Affinage

ALOX15B

Polyunsaturated fatty acid lipoxygenase ALOX15B · UniProt O15296

Length
676 aa
Mass
75.9 kDa
Annotated
2026-06-09
23 papers in source corpus 15 papers cited in narrative 16 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ALOX15B (15-LOX-2) is a non-heme iron lipoxygenase whose lipid-peroxidation products couple membrane fatty-acid oxygenation to cell-fate and inflammatory signaling (PMID:10393855, PMID:38581859). The human enzyme oxygenates arachidonic acid essentially exclusively to its 15S-hydroperoxy/hydroxy derivative (15S-HpETE/15S-HETE), a specificity that diverges from the murine ortholog (dominant 8S product) and is dictated by two active-site residues, Asp602/Val603, whose exchange to the murine Tyr/His pair switches the product pattern (PMID:10393855, PMID:27435673, PMID:37373195). Beyond free fatty acid, ALOX15B oxygenates phospholipid-esterified arachidonate within a bilayer and, upon calcium-ionophore stimulation, translocates to the plasma membrane via a membrane insertion loop (PMID:27435673). Functionally, its peroxidation products act through MAPK signaling: 15-HETE drives ERK1/2 and p38MAPK activation to promote pulmonary artery smooth muscle proliferation and vascular remodeling (PMID:22018966, PMID:25895668), and in primary macrophages ALOX15B-driven peroxidation sustains ERK1/2-dependent nuclear SREBP2 and cholesterol biosynthesis (PMID:38581859). ALOX15B also executes lipid peroxidation required for ferroptosis downstream of the p53/SLC7A11 axis (PMID:36801644), and its membrane localization, stability, and ferroptotic activity are governed by S-palmitoylation, with KRASmut/ERK1-driven ABHD17C-mediated depalmitoylation routing it for CUL4/DDB1/DCAF10-dependent proteasomal degradation (PMID:40569151). Its transcription is directly activated by IRF1 and CEBPA and repressed by HDAC1/2 promoter enrichment (PMID:40749811, PMID:41843143, PMID:41527135).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 1999 High

    Established that ALOX15B is a catalytically active lipoxygenase, defining its substrate and major product and its restriction to prostate secretory epithelium.

    Evidence HPLC analysis of [14C]arachidonic acid incubations in prostate tissue with immunohistochemical localization

    PMID:10393855

    Open questions at the time
    • Did not resolve active-site determinants of product specificity
    • No link to downstream signaling or cellular phenotype
  2. 2016 High

    Resolved the structural basis of reaction specificity, showing two active-site residues dictate whether human (15S) versus mouse (8S) product forms.

    Evidence Mutagenesis of recombinant human and mouse enzymes with HPLC/MS product analysis

    PMID:27435673 PMID:37373195

    Open questions at the time
    • Physiological consequence of species product divergence not addressed
    • Does not explain regulation of activity in cells
  3. 2016 High

    Demonstrated that ALOX15B accesses phospholipid-esterified substrate in a bilayer and undergoes calcium-triggered membrane translocation via a membrane insertion loop.

    Evidence Nanodisc reconstitution and Ca2+-ionophore-stimulated localization with insertion-loop mutants in HEK293 cells

    PMID:27435673

    Open questions at the time
    • Mechanism coupling Ca2+ to translocation not defined
    • In vivo relevance of phospholipid oxygenation untested at this stage
  4. 2023 Medium

    Reinforced the inverse-substrate-binding model for distinct reaction specificities across multiple polyunsaturated fatty acid substrates.

    Evidence Recombinant ortholog and double-mutant enzymatic assays with in silico docking and molecular dynamics

    PMID:37373195

    Open questions at the time
    • Computational model not validated by crystal structure
    • Single-lab finding
  5. 2015 Medium

    Placed ALOX15B/15-HETE upstream of ERK and p38MAPK in hypoxia-driven smooth muscle proliferation, linking enzyme product to a proliferative signaling output.

    Evidence Phospho-Western, BrdU, cell cycle/apoptosis assays with LOX and MAPK inhibitor epistasis in PASMCs

    PMID:22018966 PMID:25895668

    Open questions at the time
    • Direct molecular target of 15-HETE upstream of MAPK not identified
    • Reliance on pharmacological inhibition
  6. 2023 Medium

    Positioned ALOX15B as the effector lipoxygenase executing p53-induced ferroptosis downstream of SLC7A11 suppression.

    Evidence shRNA knockdown/overexpression with Nutlin-3a and ferrostatin-1 epistasis in bladder cancer in vitro and in vivo

    PMID:36801644

    Open questions at the time
    • Specific peroxidized phospholipid species driving ferroptosis not identified
    • Single-lab finding
  7. 2024 High

    Connected ALOX15B peroxidation to metabolic regulation, showing it sustains ERK1/2-dependent SREBP2 activity and cholesterol biosynthesis in macrophages.

    Evidence Reciprocal siRNA silencing, transcriptome, nuclear SREBP2 immunofluorescence, sterol metabolite measurement, ERK1/2 inhibitor epistasis in primary human macrophages

    PMID:38581859

    Open questions at the time
    • How peroxidation products mechanistically activate ERK1/2 unresolved
    • Identity of the relevant lipid signaling intermediate unknown
  8. 2025 Medium

    Identified palmitoylation-dependent post-translational control of ALOX15B membrane localization, stability, and ferroptotic activity.

    Evidence Co-IP of ABHD17C/ALOX15B and CUL4/DDB1/DCAF10 complex, fractionation, proteasome inhibition, and rescue in organoids and in vivo pancreatic cancer models

    PMID:40569151

    Open questions at the time
    • Palmitoylation site(s) on ALOX15B not mapped
    • Co-IP-based complex assignment without reciprocal structural validation
  9. 2025 Medium

    Extended ALOX15B function to keratinocyte inflammation and membrane lipid organization via EGFR/JAK1/STAT1 and ERK/NRF2 signaling.

    Evidence siRNA silencing, cytokine ELISA, JAK1/STAT1 and EGFR inhibitor epistasis, cholesterol/lipid raft imaging, and ML351 in skin equivalents

    PMID:39843435

    Open questions at the time
    • Mechanism linking ALOX15B to EGFR expression unclear
    • Single-lab finding
  10. 2025 Medium

    Showed ALOX15B drives hypoxia-induced autophagy in pulmonary endothelium through PI3K/AKT/mTOR signaling.

    Evidence siRNA knockdown with PI3K inhibitor epistasis in mouse PAECs and in vivo PAH models with knockout validation

    PMID:41207352

    Open questions at the time
    • How ALOX15B products engage PI3K/AKT/mTOR not defined
    • Single-lab finding
  11. 2026 Medium

    Defined transcriptional control of ALOX15B by direct activators IRF1 and CEBPA and repression via HDAC1/2 promoter enrichment, linking expression to ferroptosis and antigen presentation programs.

    Evidence Luciferase, EMSA, ChIP-qPCR/ChIP-seq, ATAC-seq, siRNA/overexpression, and in vivo knockout/PDX models across TNBC, osteoblast, and DLBCL systems

    PMID:40749811 PMID:41527135 PMID:41843143

    Open questions at the time
    • Whether these regulators act in the same or distinct cellular contexts unresolved
    • Each axis established in single labs and cell types

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how ALOX15B-generated lipid peroxidation products are sensed to selectively engage ERK/MAPK, PI3K/AKT/mTOR, and ferroptotic outputs, and which specific oxidized phospholipid species mediate each response.
  • No identified protein sensor of ALOX15B products
  • Specific causal peroxidized lipid species per pathway not defined
  • No high-resolution structure of the human enzyme

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016491 oxidoreductase activity 4 GO:0008289 lipid binding 1
Localization
GO:0005886 plasma membrane 2 GO:0005829 cytosol 1
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-5357801 Programmed Cell Death 3 R-HSA-1430728 Metabolism 1
Partners
ABHD17CCUL4DCAF10DDB1

Evidence

Reading pass · 16 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 15-LOX-2 (ALOX15B) catalyzes the conversion of arachidonic acid to 15S-HETE as the major product in benign prostate tissue, demonstrating lipoxygenase enzymatic activity with defined substrate (arachidonic acid) and product (15S-HETE); the enzyme is localized to secretory epithelial cells of peripheral zone glands and large prostatic ducts by immunohistochemistry. Reverse- and straight-phase HPLC with [14C]arachidonic acid incubation in prostate tissue; immunohistochemistry The American journal of pathology High 10393855
2016 Human 15-LOX-2 and its murine counterpart (78% sequence identity) both transform phospholipid-esterified arachidonic acid to a 15-S-product when using nanodiscs as membrane mimics, demonstrating access to substrate esterified in a bilayer. In HEK293 cells stimulated with Ca2+ ionophore, 15-LOX-2 translocates to the plasma membrane, and this localization is dependent on a putative membrane insertion loop whose sequence differences between human and mouse enzymes confer distinct mechanisms of enzyme-membrane interaction. Nanodisc reconstitution assay; transfection of HEK293 cells with Ca2+ ionophore stimulation; subcellular localization by imaging; mutant enzyme analysis The Journal of biological chemistry High 27435673
2016 Human ALOX15B oxygenates arachidonic acid exclusively to its 15-S-hydroperoxy derivative (15S-HpETE), whereas mouse Alox15b produces dominantly 8-S-HpETE; two residues (Tyr603/His604 in mouse; Asp602/Val603 in human) at the active site determine this reaction specificity, and Tyr603Asp+His604Val double mutation in mouse enzyme humanizes the product pattern. In vitro mutagenesis of recombinant enzymes; product analysis by HPLC/MS The Journal of biological chemistry High 27435673 37373195
2023 Functional characterization of wildtype human and mouse ALOX15B orthologs and their double mutants showed that Asp602Tyr+Val603His exchange murinized the product pattern of human ALOX15B with arachidonic acid and EPA, and in silico substrate docking and molecular dynamics simulations support inverse substrate binding at the active site as the mechanistic basis for distinct reaction specificities. Recombinant protein expression; enzymatic product analysis with multiple polyenoic fatty acid substrates; in silico substrate docking and molecular dynamics simulation International journal of molecular sciences Medium 37373195
2011 15-LOX-2-derived 15(S)-HETE stimulates rabbit pulmonary artery smooth muscle cell (PASMC) proliferation and induces ERK1/ERK2 phosphorylation; MEK inhibitor PD-98059 blocked 15(S)-HETE-stimulated proliferation, placing 15-LOX-2/15-HETE upstream of the ERK1/2 pathway in hypoxia-induced PASMC proliferation. Cell proliferation assay (BrdU); Western blot for ERK phosphorylation; pharmacological inhibition (MEK inhibitors, LOX inhibitors) in cultured rabbit PASMCs Prostaglandins, leukotrienes, and essential fatty acids Medium 22018966
2015 In hypoxia-treated pulmonary artery smooth muscle cells, 15-LOX-2/15-HETE activates ERK and p38MAPK phosphorylation, stimulates PASMC proliferation, cell cycle progression, migration, and suppresses apoptosis; this effect is 15-LOX-2/15-HETE activation-dependent, placing the 15-LOX-2/15-HETE axis upstream of MAPKs in pulmonary vascular remodeling. Western blot for p-ERK and p-p38MAPK; TUNEL and flow cytometry apoptosis assay; BrdU incorporation and cell cycle analysis; pharmacological inhibition Cellular physiology and biochemistry Medium 25895668
2023 p53 activates ALOX15B lipoxygenase activity by suppressing SLC7A11, and ALOX15B-mediated lipid peroxidation is required for p53-induced ferroptosis in bladder cancer cells; knockdown of ALOX15B protected bladder cancer cells from p53-induced ferroptosis, establishing ALOX15B downstream of the p53/SLC7A11 axis. shRNA knockdown and overexpression of ALOX15B; p53 agonist (Nutlin-3a) treatment; ferroptosis inhibitor (ferrostatin-1) rescue; in vitro and in vivo tumor models Laboratory investigation Medium 36801644
2024 In primary human macrophages, ALOX15B-mediated lipid peroxidation activates ERK1/2, which in turn sustains nuclear SREBP2 abundance and activity to drive cholesterol biosynthesis gene expression and production of sterol intermediates (desmosterol, lathosterol, 25- and 27-hydroxycholesterol); ALOX15B silencing reduces lipid peroxidation, attenuates ERK1/2 activation, and lowers SREBP2, rendering macrophages refractory to SREBP2 activation upon NPC1 inhibition. siRNA silencing of ALOX15B in primary human macrophages; global transcriptome analysis; immunofluorescence of nuclear SREBP2; sterol biosynthesis intermediate measurement; ERK1/2 inhibitor epistasis Redox biology High 38581859
2025 In pancreatic cancer cells, KRASmut/ERK1-driven phosphorylation of ABHD17C promotes depalmitoylation and membrane-to-cytoplasm translocation of ALOX15B, facilitating proteasome-dependent degradation of ALOX15B via interaction with the E3 ligase complex CUL4/DDB1/DCAF10; S-palmitoylation of ALOX15B maintains its membrane localization and enzymatic activity required for ferroptosis induction. Co-IP/pulldown for ABHD17C/ALOX15B interaction and CUL4/DDB1/DCAF10 complex; subcellular fractionation; proteasome inhibition; methyl protodioscin treatment disrupting ABHD17C/ALOX15B interaction; patient-derived organoids and in vivo tumor models Advanced science Medium 40569151
2025 In human keratinocytes, ALOX15B silencing reduces EGFR expression and activates JAK1/STAT1 signaling, leading to increased CCL2, CCL5, and CXCL10 secretion; reduced ERK phosphorylation upon ALOX15B silencing was dependent on EGFR and NRF2 activation, and ALOX15B silencing also reduced plasma membrane cholesterol and lipid rafts. siRNA-mediated silencing of ALOX15B; cytokine measurement (ELISA); JAK1/STAT1 inhibitor epistasis; EGFR inhibition; confocal microscopy of cholesterol and lipid rafts; skin equivalents with lipoxygenase inhibitor ML351 Cell death & disease Medium 39843435
2022 In porcine Sertoli cells under heat stress, ALOX15B expression is increased, leading to elevated 8-HETE and 15-HETE production and activation of the p38-p53 pathway causing apoptosis; inhibition or knockdown of ALOX15B reduced 8-HETE/15-HETE and decreased apoptosis; a p38 inhibitor decreased ALOX15B expression, establishing a feedback loop between ALOX15B/lipid peroxides and the p38-p53 pathway. Metabolomics (LC-MS); siRNA knockdown; pharmacological inhibition with baicalein (ALOX15B inhibitor), p38 inhibitor, p53 inhibitor; apoptosis assay Theriogenology Medium 35344833
2025 IRF1 directly transcriptionally activates ALOX15B by binding to its promoter, as demonstrated by dual-luciferase reporter assay, EMSA, and ChIP-qPCR; IRF1 overexpression increases ALOX15B expression and promotes ferroptosis in TNBC cells, while IRF1 knockdown has the opposite effect. Dual-luciferase reporter assay; EMSA; ChIP-qPCR; siRNA and overexpression in TNBC cell lines Biochimica et biophysica acta. General subjects Medium 40749811
2026 CEBPA directly binds the ALOX15B promoter to transcriptionally activate ALOX15B expression; the CEBPA/ALOX15B axis regulates osteoblast ferroptosis and osteogenesis via the AMPK/mTOR signaling pathway in postmenopausal osteoporosis. siRNA knockdown and overexpression; luciferase reporter (implied by promoter binding claim); Western blot for AMPK/mTOR pathway; ALOX15B knockout mice with OVX model; ferroptosis marker measurement Inflammation research Medium 41843143
2026 In DLBCL, ALOX15B deficiency leads to upregulation of COX-2/PGE2 signaling and downregulation of the TAP1/MHC-I antigen presentation axis; HDAC1/2 are enriched at the ALOX15B promoter and repress its expression, and HDAC inhibitor tucidinostat restores ALOX15B expression and reinstates antigen presentation. siRNA knockdown; ChIP-seq for HDAC1/2 at ALOX15B promoter; ATAC-seq; luciferase reporter; in vivo PDX and murine models; flow cytometry for antigen presentation Journal of experimental & clinical cancer research Medium 41527135
2025 In mouse PAECs under hypoxia, ALOX15B promotes autophagy through the PI3K/AKT/mTOR pathway; ALOX15B siRNA knockdown markedly reduced elevated autophagy, while subsequent PI3K inhibitor treatment restored it, placing ALOX15B upstream of PI3K-AKT-mTOR in autophagy regulation in pulmonary arterial hypertension. siRNA knockdown in mouse PAECs; PI3K inhibitor epistasis; Western blot; in vivo chronic hypoxia and Sugen5416/hypoxia PAH models with ALOX15/15B systemic knockout European journal of pharmacology Medium 41207352
2013 Three non-synonymous polymorphic variants of ALOX15B (p.Arg486His, p.Gln656Arg, p.Ile676Val) were expressed as recombinant proteins and measured for enzyme activity and Michaelis-Menten kinetics; none showed significantly altered activity or kinetics compared to wildtype, indicating these variants do not alter catalytic function. In vitro enzyme activity assay with Michaelis-Menten kinetics of recombinant variant proteins Clinical biochemistry Medium 24373925

Source papers

Stage 0 corpus · 23 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1999 15-lipoxygenase-2 (15-LOX-2) is expressed in benign prostatic epithelium and reduced in prostate adenocarcinoma. The American journal of pathology 134 10393855
2006 Reduction of isoforms of 15-lipoxygenase (15-LOX)-1 and 15-LOX-2 in human breast cancer. Prostaglandins, leukotrienes, and essential fatty acids 84 16556493
2023 p53 Activates the Lipoxygenase Activity of ALOX15B via Inhibiting SLC7A11 to Induce Ferroptosis in Bladder Cancer Cells. Laboratory investigation; a journal of technical methods and pathology 37 36801644
2016 Membrane-dependent Activities of Human 15-LOX-2 and Its Murine Counterpart: IMPLICATIONS FOR MURINE MODELS OF ATHEROSCLEROSIS. The Journal of biological chemistry 36 27435673
2008 Loss of heterozygosity of 17p13, with possible involvement of ACADVL and ALOX15B, in the pathogenesis of adrenocortical tumors. Annals of surgery 35 18156936
2015 Modulation of Pulmonary Vascular Remodeling in Hypoxia: Role of 15-LOX-2/15-HETE-MAPKs Pathway. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 33 25895668
2024 ALOX15B controls macrophage cholesterol homeostasis via lipid peroxidation, ERK1/2 and SREBP2. Redox biology 25 38581859
2020 Brozopine Inhibits 15-LOX-2 Metabolism Pathway After Transient Focal Cerebral Ischemia in Rats and OGD/R-Induced Hypoxia Injury in PC12 Cells. Frontiers in pharmacology 17 32153408
2022 The role of ALOX15B in heat stress-induced apoptosis of porcine sertoli cells. Theriogenology 14 35344833
2022 Male Knock-in Mice Expressing an Arachidonic Acid Lipoxygenase 15B (Alox15B) with Humanized Reaction Specificity Are Prematurely Growth Arrested When Aging. Biomedicines 14 35740398
2013 Association of polymorphisms in the ALOX15B gene with coronary artery disease. Clinical biochemistry 12 24373925
2011 Hypoxia promotes rabbit pulmonary artery smooth muscle cells proliferation through a 15-LOX-2 product 15(S)-hydroxyeicosatetraenoic acid. Prostaglandins, leukotrienes, and essential fatty acids 12 22018966
2025 RNAi-based ALOX15B silencing augments keratinocyte inflammation in vitro via EGFR/STAT1/JAK1 signalling. Cell death & disease 7 39843435
2025 KRAS/ABHD17C/ALOX15B Axis Promotes Pancreatic Cancer Progression via Ferroptosis Evasion. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 7 40569151
2023 Humanization of the Reaction Specificity of Mouse Alox15b Inversely Modified the Susceptibility of Corresponding Knock-In Mice in Two Different Animal Inflammation Models. International journal of molecular sciences 7 37446212
2023 Functional Characterization of Mouse and Human Arachidonic Acid Lipoxygenase 15B (ALOX15B) Orthologs and of Their Mutants Exhibiting Humanized and Murinized Reaction Specificities. International journal of molecular sciences 4 37373195
2012 Qualitative and Quantitative analysis of 3D predicted arachidonate 15-lipoxygenase-B (15-LOX-2) from Homo sapiens. Bioinformation 4 22829730
2025 ALOX15 and ALOX15B regulate autophagy to promote pulmonary arterial hypertension via the PI3K/AKT/mTOR pathway. European journal of pharmacology 2 41207352
2026 Targeting CEBPA/ALOX15B attenuates postmenopausal osteoporosis by inhibiting ferroptosis through the AMPK/mTOR signaling pathway. Inflammation research : official journal of the European Histamine Research Society ... [et al.] 1 41843143
2025 The reaction specificity of mammalian ALOX15B orthologs does not depend on the evolutionary ranking of the animals. Journal of lipid research 1 40044044
2026 Low expression of ALOX15B modulates immunosuppressive tumor microenvironment in diffuse large B-cell lymphoma via the TAP1/MHC-I axis. Journal of experimental & clinical cancer research : CR 0 41527135
2026 Gut-Derived Lipid Mediators Orchestrate Ovarian Metabolic Homeostasis and Clutch Persistence in Aging Laying Hens via the PLA2G6-ALOX15B-AGPAT3 Axis. Biomolecules 0 42194056
2025 IRF1 transcriptionally activates ALOX15B to enhance ferroptosis sensitivity in triple-negative breast cancer. Biochimica et biophysica acta. General subjects 0 40749811

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