LTA4H

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).

1. 2010 High

   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

   PMID:20813919

   Open questions at the time

   • Did not map the structural basis distinguishing aminopeptidase from epoxide hydrolase sites
   • Relative physiological balance of the two activities in vivo not quantified
2. 2010 High

   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

   PMID:20432426

   Open questions at the time

   • Mutagenesis effects on physiological substrate PGP not directly tested
   • No co-crystal structures of selective modulators
3. 2013 Medium

   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

   PMID:23504711

   Open questions at the time

   • Cellular or in vivo relevance of this inhibition not established
   • Single-lab in vitro result
4. 2014 Medium

   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

   PMID:24573245

   Open questions at the time

   • Physiological substrate beyond PGP not identified
   • Single lab in vitro kinetics
5. 2016 Medium

   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

   PMID:27856749

   Open questions at the time

   • Direct LTA4H product responsible for activin A/BAFF induction not pinned down
   • Pharmacological pathway dissection in a single system
6. 2017 Medium

   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

   PMID:28575166

   Open questions at the time

   • Whether catalytic activity is required for p27 regulation unclear
   • Direct molecular link between LTA4H and the CDK2/cyclin E complex not defined
7. 2017 High

   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

   PMID:28303931

   Open questions at the time

   • Long-term in vivo efficacy of selective compounds not assessed
   • Structural basis of selectivity not resolved here
8. 2019 Medium

   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

   PMID:31287215

   Open questions at the time

   • Functional consequence of the LTA4H-FSCN1 interaction at the molecular level unclear
   • Single cancer cell context
9. 2023 Low

   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

   PMID:36923505

   Open questions at the time

   • No functional consequence of RNA binding demonstrated
   • Single iRIP-Seq experiment, not independently confirmed
   • Direct versus indirect RNA association not distinguished
10. 2024 Medium

    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

    PMID:38387968

    Open questions at the time

    • Cleavage site and structural consequence not fully mapped
    • Effect on epoxide hydrolase activity not quantified
11. 2024 Medium

    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

    PMID:39146180

    Open questions at the time

    • Mechanism of constitutive hepatic secretion not defined
    • Single lab
12. 2025 Medium

    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

    PMID:40056904

    Open questions at the time

    • How a metalloenzyme drives HNRNPA1 phosphorylation mechanistically unresolved
    • Generality beyond HCC unknown
13. 2025 Medium

    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

    PMID:40324735

    Open questions at the time

    • Direct molecular mechanism by which HDAC2 modifies LTA4H activity not defined
    • Single lab
14. 2026 Medium

    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

    PMID:42044771

    Open questions at the time

    • E3 ligase opposing USP1 on LTA4H not identified
    • Single lab

• 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.
• 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