, retinoblastoma with reduced 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melanogaster.","date":"1991","source":"Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/1906417","citation_count":31,"is_preprint":false},{"pmid":"14741616","id":"PMC_14741616","title":"Electrostatic spray deposition (ESD) of calcium phosphate coatings, an in vitro study with osteoblast-like cells.","date":"2004","source":"Biomaterials","url":"https://pubmed.ncbi.nlm.nih.gov/14741616","citation_count":30,"is_preprint":false},{"pmid":"27556083","id":"PMC_27556083","title":"Prospective evaluation of the clinical utility of endoscopic submucosal dissection (ESD) in patients with Barrett's esophagus: a Western center experience.","date":"2016","source":"Endoscopy international open","url":"https://pubmed.ncbi.nlm.nih.gov/27556083","citation_count":29,"is_preprint":false},{"pmid":"28743132","id":"PMC_28743132","title":"Therapeutic Outcomes of Endoscopic Resection of Early Gastric Cancer with Undifferentiated-Type Histology: A Korean ESD Registry Database Analysis.","date":"2017","source":"Clinical endoscopy","url":"https://pubmed.ncbi.nlm.nih.gov/28743132","citation_count":27,"is_preprint":false},{"pmid":"30705941","id":"PMC_30705941","title":"Inadequate steroid injection after esophageal ESD might cause mural necrosis.","date":"2019","source":"Endoscopy international open","url":"https://pubmed.ncbi.nlm.nih.gov/30705941","citation_count":25,"is_preprint":false},{"pmid":"315197","id":"PMC_315197","title":"[Del (13) (q33). Exclusion of esterase D (ESD) from 13q33 and q34].","date":"1978","source":"Annales de genetique","url":"https://pubmed.ncbi.nlm.nih.gov/315197","citation_count":21,"is_preprint":false},{"pmid":"27923017","id":"PMC_27923017","title":"Expression of microRNA-328 Functions as a Biomarker for Recurrence of Early Gastric Cancer (EGC) After Endoscopic Submucosal Dissection (ESD) by Modulating CD44.","date":"2016","source":"Medical science monitor : international medical journal of experimental and clinical research","url":"https://pubmed.ncbi.nlm.nih.gov/27923017","citation_count":20,"is_preprint":false},{"pmid":"7160848","id":"PMC_7160848","title":"Frequency of the ESD*5 allele in three ethnic groups in Minnesota.","date":"1982","source":"Human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/7160848","citation_count":19,"is_preprint":false},{"pmid":"21160677","id":"PMC_21160677","title":"A prospective randomized trial of lafutidine vs rabeprazole on post-ESD gastric ulcers.","date":"2010","source":"World journal of gastrointestinal endoscopy","url":"https://pubmed.ncbi.nlm.nih.gov/21160677","citation_count":18,"is_preprint":false},{"pmid":"3862931","id":"PMC_3862931","title":"Regional assignment of the genes for TK1, GALK, ALDC, and ESD on chromosome 8 in the American mink by chromosome-mediated gene transfer.","date":"1985","source":"Molecular & general genetics : MGG","url":"https://pubmed.ncbi.nlm.nih.gov/3862931","citation_count":17,"is_preprint":false},{"pmid":"16025470","id":"PMC_16025470","title":"Osteoclastic resorption of calcium phosphate coatings applied with electrostatic spray deposition (ESD), in vitro.","date":"2005","source":"Journal of biomedical materials research. 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Journal of legal medicine","url":"https://pubmed.ncbi.nlm.nih.gov/6447424","citation_count":3,"is_preprint":false},{"pmid":"2155993","id":"PMC_2155993","title":"Evaluation of a nonequilibrium isoelectric focusing (IEF) method for the simultaneous typing of esterase D (EsD), red cell acid phosphatase (AcP1), phosphoglucomutase (PGM1), adenylate kinase (AK), and adenosine deaminase (ADA).","date":"1990","source":"Journal of forensic sciences","url":"https://pubmed.ncbi.nlm.nih.gov/2155993","citation_count":3,"is_preprint":false},{"pmid":"22487637","id":"PMC_22487637","title":"Autolysis: a plausible finding suggestive of long ESD procedure time.","date":"2012","source":"Surgical laparoscopy, endoscopy & percutaneous techniques","url":"https://pubmed.ncbi.nlm.nih.gov/22487637","citation_count":3,"is_preprint":false},{"pmid":"15481680","id":"PMC_15481680","title":"Molecular basis of ESD*5 and ESD*7 and haplotype analysis with new polymorphisms in introns.","date":"2004","source":"Human biology","url":"https://pubmed.ncbi.nlm.nih.gov/15481680","citation_count":2,"is_preprint":false},{"pmid":"7034636","id":"PMC_7034636","title":"Geographic and ethnic distribution of genetic markers in India. 2. Inv, Gm, Gc, ADA, AK, ap, PGM1, 6-PGD and EsD polymorphisms.","date":"1981","source":"Anthropologischer Anzeiger; Bericht uber die biologisch-anthropologische Literatur","url":"https://pubmed.ncbi.nlm.nih.gov/7034636","citation_count":2,"is_preprint":false},{"pmid":"40283364","id":"PMC_40283364","title":"Interposer-Based ESD Protection: A Potential Solution for μ-Packaging Reliability of 3D Chips.","date":"2025","source":"Micromachines","url":"https://pubmed.ncbi.nlm.nih.gov/40283364","citation_count":2,"is_preprint":false},{"pmid":"30914617","id":"PMC_30914617","title":"[Metachronous Gastric Intramural Metastasis following Esophageal Cancer ESD-A Case Study].","date":"2019","source":"Gan to kagaku ryoho. Cancer & chemotherapy","url":"https://pubmed.ncbi.nlm.nih.gov/30914617","citation_count":2,"is_preprint":false},{"pmid":"2591982","id":"PMC_2591982","title":"Frequency of the ESD*5 allele in a Spanish population.","date":"1989","source":"Human heredity","url":"https://pubmed.ncbi.nlm.nih.gov/2591982","citation_count":2,"is_preprint":false},{"pmid":"3679239","id":"PMC_3679239","title":"AcP and EsD polymorphisms in Central Sardinia.","date":"1987","source":"Human heredity","url":"https://pubmed.ncbi.nlm.nih.gov/3679239","citation_count":2,"is_preprint":false},{"pmid":"3710480","id":"PMC_3710480","title":"Extended polymorphism of the human esterase D isozyme system: description of a \"new\" allele EsD*11.","date":"1986","source":"Human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/3710480","citation_count":2,"is_preprint":false},{"pmid":"38230038","id":"PMC_38230038","title":"Retracted: The Use of BT-ESD Technology under General Intravenous Anesthesia in the Treatment of Nonmuscle Invasive Bladder Cancer and the Effect of PI3K/Akt Signaling Pathway on Tumor Recurrence.","date":"2024","source":"BioMed research international","url":"https://pubmed.ncbi.nlm.nih.gov/38230038","citation_count":1,"is_preprint":false},{"pmid":"1840292","id":"PMC_1840292","title":"ESD, GLO1, PGD, PGM1 and PGM2 gene frequencies in the Salerno Province (Italy).","date":"1991","source":"Gene geography : a computerized bulletin on human gene frequencies","url":"https://pubmed.ncbi.nlm.nih.gov/1840292","citation_count":1,"is_preprint":false},{"pmid":"1856651","id":"PMC_1856651","title":"Polymorphisms of the enzyme systems galactose-1-phosphate uridyltransferase (GALT) and esterase D (EsD) in the province of Cádiz, southern Spain.","date":"1991","source":"Journal of forensic sciences","url":"https://pubmed.ncbi.nlm.nih.gov/1856651","citation_count":1,"is_preprint":false},{"pmid":"12062949","id":"PMC_12062949","title":"Molecular analysis of the human esterase D gene ESD(*)Q0(yonago) responsible for incompatibility in a Japanese paternity case.","date":"2002","source":"Forensic science international","url":"https://pubmed.ncbi.nlm.nih.gov/12062949","citation_count":1,"is_preprint":false},{"pmid":"3721523","id":"PMC_3721523","title":"AcP and EsD polymorphisms in South Sardinia.","date":"1986","source":"Human heredity","url":"https://pubmed.ncbi.nlm.nih.gov/3721523","citation_count":1,"is_preprint":false},{"pmid":"33735916","id":"PMC_33735916","title":"Topical oro-dispersible budesonide tablets for stricture prevention after near circumferential ESD for esophageal squamous cell cancer - a case report.","date":"2021","source":"Zeitschrift fur Gastroenterologie","url":"https://pubmed.ncbi.nlm.nih.gov/33735916","citation_count":1,"is_preprint":false},{"pmid":"20037325","id":"PMC_20037325","title":"[A case of elder gastric cancer patient who relapsed at the local stomach wall and the regional lymph node at the time of six months after endoscopic submucosal dissection (ESD)].","date":"2009","source":"Gan to kagaku ryoho. Cancer & chemotherapy","url":"https://pubmed.ncbi.nlm.nih.gov/20037325","citation_count":1,"is_preprint":false},{"pmid":"7234140","id":"PMC_7234140","title":"[Population genetic examination of the esterase D (EsD) erythrocyte isoenzyme system in the inhabitants of Szeged and its environment (South Hungary) (author's transl)].","date":"1981","source":"Zeitschrift fur Rechtsmedizin. Journal of legal medicine","url":"https://pubmed.ncbi.nlm.nih.gov/7234140","citation_count":1,"is_preprint":false},{"pmid":"3827234","id":"PMC_3827234","title":"Genetic variation of esterase D (EsD) polymorphism in Indian populations.","date":"1986","source":"Anthropologischer Anzeiger; Bericht uber die biologisch-anthropologische Literatur","url":"https://pubmed.ncbi.nlm.nih.gov/3827234","citation_count":1,"is_preprint":false},{"pmid":"39910700","id":"PMC_39910700","title":"Single-Cell Sequencing Reveals Heterogeneity and Interactions Between Epithelial Cells and Fibroblasts in Post-ESD Oesophageal Stricture.","date":"2025","source":"Journal of cellular and molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/39910700","citation_count":0,"is_preprint":false},{"pmid":"34081250","id":"PMC_34081250","title":"LGR5-Expressing Cells in the Healing Process of Post-ESD Ulcers in Gastric Corpus.","date":"2021","source":"Digestive diseases and sciences","url":"https://pubmed.ncbi.nlm.nih.gov/34081250","citation_count":0,"is_preprint":false},{"pmid":"40467993","id":"PMC_40467993","title":"Individual risk stratification to predict metastasis for ESD of superficial esophageal squamous cell carcinoma.","date":"2025","source":"Esophagus : official journal of the Japan Esophageal Society","url":"https://pubmed.ncbi.nlm.nih.gov/40467993","citation_count":0,"is_preprint":false},{"pmid":"2534281","id":"PMC_2534281","title":"[Distributions and gene frequencies of PGM1 subtype, EsD, GLO1, AK, ADAand 6-PGD in 20 races of China].","date":"1989","source":"Yi chuan xue bao = Acta genetica Sinica","url":"https://pubmed.ncbi.nlm.nih.gov/2534281","citation_count":0,"is_preprint":false},{"pmid":"6269514","id":"PMC_6269514","title":"Hereditary of the three enzyme systems EsD, Gt and GLO in the Polish population. The family studies and mother/child combinations.","date":"1981","source":"Archivum immunologiae et therapiae experimentalis","url":"https://pubmed.ncbi.nlm.nih.gov/6269514","citation_count":0,"is_preprint":false},{"pmid":"11642115","id":"PMC_11642115","title":"[The Russian gene pool. Genogeography of erythrocyte genetic markers (ACP1, PGM1, ESD, GLO1, 6-PGD)].","date":"2001","source":"Genetika","url":"https://pubmed.ncbi.nlm.nih.gov/11642115","citation_count":0,"is_preprint":false},{"pmid":"10806763","id":"PMC_10806763","title":"[Distribution of erythrocyte EsD and PGM1 (phosphoglucomutase) phenotypes in the Han population of Changsha district].","date":"1998","source":"Hunan yi ke da xue xue bao = Hunan yike daxue xuebao = Bulletin of Hunan Medical University","url":"https://pubmed.ncbi.nlm.nih.gov/10806763","citation_count":0,"is_preprint":false},{"pmid":"8834612","id":"PMC_8834612","title":"Esterase D (ESD, EC 3.1.1.1) polymorphism in hemolysates and bloodstains. I. Usefulness of selected methods of ESD phenotyping.","date":"1995","source":"Roczniki Akademii Medycznej w Bialymstoku (1995)","url":"https://pubmed.ncbi.nlm.nih.gov/8834612","citation_count":0,"is_preprint":false},{"pmid":"8834613","id":"PMC_8834613","title":"Esterase D (ESD EC 3.1.1.1) polymorphism in hemolysates and bloodstains. II. Comparison of ESD stability in dried bloodstains in relation to the temperature of storage and the type and character of substrate.","date":"1995","source":"Roczniki Akademii Medycznej w Bialymstoku (1995)","url":"https://pubmed.ncbi.nlm.nih.gov/8834613","citation_count":0,"is_preprint":false},{"pmid":"6542041","id":"PMC_6542041","title":"[Population genetics of taiga hunters and reindeer breeders in central Siberia. The biochemical markers of genes Hp, Tf, Gc, A1b, GLO1, PGM1, AcP and EsD].","date":"1984","source":"Genetika","url":"https://pubmed.ncbi.nlm.nih.gov/6542041","citation_count":0,"is_preprint":false},{"pmid":"41921213","id":"PMC_41921213","title":"Finite element optimization of a magnetic anchor traction system for colonic ESD.","date":"2026","source":"Computer methods in biomechanics and biomedical engineering","url":"https://pubmed.ncbi.nlm.nih.gov/41921213","citation_count":0,"is_preprint":false},{"pmid":"2629916","id":"PMC_2629916","title":"[Genetic polymorphism of AcP, EsD, 6-PGD and GPT in eleven ethnic groups of China].","date":"1989","source":"Yi chuan xue bao = Acta genetica Sinica","url":"https://pubmed.ncbi.nlm.nih.gov/2629916","citation_count":0,"is_preprint":false},{"pmid":"1908400","id":"PMC_1908400","title":"[Genetic structure of the Mongols as derived from the ABO, MN, Rh, EsD, GLO1, PGM1, AcP, 6-PGD, Hp, Gc, Tf, C'3 and ChE2 loci].","date":"1991","source":"Genetika","url":"https://pubmed.ncbi.nlm.nih.gov/1908400","citation_count":0,"is_preprint":false},{"pmid":"7223072","id":"PMC_7223072","title":"[EsD gene defect in the myocardium of a 33-year-old man (author's transl)].","date":"1981","source":"Zeitschrift fur Rechtsmedizin. Journal of legal medicine","url":"https://pubmed.ncbi.nlm.nih.gov/7223072","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.10.26.684666","title":"Species interactions, divergence, and the rapid evolution of ecological sexual dimorphism in threespine sticklebacks","date":"2025-10-27","source":"bioRxiv","url":"https://doi.org/10.1101/2025.10.26.684666","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.11.04.686318","title":"Environmental sex determination in the cyst nematode  <i>Globodera pallida</i>  defaults to male development","date":"2025-11-05","source":"bioRxiv","url":"https://doi.org/10.1101/2025.11.04.686318","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.09.08.674940","title":"Emergence of Genetic Sex Determination in an Environmentally Sex-Determined Animal","date":"2025-09-12","source":"bioRxiv","url":"https://doi.org/10.1101/2025.09.08.674940","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.11.09.25339830","title":"Longitudinal Tracking of Chromosomal Instability Informs Timely Intervention in the Gastric Precancerous Cascade","date":"2025-11-10","source":"bioRxiv","url":"https://doi.org/10.1101/2025.11.09.25339830","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":35008,"output_tokens":1541,"usd":0.06407,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7812,"output_tokens":1795,"usd":0.041967,"stage2_stop_reason":"end_turn"},"total_usd":0.106037,"stage1_batch_id":"msgbatch_01AsR7g8dGTEiEw9U83bJeWn","stage2_batch_id":"msgbatch_01YV5ZyxtFNUZEjxRcpd9jzb","note":"batch pricing = 50% of standard"},"stage1_raw":"Looking through the corpus, I need to identify papers about the human gene ESD (Esterase D, EC 3.1.1.-), which encodes a serine hydrolase/esterase enzyme. The vast majority of papers in this corpus are about endoscopic submucosal dissection (ESD, the procedure), population genetics surveys, or unrelated topics. I need to find papers with direct mechanistic experiments about the ESD protein.\n\nRelevant mechanistic papers:\n- PMID 33615471: Describes ESD as a deacetylase, interaction with JAB1, role in cholesterol metabolism — mechanistic experiments\n- PMID 21596165: Activity-based proteomics identifying ESD serine hydrolase activity as biomarker — some functional data\n- PMID 15481680: Molecular basis of ESD*5 and ESD*7 alleles — SNP characterization\n- PMID 12062949: Molecular analysis of null allele ESD(*)Q0 — stop codon mutation\n- PMID 7679066: Chromosomal mapping of ESD gene\n- PMID 3862931: Syntenic assignment of ESD in mink\n- PMID 8672130: Syntenic mapping in bovine\n\nOnly PMID 33615471 and PMID 21596165 contain direct mechanistic experiments about the ESD protein function.\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2020,\n      \"finding\": \"ESD (Esterase D) functions as a nonclassical deacetylase that hydrolyzes serine/threonine acetyl groups. Specifically, ESD removes Thr89 acetylation from JAB1 (Jun activation domain binding protein 1), increasing JAB1 activity. Activated JAB1 then promotes ABCA1 (ATP-binding cassette transporter A1) expression to accelerate cholesterol efflux. The small-molecule activator FPD5 triggered ESD aggregation in lysosomes and its interaction with JAB1, reducing blood cholesterol in apoE-/- mice on a high-fat diet and inhibiting foam cell formation from oxLDL-treated cells.\",\n      \"method\": \"Co-immunoprecipitation (ESD–JAB1 interaction), in vitro/cell-based deacetylase assay (Thr89 acetylation of JAB1), lysosomal fractionation/localization, mouse model (apoE-/- high-fat diet), foam cell assay, pharmacological activation with FPD5\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — single lab, multiple orthogonal methods (Co-IP, acetylation assay, fractionation, in vivo mouse model, foam cell assay), but not independently replicated\",\n      \"pmids\": [\"33615471\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"ESD exhibits serine hydrolase enzymatic activity detectable in human lung tissue by activity-based protein profiling (ABPP). ESD activity (but not expression level alone) was measurable and correlated with aggressive lung adenocarcinoma phenotype, confirming the protein's catalytic serine hydrolase function is active in human tissue.\",\n      \"method\": \"Activity-based protein profiling (ABPP) coupled to mass spectrometry on 40 paired fresh-frozen human lung adenocarcinoma and non-neoplastic tissue samples\",\n      \"journal\": \"Journal of proteomics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single activity-based method; establishes active serine hydrolase function in human tissue but no mechanistic pathway placement or mutagenesis\",\n      \"pmids\": [\"21596165\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"The molecular basis of ESD allelic variants ESD*5 and ESD*7 was characterized: ESD*5 arises from ESD*1 via a G-to-A transition causing Gly257→Asp; ESD*7 arises from ESD*2 via an A-to-G transition causing Asp231→Gly. The common ESD*1/ESD*2 polymorphism involves Gly190→Glu. Haplotype analysis showed strong linkage disequilibrium across the ~25 kb, 10-exon ESD gene with little recombination.\",\n      \"method\": \"PCR amplification and DNA sequencing of all coding exons; intragenic SNP haplotype analysis in German and Japanese populations\",\n      \"journal\": \"Human biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct DNA sequencing with amino acid identification; single lab but definitive molecular characterization of coding variants\",\n      \"pmids\": [\"15481680\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"A null allele ESD(*)Q0(yonago) was characterized at the molecular level: a C-to-T transition in codon 63 converts TCA (Ser) to TGA (stop codon), abolishing ESD protein production from this allele.\",\n      \"method\": \"PCR amplification and DNA sequencing of all eight coding exons from a paternity case sample\",\n      \"journal\": \"Forensic science international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — direct sequencing identifying a premature stop codon; single case, single lab, but molecularly definitive\",\n      \"pmids\": [\"12062949\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ESD (Esterase D) is a serine hydrolase that, beyond its classical esterase activity, functions as a nonclassical deacetylase capable of removing acetyl groups from serine/threonine residues; in the context of cholesterol metabolism, ESD localizes to lysosomes, interacts with and deacetylates JAB1 at Thr89 to increase its activity, which in turn promotes ABCA1-mediated cholesterol efflux, thereby reducing blood cholesterol levels.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ESD (Esterase D) is a catalytically active serine hydrolase whose enzymatic activity is detectable in human tissue and, beyond classical esterase function, extends to a nonclassical deacetylase activity acting on serine/threonine residues [#0, #1]. In the context of cholesterol homeostasis, ESD localizes to lysosomes, interacts with JAB1 (Jun activation domain binding protein 1), and removes the Thr89 acetyl mark from JAB1 to increase its activity; activated JAB1 in turn promotes ABCA1 expression to accelerate cholesterol efflux, an axis that lowers blood cholesterol and inhibits foam cell formation in apoE-/- mice and oxLDL-treated cells [#0]. The coding sequence of ESD has been resolved at the variant level, including missense polymorphisms and a premature-stop null allele that abolishes protein production [#2, #3]. Beyond the JAB1–ABCA1 cholesterol-efflux axis and its catalytic activity in human tissue, no further mechanistic detail has been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"Establishing the molecular genetics of ESD: defining a null allele clarified that specific coding mutations can fully abolish ESD protein production, framing the gene's allelic landscape.\",\n      \"evidence\": \"PCR and DNA sequencing of all eight coding exons from a forensic paternity case identifying a C-to-T transition creating a premature stop at codon 63\",\n      \"pmids\": [\"12062949\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not address ESD protein function or biochemical activity\", \"Single case observation\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Characterizing common and rare ESD allelic variants at the amino-acid level mapped the polymorphic coding architecture of the gene across populations.\",\n      \"evidence\": \"PCR amplification, DNA sequencing, and intragenic SNP haplotype analysis in German and Japanese populations\",\n      \"pmids\": [\"15481680\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No functional consequence assigned to the identified amino-acid substitutions\", \"Does not connect variants to enzymatic activity or disease\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Demonstrating that ESD's serine hydrolase activity is catalytically active in human tissue established the protein as a functional enzyme in vivo rather than an inferred activity.\",\n      \"evidence\": \"Activity-based protein profiling coupled to mass spectrometry on 40 paired human lung adenocarcinoma and non-neoplastic tissue samples\",\n      \"pmids\": [\"21596165\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single activity-based method with no mutagenesis confirming the catalytic serine\", \"No substrate identified\", \"No mechanistic pathway placement\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identifying ESD as a nonclassical Ser/Thr deacetylase acting on JAB1 placed it in a defined signaling axis controlling cholesterol efflux, moving ESD from an enzyme of unknown physiological substrate to a regulator of lipid metabolism.\",\n      \"evidence\": \"Co-immunoprecipitation, cell-based deacetylase assay for JAB1 Thr89, lysosomal fractionation, apoE-/- high-fat-diet mouse model, foam cell assay, and pharmacological activation with FPD5\",\n      \"pmids\": [\"33615471\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab without independent replication\", \"Mechanism of ESD lysosomal aggregation and JAB1 recruitment not structurally defined\", \"Direct enzymatic measurement of deacetylation kinetics on a purified substrate not established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Whether the cataloged ESD coding variants alter its deacetylase/esterase activity or the JAB1–ABCA1 cholesterol-efflux axis remains unresolved, and the full substrate repertoire of ESD beyond JAB1 is unknown.\",\n      \"evidence\": \"No timeline discovery links the sequenced variants to functional or pathway-level consequences\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No genotype-to-activity mapping for ESD variants\", \"No substrate beyond JAB1 Thr89 characterized\", \"No structural model of substrate engagement\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"JAB1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":2,"faith_total":3,"faith_pct":66.66666666666667}}