{"gene":"LTA4H","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":2010,"finding":"LTA4H aminopeptidase activity degrades the neutrophil chemoattractant proline-glycine-proline (PGP), thereby facilitating resolution of acute neutrophilic inflammation. Cigarette smoke selectively inhibits this aminopeptidase activity, causing PGP accumulation and persistent neutrophil recruitment.","method":"In vitro aminopeptidase assay, mouse models of acute inflammation, cigarette smoke exposure models","journal":"Science","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean loss-of-function with defined cellular phenotype, substrate identification with functional consequence, replicated mechanistic findings in both in vitro and in vivo settings","pmids":["20813919"],"is_preprint":false},{"year":2013,"finding":"Synthetic 13S,14S-epoxy-DHA (13,14-epoxy-maresin) inhibits LTA4H epoxide hydrolase activity (~40-50% inhibition of LTB4 formation) but is not converted to MaR1 by LTA4H, demonstrating that LTA4H can be inhibited by this lipid epoxide intermediate.","method":"In vitro enzyme assay with synthetic 13S,14S-epoxy-DHA incubated with human LTA4H; LTB4 production measured","journal":"FASEB Journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro enzyme assay with stereocontrolled synthetic substrate and NMR-confirmed stereochemistry, single lab","pmids":["23504711"],"is_preprint":false},{"year":2010,"finding":"LTA4H aminopeptidase specificity profiling using chemical modulators (diphenyl ether, 4-phenoxyphenol derivatives) revealed a non-overlapping binding site distinct from the epoxide hydrolase active site; site-directed mutagenesis of F314E and V367W altered substrate specificity from arginyl to alanyl peptides, confirming these residues govern aminopeptidase substrate selectivity.","method":"Chemical modulator screening, molecular modeling, site-directed mutagenesis with enzyme kinetic assays","journal":"ChemBioChem","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro enzyme assay combined with mutagenesis confirming specific residue roles, single lab but multiple orthogonal methods","pmids":["20432426"],"is_preprint":false},{"year":2014,"finding":"LTA4H aminopeptidase has broad substrate specificity with highest activity toward arginine as the best proteinogenic amino acid; however, unnatural amino acids (e.g., benzyl ester of aspartic acid) exhibit >100-fold higher kcat/Km values, revealing extended active site accommodating non-canonical substrates.","method":"Library of 130 fluorogenic amino acid substrates screened against recombinant human LTA4H; kinetic constants (kcat/Km) determined","journal":"Amino Acids","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — rigorous in vitro kinetic assay with large substrate library, single lab","pmids":["24573245"],"is_preprint":false},{"year":2017,"finding":"Conventional LTA4H inhibitors (including clinical candidates) fail to discriminate between the dual enzymatic activities of LTA4H, inhibiting both LTB4 generation and PGP degradation and enabling PGP accumulation in mice. Novel selective compounds were developed that potently inhibit LTB4 generation while leaving PGP aminopeptidase activity unperturbed.","method":"In vitro dual-activity assays, mouse in vivo PGP accumulation measurements with pharmacological LTA4H inhibitors and novel selective compounds","journal":"Scientific Reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — in vitro enzyme assays and in vivo mouse models, multiple inhibitor classes tested, mechanistic distinction between two active sites established","pmids":["28303931"],"is_preprint":false},{"year":2017,"finding":"LTA4H acts as a key regulator of cell cycle at the G0/G1 phase by negatively regulating p27 protein stability. LTA4H depletion enhanced p27 stability associated with decreased CDK2 phosphorylation at Thr160 and inhibition of the CDK2/cyclin E complex, resulting in reduced p27 ubiquitination and cell cycle arrest.","method":"LTA4H knockout mouse model (two-stage skin carcinogenesis), siRNA knockdown in cancer cell lines, cell cycle analysis, western blotting for CDK2 phosphorylation and CDK2/cyclin E complex, ubiquitination assay","journal":"Carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse model plus cell-based loss-of-function with multiple pathway readouts, single lab","pmids":["28575166"],"is_preprint":false},{"year":2019,"finding":"LTA4H physically binds to FSCN1 (fascin actin-bundling protein 1) in laryngeal squamous cell carcinoma cells, as confirmed by co-immunoprecipitation and immunofluorescence colocalization; LTA4H knockdown inhibits LSCC cell proliferation, migration, and invasion.","method":"Co-immunoprecipitation with mass spectrometry, western blotting validation, immunofluorescence colocalization, siRNA knockdown with functional assays","journal":"Proteomics","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — reciprocal Co-IP and immunofluorescence confirm interaction, functional knockdown phenotype, single lab but multiple orthogonal methods","pmids":["31287215"],"is_preprint":false},{"year":2016,"finding":"P4N (a nordihydroguaiaretic acid derivative) promotes B-cell proliferation and autoantibody production through a LTA4H/activin A/BAFF signaling pathway in monocytes, linking LTA4H enzymatic activity to immunoregulatory cytokine signaling.","method":"In vitro monocyte/B-cell co-culture assays, in vivo mouse tumor models, pathway analysis with LTA4H inhibitors and activin A/BAFF measurements","journal":"PNAS","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro and in vivo experiments linking LTA4H activity to downstream cytokine signaling, single lab","pmids":["27856749"],"is_preprint":false},{"year":2024,"finding":"Neutrophil elastase cleaves LTA4H upon neutrophil activation, altering its aminopeptidase activity in the cystic fibrosis lung, identifying neutrophil elastase as a post-translational regulator of LTA4H function.","method":"Biochemical cleavage assays, cystic fibrosis airway samples, neutrophil activation experiments","journal":"European Respiratory Journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct biochemical demonstration of proteolytic cleavage with functional consequence on enzymatic activity, single study","pmids":["38387968"],"is_preprint":false},{"year":2024,"finding":"Airway extracellular LTA4H originates primarily from liver hepatocytes (released constitutively and upregulated during acute phase response) and reaches the airway via increased pulmonary vascular permeability, demonstrating that extracellular LTA4H levels are governed by hepatic secretion and vascular leak rather than local production.","method":"Cell fractionation, hepatocyte culture experiments, mouse models of vascular permeability, airway lavage measurements, acute phase response induction","journal":"Cell Reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple in vitro and in vivo approaches identifying cellular source of extracellular LTA4H, single lab","pmids":["39146180"],"is_preprint":false},{"year":2025,"finding":"LTA4H induces HNRNPA1 phosphorylation, enhancing LTA4H-HNRNPA1 interaction and functionally inhibiting HNRNPA1-mediated regulation of Ltbp1 mRNA maturation and processing in the nucleus; LTA4H deficiency leads to upregulated LTBP1 expression, increased TGF-β secretion, and CD206+ macrophage polarization promoting HCC progression.","method":"Co-immunoprecipitation, phosphorylation assays, mRNA processing/splicing assays, LTA4H knockout mouse model (Hepa1-6), immune cell phenotyping, rescue experiments","journal":"Cell Reports Medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal experiments (Co-IP, phosphorylation, mRNA processing, in vivo KO) in a single lab establishing a novel nuclear role for LTA4H","pmids":["40056904"],"is_preprint":false},{"year":2025,"finding":"HDAC2 activity (activated by casein kinase 2) upregulates LTA4H activity in renal ischemia-reperfusion injury, driving LTB4 production; HDAC2 inhibition with BRD6688 suppresses LTA4H activity and reduces LTB4-mediated M1 macrophage polarization.","method":"HDAC2 inhibitor treatment, HDAC2 genetic ablation in HREpiC cells, LTA4H activity assays, LTB4 measurement, macrophage polarization assays, mouse I/R model","journal":"BBA Molecular Basis of Disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic ablation and pharmacological inhibition with direct LTA4H activity measurements and downstream macrophage phenotype, single lab","pmids":["40324735"],"is_preprint":false},{"year":2026,"finding":"USP1 (ubiquitin-specific protease 1) stabilizes LTA4H by removing K48-linked polyubiquitin chains and preventing its proteasomal degradation; USP1-stabilized LTA4H promotes HCC angiogenesis through reactivation of ERK signaling in endothelial cells.","method":"Mass spectrometry identification of LTA4H as USP1 substrate, Co-IP validation, ubiquitination assays (K48-linkage specific), functional rescue experiments, in vivo xenograft models, conditioned medium endothelial assays","journal":"BBA Molecular Basis of Disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mass spectrometry plus Co-IP validation, ubiquitin chain-type specificity demonstrated, functional rescue in vitro and in vivo, single lab","pmids":["42044771"],"is_preprint":false},{"year":2023,"finding":"LTA4H functions as an RNA-binding protein, extensively binding mRNAs/pre-mRNAs and lncRNAs in cells; the AAGG motif is enriched in LTA4H binding peaks; LTA4H-bound genes are enriched in mitotic cell cycle, DNA repair, RNA splicing, and RNA metabolism pathways. LTA4H specifically binds mRNAs of carcinogenesis-associated genes including LTBP3, ROR2, EGFR, HSP90B1, and lncRNA NEAT1.","method":"Improved RNA immunoprecipitation and sequencing (iRIP-Seq) in HeLa cells, qRT-PCR validation","journal":"PeerJ","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single iRIP-Seq experiment with qRT-PCR validation, no functional consequence of RNA binding demonstrated, single lab","pmids":["36923505"],"is_preprint":false}],"current_model":"LTA4H is a bifunctional zinc metalloenzyme that operates both intracellularly (primarily in myeloid cells and hepatocytes) and extracellularly: its epoxide hydrolase activity converts LTA4 to the pro-inflammatory mediator LTB4, while its aminopeptidase activity degrades the neutrophil chemoattractant PGP to resolve inflammation—two activities sharing overlapping but distinct active sites, with specific residues (E271, R563, K565, F314, V367) governing each function; LTA4H is post-translationally regulated by neutrophil elastase cleavage and by USP1-mediated deubiquitination (removing K48-linked chains to prevent proteasomal degradation), and by HDAC2/CK2-dependent activity upregulation; beyond lipid metabolism, LTA4H regulates cell cycle progression by destabilizing p27 via CDK2/cyclin E, interacts with FSCN1 and HNRNPA1 to modulate mRNA processing and TGF-β signaling, and functions as an RNA-binding protein associating with mRNAs involved in cell cycle and RNA metabolism."},"narrative":{"mechanistic_narrative":"LTA4H is a bifunctional zinc metalloenzyme with two opposing roles in inflammation: its epoxide hydrolase activity generates the pro-inflammatory mediator LTB4, while its aminopeptidase activity degrades the neutrophil chemoattractant proline-glycine-proline (PGP) to promote resolution of acute neutrophilic inflammation [PMID:20813919]. The two catalytic functions occupy non-overlapping sites within the protein, with residues F314 and V367 governing aminopeptidase substrate selectivity [PMID:20432426], and the aminopeptidase accommodating a broad range of substrates with highest activity toward arginine [PMID:24573245]. This functional separability is therapeutically exploitable: selective inhibitors can block LTB4 generation while sparing PGP-degrading activity, whereas conventional inhibitors inhibit both and cause PGP accumulation [PMID:28303931]; the epoxide hydrolase can also be inhibited by the lipid epoxide 13S,14S-epoxy-DHA without being converted to a product [PMID:23504711]. LTA4H function is set by post-translational regulation—neutrophil elastase cleaves LTA4H upon neutrophil activation to alter aminopeptidase activity in the cystic fibrosis lung [PMID:38387968], HDAC2 (activated by casein kinase 2) upregulates LTA4H activity to drive LTB4 production and M1 macrophage polarization in renal ischemia-reperfusion injury [PMID:40324735], and USP1 removes K48-linked polyubiquitin to prevent proteasomal degradation and stabilize the enzyme [PMID:42044771]; extracellular airway LTA4H derives largely from hepatocyte secretion reaching the lung via vascular leak rather than local production [PMID:39146180]. Beyond lipid metabolism, LTA4H regulates the G0/G1 cell cycle transition by destabilizing p27 through CDK2/cyclin E activity [PMID:28575166], physically binds FSCN1 to support tumor cell proliferation and invasion [PMID:31287215], and interacts with phosphorylated HNRNPA1 to modulate Ltbp1 mRNA processing, TGF-β secretion, and macrophage polarization in hepatocellular carcinoma [PMID:40056904].","teleology":[{"year":2010,"claim":"Established that LTA4H is not solely pro-inflammatory but harbors an aminopeptidase activity that resolves inflammation by degrading the chemoattractant PGP, reframing the enzyme as a bidirectional regulator.","evidence":"In vitro aminopeptidase assays, mouse acute inflammation and cigarette-smoke exposure models","pmids":["20813919"],"confidence":"High","gaps":["Did not map the structural basis distinguishing aminopeptidase from epoxide hydrolase sites","Relative physiological balance of the two activities in vivo not quantified"]},{"year":2010,"claim":"Defined that the aminopeptidase active site is structurally distinct from the epoxide hydrolase site and identified residues controlling substrate selectivity, providing the molecular handle for selective targeting.","evidence":"Chemical modulator screening, molecular modeling, and site-directed mutagenesis (F314E, V367W) with kinetic assays","pmids":["20432426"],"confidence":"High","gaps":["Mutagenesis effects on physiological substrate PGP not directly tested","No co-crystal structures of selective modulators"]},{"year":2013,"claim":"Showed the epoxide hydrolase can be inhibited by a lipid epoxide intermediate that is not itself turned over, expanding the modes of catalytic inhibition.","evidence":"In vitro enzyme assay with synthetic stereodefined 13S,14S-epoxy-DHA measuring LTB4 production","pmids":["23504711"],"confidence":"Medium","gaps":["Cellular or in vivo relevance of this inhibition not established","Single-lab in vitro result"]},{"year":2014,"claim":"Characterized the aminopeptidase substrate range, revealing an extended active site that prefers arginine among proteinogenic residues but accommodates non-canonical substrates far more efficiently.","evidence":"Kinetic screening of a 130-member fluorogenic amino acid substrate library against recombinant human LTA4H","pmids":["24573245"],"confidence":"Medium","gaps":["Physiological substrate beyond PGP not identified","Single lab in vitro kinetics"]},{"year":2016,"claim":"Linked LTA4H enzymatic activity to immunoregulatory cytokine output, connecting the lipid mediator pathway to B-cell responses.","evidence":"Monocyte/B-cell co-culture and mouse tumor models with LTA4H inhibitors and activin A/BAFF measurements","pmids":["27856749"],"confidence":"Medium","gaps":["Direct LTA4H product responsible for activin A/BAFF induction not pinned down","Pharmacological pathway dissection in a single system"]},{"year":2017,"claim":"Revealed a non-enzymatic-context role in cell cycle control, showing LTA4H destabilizes the CDK inhibitor p27 via the CDK2/cyclin E axis to permit G0/G1 progression.","evidence":"LTA4H knockout mouse carcinogenesis model and siRNA knockdown with cell cycle, CDK2 phosphorylation, and ubiquitination readouts","pmids":["28575166"],"confidence":"Medium","gaps":["Whether catalytic activity is required for p27 regulation unclear","Direct molecular link between LTA4H and the CDK2/cyclin E complex not defined"]},{"year":2017,"claim":"Demonstrated that the dual activities can be pharmacologically uncoupled, providing proof-of-concept for selective LTB4-blocking inhibitors that spare PGP resolution.","evidence":"In vitro dual-activity assays and in vivo mouse PGP accumulation measurements across multiple inhibitor classes","pmids":["28303931"],"confidence":"High","gaps":["Long-term in vivo efficacy of selective compounds not assessed","Structural basis of selectivity not resolved here"]},{"year":2019,"claim":"Identified a direct protein partner, FSCN1, implicating LTA4H in cytoskeletal/actin-bundling-associated tumor cell motility.","evidence":"Reciprocal Co-IP with mass spectrometry, immunofluorescence colocalization, and siRNA knockdown functional assays in laryngeal carcinoma cells","pmids":["31287215"],"confidence":"Medium","gaps":["Functional consequence of the LTA4H-FSCN1 interaction at the molecular level unclear","Single cancer cell context"]},{"year":2023,"claim":"Proposed an RNA-binding function for LTA4H, with sequence-specific motif preference and association with cell cycle and RNA metabolism transcripts.","evidence":"iRIP-Seq in HeLa cells with qRT-PCR validation","pmids":["36923505"],"confidence":"Low","gaps":["No functional consequence of RNA binding demonstrated","Single iRIP-Seq experiment, not independently confirmed","Direct versus indirect RNA association not distinguished"]},{"year":2024,"claim":"Identified neutrophil elastase as a proteolytic regulator that modifies LTA4H aminopeptidase function during neutrophil activation in disease tissue.","evidence":"Biochemical cleavage assays, neutrophil activation experiments, and cystic fibrosis airway samples","pmids":["38387968"],"confidence":"Medium","gaps":["Cleavage site and structural consequence not fully mapped","Effect on epoxide hydrolase activity not quantified"]},{"year":2024,"claim":"Established the cellular source of extracellular LTA4H, showing it is hepatocyte-derived and reaches the airway through vascular leak rather than local synthesis.","evidence":"Cell fractionation, hepatocyte culture, vascular permeability and acute-phase mouse models, airway lavage measurements","pmids":["39146180"],"confidence":"Medium","gaps":["Mechanism of constitutive hepatic secretion not defined","Single lab"]},{"year":2025,"claim":"Uncovered a nuclear role in which LTA4H phosphorylates and binds HNRNPA1 to control Ltbp1 mRNA maturation, linking it to TGF-β signaling and tumor-associated macrophage polarization.","evidence":"Co-IP, phosphorylation and mRNA processing assays, LTA4H knockout mouse HCC model, immune phenotyping, and rescue experiments","pmids":["40056904"],"confidence":"Medium","gaps":["How a metalloenzyme drives HNRNPA1 phosphorylation mechanistically unresolved","Generality beyond HCC unknown"]},{"year":2025,"claim":"Showed HDAC2, activated by casein kinase 2, upregulates LTA4H activity to drive LTB4-mediated M1 macrophage polarization in ischemia-reperfusion injury.","evidence":"HDAC2 inhibition (BRD6688) and genetic ablation, LTA4H activity and LTB4 assays, macrophage polarization, and a mouse I/R model","pmids":["40324735"],"confidence":"Medium","gaps":["Direct molecular mechanism by which HDAC2 modifies LTA4H activity not defined","Single lab"]},{"year":2026,"claim":"Identified USP1-mediated deubiquitination as a stabilizing post-translational control that protects LTA4H from K48-linked proteasomal degradation, with downstream tumor angiogenesis consequences.","evidence":"Mass spectrometry substrate identification, Co-IP, K48-linkage-specific ubiquitination assays, rescue experiments, and xenograft/endothelial assays","pmids":["42044771"],"confidence":"Medium","gaps":["E3 ligase opposing USP1 on LTA4H not identified","Single lab"]},{"year":null,"claim":"How LTA4H's catalytic, protein-binding, nuclear RNA/HNRNPA1, and cell-cycle functions are integrated within a single protein—and whether the moonlighting roles require enzymatic activity—remains unresolved.","evidence":"No single study reconciles the enzymatic and non-enzymatic activities mechanistically","pmids":[],"confidence":"Low","gaps":["Structural basis coupling enzymatic and moonlighting roles unknown","Whether nuclear and RNA-binding functions depend on catalytic residues untested","In vivo dominance of each function across tissues unclear"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[0,1,2,3,4]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,2,3]},{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[1,4]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[5,6]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[10]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[8,9]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0,1,4]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,7,11]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[5]}],"complexes":[],"partners":["FSCN1","HNRNPA1","USP1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P09960","full_name":"Leukotriene A-4 hydrolase","aliases":["Leukotriene A(4) hydrolase","Tripeptide aminopeptidase LTA4H"],"length_aa":611,"mass_kda":69.3,"function":"Bifunctional zinc metalloenzyme that comprises both epoxide hydrolase (EH) and aminopeptidase activities. Acts as an epoxide hydrolase to catalyze the conversion of LTA4 to the pro-inflammatory mediator leukotriene B4 (LTB4) (PubMed:11917124, PubMed:12207002, PubMed:15078870, PubMed:18804029, PubMed:1897988, PubMed:1975494, PubMed:2244921, PubMed:2996528). Can utilize LTA5 less effectively as a substrate than LTA4, and produce LTB5 (PubMed:2996528). Also has aminopeptidase activity, with high affinity for N-terminal arginines of various synthetic tripeptides (PubMed:18804029, PubMed:20813919). In addition to its pro-inflammatory EH activity, may also counteract inflammation by its aminopeptidase activity, which inactivates by cleavage another neutrophil attractant, the tripeptide Pro-Gly-Pro (PGP), a bioactive fragment of collagen generated by the action of matrix metalloproteinase-9 (MMP9) and prolylendopeptidase (PREPL) (PubMed:20813919, PubMed:24591641). Involved also in the biosynthesis of resolvin E1 and 18S-resolvin E1 from eicosapentaenoic acid, two lipid mediators that show potent anti-inflammatory and pro-resolving actions (PubMed:21206090)","subcellular_location":"Cytoplasm","url":"https://www.uniprot.org/uniprotkb/P09960/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/LTA4H","classification":"Not Classified","n_dependent_lines":3,"n_total_lines":1208,"dependency_fraction":0.0024834437086092716},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"COPB2","stoichiometry":0.2},{"gene":"SAR1B","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/LTA4H","total_profiled":1310},"omim":[{"mim_id":"609888","title":"LEPROSY, SUSCEPTIBILITY TO, 1; LPRS1","url":"https://www.omim.org/entry/609888"},{"mim_id":"607948","title":"MYCOBACTERIUM TUBERCULOSIS, SUSCEPTIBILITY TO","url":"https://www.omim.org/entry/607948"},{"mim_id":"606264","title":"C-TYPE LECTIN DOMAIN FAMILY 7, MEMBER A; CLEC7A","url":"https://www.omim.org/entry/606264"},{"mim_id":"604672","title":"CD209 ANTIGEN; CD209","url":"https://www.omim.org/entry/604672"},{"mim_id":"153618","title":"MANNOSE RECEPTOR, C-TYPE, 1; MRC1","url":"https://www.omim.org/entry/153618"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Cytosol","reliability":"Supported"},{"location":"Nucleoplasm","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/LTA4H"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"P09960","domains":[{"cath_id":"2.60.40.1730","chopping":"1-208","consensus_level":"medium","plddt":96.5612,"start":1,"end":208},{"cath_id":"3.30.2010.30","chopping":"209-301","consensus_level":"medium","plddt":97.0226,"start":209,"end":301},{"cath_id":"1.10.390.10","chopping":"311-449","consensus_level":"high","plddt":97.3161,"start":311,"end":449},{"cath_id":"1.25.40.320","chopping":"462-607","consensus_level":"medium","plddt":95.3439,"start":462,"end":607}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P09960","model_url":"https://alphafold.ebi.ac.uk/files/AF-P09960-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P09960-F1-predicted_aligned_error_v6.png","plddt_mean":96.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=LTA4H","jax_strain_url":"https://www.jax.org/strain/search?query=LTA4H"},"sequence":{"accession":"P09960","fasta_url":"https://rest.uniprot.org/uniprotkb/P09960.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P09960/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P09960"}},"corpus_meta":[{"pmid":"23504711","id":"PMC_23504711","title":"The novel 13S,14S-epoxy-maresin is converted by human macrophages to maresin 1 (MaR1), inhibits leukotriene A4 hydrolase (LTA4H), and shifts macrophage phenotype.","date":"2013","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/23504711","citation_count":239,"is_preprint":false},{"pmid":"20813919","id":"PMC_20813919","title":"A critical role for LTA4H in limiting chronic pulmonary neutrophilic inflammation.","date":"2010","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/20813919","citation_count":206,"is_preprint":false},{"pmid":"28419315","id":"PMC_28419315","title":"Clinical Parameters, Routine Inflammatory Markers, and LTA4H Genotype as Predictors of Mortality Among 608 Patients With Tuberculous Meningitis in Indonesia.","date":"2017","source":"The Journal of infectious 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docking, cytotoxicity, and LTA4H inhibitory activity of new gingerol derivatives as potential colorectal cancer therapy.","date":"2016","source":"Bioorganic & medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/28065501","citation_count":27,"is_preprint":false},{"pmid":"28303931","id":"PMC_28303931","title":"The development of novel LTA4H modulators to selectively target LTB4 generation.","date":"2017","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/28303931","citation_count":26,"is_preprint":false},{"pmid":"28575166","id":"PMC_28575166","title":"LTA4H regulates cell cycle and skin carcinogenesis.","date":"2017","source":"Carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/28575166","citation_count":25,"is_preprint":false},{"pmid":"25721704","id":"PMC_25721704","title":"Variants in ALOX5, ALOX5AP and LTA4H are not associated with atherosclerotic plaque phenotypes: the Athero-Express Genomics 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Life sciences","url":"https://pubmed.ncbi.nlm.nih.gov/38300441","citation_count":15,"is_preprint":false},{"pmid":"21112816","id":"PMC_21112816","title":"Association analysis of the LTA4H gene polymorphisms and pulmonary tuberculosis in 9115 subjects.","date":"2010","source":"Tuberculosis (Edinburgh, Scotland)","url":"https://pubmed.ncbi.nlm.nih.gov/21112816","citation_count":15,"is_preprint":false},{"pmid":"20810156","id":"PMC_20810156","title":"ALOX5AP and LTA4H polymorphisms modify augmentation of bronchodilator responsiveness by leukotriene modifiers in Latinos.","date":"2010","source":"The Journal of allergy and clinical immunology","url":"https://pubmed.ncbi.nlm.nih.gov/20810156","citation_count":15,"is_preprint":false},{"pmid":"25257262","id":"PMC_25257262","title":"Relationship between human LTA4H polymorphisms and extra-pulmonary tuberculosis in an ethnic Han Chinese population in Eastern China.","date":"2014","source":"Tuberculosis (Edinburgh, Scotland)","url":"https://pubmed.ncbi.nlm.nih.gov/25257262","citation_count":14,"is_preprint":false},{"pmid":"22496831","id":"PMC_22496831","title":"Molecular dynamics simulation study and hybrid pharmacophore model development in human LTA4H inhibitor design.","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/22496831","citation_count":14,"is_preprint":false},{"pmid":"22206291","id":"PMC_22206291","title":"The role of ALOX5AP, LTA4H and LTB4R polymorphisms in determining baseline lung function and COPD susceptibility in UK smokers.","date":"2011","source":"BMC medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/22206291","citation_count":12,"is_preprint":false},{"pmid":"33856122","id":"PMC_33856122","title":"Development and in vitro Profiling of Dual FXR/LTA4H Modulators.","date":"2021","source":"ChemMedChem","url":"https://pubmed.ncbi.nlm.nih.gov/33856122","citation_count":10,"is_preprint":false},{"pmid":"27856749","id":"PMC_27856749","title":"In vivo amelioration of endogenous antitumor autoantibodies via low-dose P4N through the LTA4H/activin A/BAFF pathway.","date":"2016","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/27856749","citation_count":9,"is_preprint":false},{"pmid":"20432426","id":"PMC_20432426","title":"Modulating the substrate specificity of LTA4H aminopeptidase by using chemical compounds and small-molecule-guided mutagenesis.","date":"2010","source":"Chembiochem : a European journal of chemical biology","url":"https://pubmed.ncbi.nlm.nih.gov/20432426","citation_count":9,"is_preprint":false},{"pmid":"27914004","id":"PMC_27914004","title":"Hybrid Receptor-Bound/MM-GBSA-Per-residue Energy-Based Pharmacophore Modelling: Enhanced Approach for Identification of Selective LTA4H Inhibitors as Potential Anti-inflammatory Drugs.","date":"2016","source":"Cell biochemistry and biophysics","url":"https://pubmed.ncbi.nlm.nih.gov/27914004","citation_count":7,"is_preprint":false},{"pmid":"34355673","id":"PMC_34355673","title":"In silico investigations of some Cyperus rotundus compounds as potential anti-inflammatory inhibitors of 5-LO and LTA4H enzymes.","date":"2021","source":"Journal of biomolecular structure & dynamics","url":"https://pubmed.ncbi.nlm.nih.gov/34355673","citation_count":6,"is_preprint":false},{"pmid":"22848428","id":"PMC_22848428","title":"Structural origins for the loss of catalytic activities of bifunctional human LTA4H revealed through molecular dynamics simulations.","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/22848428","citation_count":6,"is_preprint":false},{"pmid":"25215090","id":"PMC_25215090","title":"Association of ALOX5, LTA4H and LTC4S gene polymorphisms with ischemic stroke risk in a cohort of Chinese in east China.","date":"2013","source":"World journal of emergency medicine","url":"https://pubmed.ncbi.nlm.nih.gov/25215090","citation_count":5,"is_preprint":false},{"pmid":"36879040","id":"PMC_36879040","title":"Leukotriene A4 hydrolase (LTA4H rs17525495) gene polymorphisms and paradoxical reactions in extrapulmonary tuberculosis.","date":"2023","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/36879040","citation_count":4,"is_preprint":false},{"pmid":"36923505","id":"PMC_36923505","title":"LTA4H extensively associates with mRNAs and lncRNAs indicative of its novel regulatory targets.","date":"2023","source":"PeerJ","url":"https://pubmed.ncbi.nlm.nih.gov/36923505","citation_count":3,"is_preprint":false},{"pmid":"29376243","id":"PMC_29376243","title":"[Discover potential inhibitors of 5-LOX and LTA4H from Rhei Radix et Rhizoma, Notopterygii Rhizoma et Radix and Genitana Macrophyllae Radix based on molecular simulation methods].","date":"2017","source":"Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica","url":"https://pubmed.ncbi.nlm.nih.gov/29376243","citation_count":3,"is_preprint":false},{"pmid":"40324735","id":"PMC_40324735","title":"Down-regulating HDAC2-LTA4H pathway ameliorates renal ischemia-reperfusion injury.","date":"2025","source":"Biochimica et biophysica acta. Molecular basis of disease","url":"https://pubmed.ncbi.nlm.nih.gov/40324735","citation_count":2,"is_preprint":false},{"pmid":"38387968","id":"PMC_38387968","title":"Neutrophil elastase-dependent cleavage of LTA4H alters its aminopeptidase activity in cystic fibrosis.","date":"2024","source":"The European respiratory journal","url":"https://pubmed.ncbi.nlm.nih.gov/38387968","citation_count":2,"is_preprint":false},{"pmid":"36088846","id":"PMC_36088846","title":"An enzyme activated fluorescent probe for LTA4H activity sensing and its application in cancer screening.","date":"2022","source":"Talanta","url":"https://pubmed.ncbi.nlm.nih.gov/36088846","citation_count":2,"is_preprint":false},{"pmid":"39146180","id":"PMC_39146180","title":"Airway extracellular LTA4H concentrations are governed by release from liver hepatocytes and changes in lung vascular permeability.","date":"2024","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/39146180","citation_count":2,"is_preprint":false},{"pmid":"34966807","id":"PMC_34966807","title":"Molecular and Immunohistochemical Expression of LTA4H and FXR1 in Canine Oral Melanoma.","date":"2021","source":"Frontiers in veterinary science","url":"https://pubmed.ncbi.nlm.nih.gov/34966807","citation_count":1,"is_preprint":false},{"pmid":"31093505","id":"PMC_31093505","title":"The Polymorphism rs17525495 of LTA4H Is Associated with Susceptibility of Crohn's Disease instead of Intestinal Tuberculosis in a Chinese Han Population.","date":"2019","source":"BioMed research international","url":"https://pubmed.ncbi.nlm.nih.gov/31093505","citation_count":1,"is_preprint":false},{"pmid":"42044771","id":"PMC_42044771","title":"USP1 dependent stabilization of LTA4H drives hepatocellular carcinoma angiogenesis.","date":"2026","source":"Biochimica et biophysica acta. Molecular basis of disease","url":"https://pubmed.ncbi.nlm.nih.gov/42044771","citation_count":0,"is_preprint":false},{"pmid":"41830171","id":"PMC_41830171","title":"Uncovering the role of dimerization on dynamics and inhibitor stability in human versus Xenopus LTA4H.","date":"2026","source":"Biophysical journal","url":"https://pubmed.ncbi.nlm.nih.gov/41830171","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.02.27.640170","title":"Targeting ALOX5/LTA4H driven granuloma caseation as a host-directed strategy for control of TB associated lung damage","date":"2025-03-03","source":"bioRxiv","url":"https://doi.org/10.1101/2025.02.27.640170","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":22024,"output_tokens":3596,"usd":0.060006,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11339,"output_tokens":4490,"usd":0.084473,"stage2_stop_reason":"end_turn"},"total_usd":0.144479,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2010,\n      \"finding\": \"LTA4H aminopeptidase activity degrades the neutrophil chemoattractant proline-glycine-proline (PGP), thereby facilitating resolution of acute neutrophilic inflammation. Cigarette smoke selectively inhibits this aminopeptidase activity, causing PGP accumulation and persistent neutrophil recruitment.\",\n      \"method\": \"In vitro aminopeptidase assay, mouse models of acute inflammation, cigarette smoke exposure models\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean loss-of-function with defined cellular phenotype, substrate identification with functional consequence, replicated mechanistic findings in both in vitro and in vivo settings\",\n      \"pmids\": [\"20813919\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Synthetic 13S,14S-epoxy-DHA (13,14-epoxy-maresin) inhibits LTA4H epoxide hydrolase activity (~40-50% inhibition of LTB4 formation) but is not converted to MaR1 by LTA4H, demonstrating that LTA4H can be inhibited by this lipid epoxide intermediate.\",\n      \"method\": \"In vitro enzyme assay with synthetic 13S,14S-epoxy-DHA incubated with human LTA4H; LTB4 production measured\",\n      \"journal\": \"FASEB Journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro enzyme assay with stereocontrolled synthetic substrate and NMR-confirmed stereochemistry, single lab\",\n      \"pmids\": [\"23504711\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"LTA4H aminopeptidase specificity profiling using chemical modulators (diphenyl ether, 4-phenoxyphenol derivatives) revealed a non-overlapping binding site distinct from the epoxide hydrolase active site; site-directed mutagenesis of F314E and V367W altered substrate specificity from arginyl to alanyl peptides, confirming these residues govern aminopeptidase substrate selectivity.\",\n      \"method\": \"Chemical modulator screening, molecular modeling, site-directed mutagenesis with enzyme kinetic assays\",\n      \"journal\": \"ChemBioChem\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro enzyme assay combined with mutagenesis confirming specific residue roles, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"20432426\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"LTA4H aminopeptidase has broad substrate specificity with highest activity toward arginine as the best proteinogenic amino acid; however, unnatural amino acids (e.g., benzyl ester of aspartic acid) exhibit >100-fold higher kcat/Km values, revealing extended active site accommodating non-canonical substrates.\",\n      \"method\": \"Library of 130 fluorogenic amino acid substrates screened against recombinant human LTA4H; kinetic constants (kcat/Km) determined\",\n      \"journal\": \"Amino Acids\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — rigorous in vitro kinetic assay with large substrate library, single lab\",\n      \"pmids\": [\"24573245\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Conventional LTA4H inhibitors (including clinical candidates) fail to discriminate between the dual enzymatic activities of LTA4H, inhibiting both LTB4 generation and PGP degradation and enabling PGP accumulation in mice. Novel selective compounds were developed that potently inhibit LTB4 generation while leaving PGP aminopeptidase activity unperturbed.\",\n      \"method\": \"In vitro dual-activity assays, mouse in vivo PGP accumulation measurements with pharmacological LTA4H inhibitors and novel selective compounds\",\n      \"journal\": \"Scientific Reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro enzyme assays and in vivo mouse models, multiple inhibitor classes tested, mechanistic distinction between two active sites established\",\n      \"pmids\": [\"28303931\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"LTA4H acts as a key regulator of cell cycle at the G0/G1 phase by negatively regulating p27 protein stability. LTA4H depletion enhanced p27 stability associated with decreased CDK2 phosphorylation at Thr160 and inhibition of the CDK2/cyclin E complex, resulting in reduced p27 ubiquitination and cell cycle arrest.\",\n      \"method\": \"LTA4H knockout mouse model (two-stage skin carcinogenesis), siRNA knockdown in cancer cell lines, cell cycle analysis, western blotting for CDK2 phosphorylation and CDK2/cyclin E complex, ubiquitination assay\",\n      \"journal\": \"Carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse model plus cell-based loss-of-function with multiple pathway readouts, single lab\",\n      \"pmids\": [\"28575166\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"LTA4H physically binds to FSCN1 (fascin actin-bundling protein 1) in laryngeal squamous cell carcinoma cells, as confirmed by co-immunoprecipitation and immunofluorescence colocalization; LTA4H knockdown inhibits LSCC cell proliferation, migration, and invasion.\",\n      \"method\": \"Co-immunoprecipitation with mass spectrometry, western blotting validation, immunofluorescence colocalization, siRNA knockdown with functional assays\",\n      \"journal\": \"Proteomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — reciprocal Co-IP and immunofluorescence confirm interaction, functional knockdown phenotype, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"31287215\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"P4N (a nordihydroguaiaretic acid derivative) promotes B-cell proliferation and autoantibody production through a LTA4H/activin A/BAFF signaling pathway in monocytes, linking LTA4H enzymatic activity to immunoregulatory cytokine signaling.\",\n      \"method\": \"In vitro monocyte/B-cell co-culture assays, in vivo mouse tumor models, pathway analysis with LTA4H inhibitors and activin A/BAFF measurements\",\n      \"journal\": \"PNAS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro and in vivo experiments linking LTA4H activity to downstream cytokine signaling, single lab\",\n      \"pmids\": [\"27856749\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Neutrophil elastase cleaves LTA4H upon neutrophil activation, altering its aminopeptidase activity in the cystic fibrosis lung, identifying neutrophil elastase as a post-translational regulator of LTA4H function.\",\n      \"method\": \"Biochemical cleavage assays, cystic fibrosis airway samples, neutrophil activation experiments\",\n      \"journal\": \"European Respiratory Journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct biochemical demonstration of proteolytic cleavage with functional consequence on enzymatic activity, single study\",\n      \"pmids\": [\"38387968\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Airway extracellular LTA4H originates primarily from liver hepatocytes (released constitutively and upregulated during acute phase response) and reaches the airway via increased pulmonary vascular permeability, demonstrating that extracellular LTA4H levels are governed by hepatic secretion and vascular leak rather than local production.\",\n      \"method\": \"Cell fractionation, hepatocyte culture experiments, mouse models of vascular permeability, airway lavage measurements, acute phase response induction\",\n      \"journal\": \"Cell Reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple in vitro and in vivo approaches identifying cellular source of extracellular LTA4H, single lab\",\n      \"pmids\": [\"39146180\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"LTA4H induces HNRNPA1 phosphorylation, enhancing LTA4H-HNRNPA1 interaction and functionally inhibiting HNRNPA1-mediated regulation of Ltbp1 mRNA maturation and processing in the nucleus; LTA4H deficiency leads to upregulated LTBP1 expression, increased TGF-β secretion, and CD206+ macrophage polarization promoting HCC progression.\",\n      \"method\": \"Co-immunoprecipitation, phosphorylation assays, mRNA processing/splicing assays, LTA4H knockout mouse model (Hepa1-6), immune cell phenotyping, rescue experiments\",\n      \"journal\": \"Cell Reports Medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal experiments (Co-IP, phosphorylation, mRNA processing, in vivo KO) in a single lab establishing a novel nuclear role for LTA4H\",\n      \"pmids\": [\"40056904\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"HDAC2 activity (activated by casein kinase 2) upregulates LTA4H activity in renal ischemia-reperfusion injury, driving LTB4 production; HDAC2 inhibition with BRD6688 suppresses LTA4H activity and reduces LTB4-mediated M1 macrophage polarization.\",\n      \"method\": \"HDAC2 inhibitor treatment, HDAC2 genetic ablation in HREpiC cells, LTA4H activity assays, LTB4 measurement, macrophage polarization assays, mouse I/R model\",\n      \"journal\": \"BBA Molecular Basis of Disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic ablation and pharmacological inhibition with direct LTA4H activity measurements and downstream macrophage phenotype, single lab\",\n      \"pmids\": [\"40324735\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"USP1 (ubiquitin-specific protease 1) stabilizes LTA4H by removing K48-linked polyubiquitin chains and preventing its proteasomal degradation; USP1-stabilized LTA4H promotes HCC angiogenesis through reactivation of ERK signaling in endothelial cells.\",\n      \"method\": \"Mass spectrometry identification of LTA4H as USP1 substrate, Co-IP validation, ubiquitination assays (K48-linkage specific), functional rescue experiments, in vivo xenograft models, conditioned medium endothelial assays\",\n      \"journal\": \"BBA Molecular Basis of Disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mass spectrometry plus Co-IP validation, ubiquitin chain-type specificity demonstrated, functional rescue in vitro and in vivo, single lab\",\n      \"pmids\": [\"42044771\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"LTA4H functions as an RNA-binding protein, extensively binding mRNAs/pre-mRNAs and lncRNAs in cells; the AAGG motif is enriched in LTA4H binding peaks; LTA4H-bound genes are enriched in mitotic cell cycle, DNA repair, RNA splicing, and RNA metabolism pathways. LTA4H specifically binds mRNAs of carcinogenesis-associated genes including LTBP3, ROR2, EGFR, HSP90B1, and lncRNA NEAT1.\",\n      \"method\": \"Improved RNA immunoprecipitation and sequencing (iRIP-Seq) in HeLa cells, qRT-PCR validation\",\n      \"journal\": \"PeerJ\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single iRIP-Seq experiment with qRT-PCR validation, no functional consequence of RNA binding demonstrated, single lab\",\n      \"pmids\": [\"36923505\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"LTA4H is a bifunctional zinc metalloenzyme that operates both intracellularly (primarily in myeloid cells and hepatocytes) and extracellularly: its epoxide hydrolase activity converts LTA4 to the pro-inflammatory mediator LTB4, while its aminopeptidase activity degrades the neutrophil chemoattractant PGP to resolve inflammation—two activities sharing overlapping but distinct active sites, with specific residues (E271, R563, K565, F314, V367) governing each function; LTA4H is post-translationally regulated by neutrophil elastase cleavage and by USP1-mediated deubiquitination (removing K48-linked chains to prevent proteasomal degradation), and by HDAC2/CK2-dependent activity upregulation; beyond lipid metabolism, LTA4H regulates cell cycle progression by destabilizing p27 via CDK2/cyclin E, interacts with FSCN1 and HNRNPA1 to modulate mRNA processing and TGF-β signaling, and functions as an RNA-binding protein associating with mRNAs involved in cell cycle and RNA metabolism.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"LTA4H is a bifunctional zinc metalloenzyme with two opposing roles in inflammation: its epoxide hydrolase activity generates the pro-inflammatory mediator LTB4, while its aminopeptidase activity degrades the neutrophil chemoattractant proline-glycine-proline (PGP) to promote resolution of acute neutrophilic inflammation [#0]. The two catalytic functions occupy non-overlapping sites within the protein, with residues F314 and V367 governing aminopeptidase substrate selectivity [#2], and the aminopeptidase accommodating a broad range of substrates with highest activity toward arginine [#3]. This functional separability is therapeutically exploitable: selective inhibitors can block LTB4 generation while sparing PGP-degrading activity, whereas conventional inhibitors inhibit both and cause PGP accumulation [#4]; the epoxide hydrolase can also be inhibited by the lipid epoxide 13S,14S-epoxy-DHA without being converted to a product [#1]. LTA4H function is set by post-translational regulation—neutrophil elastase cleaves LTA4H upon neutrophil activation to alter aminopeptidase activity in the cystic fibrosis lung [#8], HDAC2 (activated by casein kinase 2) upregulates LTA4H activity to drive LTB4 production and M1 macrophage polarization in renal ischemia-reperfusion injury [#11], and USP1 removes K48-linked polyubiquitin to prevent proteasomal degradation and stabilize the enzyme [#12]; extracellular airway LTA4H derives largely from hepatocyte secretion reaching the lung via vascular leak rather than local production [#9]. Beyond lipid metabolism, LTA4H regulates the G0/G1 cell cycle transition by destabilizing p27 through CDK2/cyclin E activity [#5], physically binds FSCN1 to support tumor cell proliferation and invasion [#6], and interacts with phosphorylated HNRNPA1 to modulate Ltbp1 mRNA processing, TGF-\\u03b2 secretion, and macrophage polarization in hepatocellular carcinoma [#10].\",\n  \"teleology\": [\n    {\n      \"year\": 2010,\n      \"claim\": \"Established that LTA4H is not solely pro-inflammatory but harbors an aminopeptidase activity that resolves inflammation by degrading the chemoattractant PGP, reframing the enzyme as a bidirectional regulator.\",\n      \"evidence\": \"In vitro aminopeptidase assays, mouse acute inflammation and cigarette-smoke exposure models\",\n      \"pmids\": [\"20813919\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not map the structural basis distinguishing aminopeptidase from epoxide hydrolase sites\", \"Relative physiological balance of the two activities in vivo not quantified\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Defined that the aminopeptidase active site is structurally distinct from the epoxide hydrolase site and identified residues controlling substrate selectivity, providing the molecular handle for selective targeting.\",\n      \"evidence\": \"Chemical modulator screening, molecular modeling, and site-directed mutagenesis (F314E, V367W) with kinetic assays\",\n      \"pmids\": [\"20432426\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mutagenesis effects on physiological substrate PGP not directly tested\", \"No co-crystal structures of selective modulators\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Showed the epoxide hydrolase can be inhibited by a lipid epoxide intermediate that is not itself turned over, expanding the modes of catalytic inhibition.\",\n      \"evidence\": \"In vitro enzyme assay with synthetic stereodefined 13S,14S-epoxy-DHA measuring LTB4 production\",\n      \"pmids\": [\"23504711\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cellular or in vivo relevance of this inhibition not established\", \"Single-lab in vitro result\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Characterized the aminopeptidase substrate range, revealing an extended active site that prefers arginine among proteinogenic residues but accommodates non-canonical substrates far more efficiently.\",\n      \"evidence\": \"Kinetic screening of a 130-member fluorogenic amino acid substrate library against recombinant human LTA4H\",\n      \"pmids\": [\"24573245\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological substrate beyond PGP not identified\", \"Single lab in vitro kinetics\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Linked LTA4H enzymatic activity to immunoregulatory cytokine output, connecting the lipid mediator pathway to B-cell responses.\",\n      \"evidence\": \"Monocyte/B-cell co-culture and mouse tumor models with LTA4H inhibitors and activin A/BAFF measurements\",\n      \"pmids\": [\"27856749\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct LTA4H product responsible for activin A/BAFF induction not pinned down\", \"Pharmacological pathway dissection in a single system\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Revealed a non-enzymatic-context role in cell cycle control, showing LTA4H destabilizes the CDK inhibitor p27 via the CDK2/cyclin E axis to permit G0/G1 progression.\",\n      \"evidence\": \"LTA4H knockout mouse carcinogenesis model and siRNA knockdown with cell cycle, CDK2 phosphorylation, and ubiquitination readouts\",\n      \"pmids\": [\"28575166\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether catalytic activity is required for p27 regulation unclear\", \"Direct molecular link between LTA4H and the CDK2/cyclin E complex not defined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Demonstrated that the dual activities can be pharmacologically uncoupled, providing proof-of-concept for selective LTB4-blocking inhibitors that spare PGP resolution.\",\n      \"evidence\": \"In vitro dual-activity assays and in vivo mouse PGP accumulation measurements across multiple inhibitor classes\",\n      \"pmids\": [\"28303931\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Long-term in vivo efficacy of selective compounds not assessed\", \"Structural basis of selectivity not resolved here\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified a direct protein partner, FSCN1, implicating LTA4H in cytoskeletal/actin-bundling-associated tumor cell motility.\",\n      \"evidence\": \"Reciprocal Co-IP with mass spectrometry, immunofluorescence colocalization, and siRNA knockdown functional assays in laryngeal carcinoma cells\",\n      \"pmids\": [\"31287215\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of the LTA4H-FSCN1 interaction at the molecular level unclear\", \"Single cancer cell context\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Proposed an RNA-binding function for LTA4H, with sequence-specific motif preference and association with cell cycle and RNA metabolism transcripts.\",\n      \"evidence\": \"iRIP-Seq in HeLa cells with qRT-PCR validation\",\n      \"pmids\": [\"36923505\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No functional consequence of RNA binding demonstrated\", \"Single iRIP-Seq experiment, not independently confirmed\", \"Direct versus indirect RNA association not distinguished\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified neutrophil elastase as a proteolytic regulator that modifies LTA4H aminopeptidase function during neutrophil activation in disease tissue.\",\n      \"evidence\": \"Biochemical cleavage assays, neutrophil activation experiments, and cystic fibrosis airway samples\",\n      \"pmids\": [\"38387968\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cleavage site and structural consequence not fully mapped\", \"Effect on epoxide hydrolase activity not quantified\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established the cellular source of extracellular LTA4H, showing it is hepatocyte-derived and reaches the airway through vascular leak rather than local synthesis.\",\n      \"evidence\": \"Cell fractionation, hepatocyte culture, vascular permeability and acute-phase mouse models, airway lavage measurements\",\n      \"pmids\": [\"39146180\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of constitutive hepatic secretion not defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Uncovered a nuclear role in which LTA4H phosphorylates and binds HNRNPA1 to control Ltbp1 mRNA maturation, linking it to TGF-\\u03b2 signaling and tumor-associated macrophage polarization.\",\n      \"evidence\": \"Co-IP, phosphorylation and mRNA processing assays, LTA4H knockout mouse HCC model, immune phenotyping, and rescue experiments\",\n      \"pmids\": [\"40056904\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How a metalloenzyme drives HNRNPA1 phosphorylation mechanistically unresolved\", \"Generality beyond HCC unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showed HDAC2, activated by casein kinase 2, upregulates LTA4H activity to drive LTB4-mediated M1 macrophage polarization in ischemia-reperfusion injury.\",\n      \"evidence\": \"HDAC2 inhibition (BRD6688) and genetic ablation, LTA4H activity and LTB4 assays, macrophage polarization, and a mouse I/R model\",\n      \"pmids\": [\"40324735\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular mechanism by which HDAC2 modifies LTA4H activity not defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Identified USP1-mediated deubiquitination as a stabilizing post-translational control that protects LTA4H from K48-linked proteasomal degradation, with downstream tumor angiogenesis consequences.\",\n      \"evidence\": \"Mass spectrometry substrate identification, Co-IP, K48-linkage-specific ubiquitination assays, rescue experiments, and xenograft/endothelial assays\",\n      \"pmids\": [\"42044771\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"E3 ligase opposing USP1 on LTA4H not identified\", \"Single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How LTA4H's catalytic, protein-binding, nuclear RNA/HNRNPA1, and cell-cycle functions are integrated within a single protein—and whether the moonlighting roles require enzymatic activity—remains unresolved.\",\n      \"evidence\": \"No single study reconciles the enzymatic and non-enzymatic activities mechanistically\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Structural basis coupling enzymatic and moonlighting roles unknown\", \"Whether nuclear and RNA-binding functions depend on catalytic residues untested\", \"In vivo dominance of each function across tissues unclear\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [0, 1, 2, 3, 4]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 2, 3]},\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [1, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [5, 6]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [10]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [8, 9]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 1, 4]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 7, 11]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"FSCN1\", \"HNRNPA1\", \"USP1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":5,"faith_pct":80.0}}