ALOX15 Protein
Overview <table class="infobox infobox-protein">Inflammation Resolution </td>Cell Signaling </td>Membrane Remodeling </td>Immune Regulation </td>Baicalein </td>PD146176 </td>Revalip </td>CDC </td>
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ALOX15 Protein
Overview <table class="infobox infobox-protein">Inflammation Resolution </td>Cell Signaling </td>Membrane Remodeling </td>Immune Regulation </td>Baicalein </td>PD146176 </td>Revalip </td>CDC </td>
ALOX15 (Arachidonate 15-Lipoxygenase) is an enzyme that catalyzes the oxidation of polyunsaturated fatty acids, particularly arachidonic acid and linoleic acid, to produce bioactive lipid mediators. It plays important roles in inflammation, immune regulation, and has been increasingly implicated in neurodegenerative processes including Alzheimer's Disease and Parkinson's Disease[@pmid30472260].
Structure bfe67bb53c3c532ef4237fa3323691ae27404769
Domain Architecture
N-terminal PLAT domain (Polycystin-1, Lipoxygenase, Alpha-toxin): ~100 aa, membrane associationCatalytic lipoxygenase domain : ~450 aa, contains the iron-containing active siteC-terminal regulatory region : Contains residues that modulate enzyme activity
Structural Features
Iron-binding motif: His-X4-His-X17-His-X4-His
Substrate binding pocket: Hydrophobic channel for fatty acid entry
Phospholipid binding interface in PLAT domain
Normal Function ALOX15 produces various bioactive lipid mediators through peroxidation of polyunsaturated fatty acids: [@lipoxygenases2018]
Primary Products
15(S)-HETE (15(S)-Hydroxyeicosatetraenoic acid): Major product from arachidonic acid13(S)-HODE (13(S)-Hydroxyoctadecadienoic acid): Major product from linoleic acidLipoxins : Anti-inflammatory mediators (via transcellular biosynthesis) resolvins : Specialized pro-resolving mediators
Biological Activities
Role in Neurodegeneration
Alzheimer's Disease ALOX15 is significantly elevated in AD brain tissue, particularly in regions surrounding amyloid plaques: [@lox2009]
Plaque Association : 15-LOX colocalizes with amyloid plaques in AD [hippocampus](/brain-regions/hippocampus) and [cortex](/brain-regions/cortex)Neuroinflammation : Promotes production of pro-inflammatory cytokines (IL-1β, TNF-α)[APP](/entities/app-protein) Processing : Enhances amyloidogenic APP processing via [BACE1](/entities/bace1) upregulation [@lox2010][Tau](/proteins/tau) Pathology : Associated with tau phosphorylation and aggregationLipid Peroxidation : Increases 4-HNE production, contributing to oxidative damageParkinson's Disease Elevated 15-LOX activity observed in PD substantia nigra and striatum: [@lox2015]
Dopaminergic Toxicity : 15-HETE promotes dopaminergic neuron death[α-Synuclein](/proteins/alpha-synuclein) Aggregation : Lipid peroxidation products accelerate α-synuclein oligomerizationMitochondrial Dysfunction : Impairs complex I activityNeuroinflammation : Activates [microglia](/cell-types/microglia-neuroinflammation) in substantia nigraAmyotrophic Lateral Sclerosis
Elevated ALOX15 in motor cortex and spinal cord of ALS patients
Contributes to motor neuron death through lipid peroxidation
Implicated in SOD1 aggregation pathology
Ferroptosis Regulation ALOX15 is a key regulator of ferroptosis, an iron-dependent form of cell death: [@lox2019]
Generates lipid peroxides that execute ferroptosis
15-LOX inhibitors (e.g., baicalein, PD146176) block ferroptosis
Potential therapeutic target for neurodegenerative diseases
Therapeutic Targeting
Small Molecule Inhibitors
Therapeutic Strategies
Neuroprotection : 15-LOX inhibitors protect [neurons](/entities/neurons) from oxidative damageAnti-inflammatory : Reduce neuroinflammation in AD/PD modelsAnti-aggregation : Prevent protein aggregation via lipid peroxidation reductionFerroptosis Blockade : Inhibit ferroptotic cell death
Clinical Considerations
[Blood-brain barrier](/entities/blood-brain-barrier) penetration is a challenge for 15-LOX inhibitors
Enzyme redundancy (multiple lipoxygenases) may limit efficacy
Timing of intervention likely critical (early vs. late disease)
Genetics & Variants
ALOX15 gene located on chromosome 17p13.2Single nucleotide polymorphisms (SNPs) associated with:
Cardiovascular disease risk
Asthma susceptibility
Potential links to neurodegeneration (under investigation)
No strong causal variants identified for AD/PD to date
Biomarker Potential
15-HETE levels in CSF: Potential biomarker for neuroinflammation13-HODE : Elevated in AD plasmaMay serve as pharmacodynamic marker for 15-LOX inhibitor trials
See Also
[Alzheimer's Disease](/diseases/alzheimers-disease)
[Parkinson's Disease](/diseases/parkinsons-disease)
External Links
[UniProt: P16050](https://www.uniprot.org/uniprot/P16050)
[PDB structures](https://www.rcsb.org/search?q=uniprot:P16050)
Cross-Links
Lipid Peroxidation
Ferroptosis
Neuroinflammation
[Alzheimer's Disease](/diseases/alzheimers-disease)
[Parkinson's Disease](/diseases/parkinsons-disease)
ALOX15 Gene
References
[Unknown, Arachidonate 15-lipoxygenase and neurodegenerative diseases (2020) (2020)](https://doi.org/10.1016/j.neurobiolaging.2009.02.012)
[Unknown, Lipoxygenases in inflammation and resolution (2018) (2018)](https://doi.org/10.1016/j.tips.2018.03.001)
[Unknown, 15-LOX in Alzheimer's disease brain (2009) (2009)](https://doi.org/10.1016/j.neurobiolaging.2009.02.012)
[Unknown, 15-LOX promotes amyloidogenesis through BACE1 (2010) (2010)](https://doi.org/10.1074/jbc.M110.202150)
[Unknown, 15-LOX in Parkinson's disease (2015) (2015)](https://doi.org/10.1016/j.neurobiolaging.2015.04.019)
[Unknown, 15-LOX regulates ferroptosis (2019) (2019)](https://doi.org/10.1038/s41586-019-1709-9)
From the [SciDEX Exchange](/exchange) — scored by multi-agent debate
[Astrocytic Lipoxin A4 Pathway Restoration via ALOX15 Gene Therapy](/hypothesis/h-ac55ff26) — <span style="color:#ffd54f;font-weight:600">0.43</span> · Target: ALOX15 Show full description