Details for: ALOX15

Gene ID: 246

Gene Type:  Protein-coding  - A gene that serves as a template for producing a messenger RNA (mRNA) molecule, which is then translated into a functional protein.

Symbol: ALOX15

Ensembl ID: ENSG00000161905

Description: arachidonate 15-lipoxygenase

Selected Context(s):  Overall

Cell Significance Landscape

Contexts:

Associated with

Significant Cells

Cell Significance Index (CSI) scores for the chosen context(s)

  • secretory cell CL0000151
    CSI 6.54
    rCSI 6.82%
    PRS 98.2
  • multi-ciliated epithelial cell CL0005012
    CSI 5.68
    rCSI 5.67%
    PRS 96.47
  • dendritic cell CL0000451
    CSI 3.6
    rCSI 4.44%
    PRS 97.74
  • nasal mucosa goblet cell CL0002480
    CSI 3.59
    rCSI 4.16%
    PRS 97.92
  • respiratory suprabasal cell CL4033048
    CSI 3.52
    rCSI 4.51%
    PRS 98.93
  • respiratory basal cell CL0002633
    CSI 3.49
    rCSI 3.61%
    PRS 98.8
  • ionocyte CL0005006
    CSI 3.42
    rCSI 3.66%
    PRS 98.8
  • club cell CL0000158
    CSI 3.27
    rCSI 4.78%
    PRS 98.02
  • ciliated epithelial cell CL0000067
    CSI 3.2
    rCSI 2.82%
    PRS 95.5
  • lung ciliated cell CL1000271
    CSI 3.14
    rCSI 3.63%
    PRS 96.76
  • goblet cell CL0000160
    CSI 3.08
    rCSI 2.91%
    PRS 97.99
  • ciliated cell CL0000064
    CSI 2.54
    rCSI 4.11%
    PRS 95.83
  • squamous epithelial cell CL0000076
    CSI 2.5
    rCSI 5.94%
    PRS 96.03
  • tracheal goblet cell CL1000329
    CSI 1.96
    rCSI 4.27%
    PRS 98.81
  • ciliated columnar cell of tracheobronchial tree CL0002145
    CSI 1.28
    rCSI 2.91%
    PRS 95.43
  • mesothelial cell CL0000077
    CSI 1.27
    rCSI 4.98%
    PRS 94.09
  • deuterosomal cell CL4033044
    CSI 1.15
    rCSI 3.89%
    PRS 95.42
  • basal cell of epithelium of trachea CL1000348
    CSI 0.72
    rCSI 5.07%
    PRS 98.3

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this specific cell.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.
Network Configuration

Explore relationships of the current gene. Select an Interaction Source: 'ONTOLOGY' for shared pathways (GO/Reactome) or 'STRING' for protein-protein interactions. Further refine by selecting context genes and comparing Cell Significance Index (CSI) scores between baseline and target cell types and their specific contexts.

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Legend:
  • Query Gene
  • Node Color (Target Cell CSI, relative to current network):
    • Very High
    • High
    • Medium
    • Low
    • Very Low
    • CSI N/A
  • Node Size: Proportional to Target Cell CSI magnitude
  • STRING PPI Edge
  • Shared Pathway Edge (ONTOLOGY)

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Other Information

This section provides additional information about the gene, including a description generated by an AI language model and details about associated proteins.

## Summary [ALOX15](/details-gene/246) (arachidonate 15-lipoxygenase) is a protein-coding gene located on chromosome 17p13.2 that encodes a key enzyme in lipid metabolism. The protein, a member of the lipoxygenase family, catalyzes the oxygenation of polyunsaturated fatty acids like arachidonic and linoleic acid to produce a variety of bioactive lipid mediators. **Overall**, expression data reveals that [ALOX15](/details-gene/246) is a highly significant gene in mucosal tissues, with exceptionally high expression in various epithelial and secretory cell types of the respiratory tract, including [secretory cells](/details-cell/CL0000151) and [multi-ciliated epithelial cells](/details-cell/CL0005012). Functionally, [ALOX15](/details-gene/246) is integral to the [lipoxygenase pathway](/details-cell/GO:0019372) and is deeply involved in the inflammatory response, particularly in the biosynthesis of specialized pro-resolving mediators (SPMs) that play a critical role in the resolution of inflammation and tissue repair ([GO:0006954](https://www.ebi.ac.uk/QuickGO/term/GO:0006954), [R-HSA-9018678](https://reactome.org/content/detail/R-HSA-9018678)). Its clinical relevance is associated with inflammatory diseases and is cataloged in OMIM ([152392](https://omim.org/entry/152392)). ## Cellular Roles and Expression Landscape The expression profile of [ALOX15](/details-gene/246) strongly points to a specialized role in mucosal biology, particularly within the respiratory system. **Overall**, the gene shows its highest significance in [secretory cells](/details-cell/CL0000151) (CSI: 6.54), [multi-ciliated epithelial cells](/details-cell/CL0005012) (CSI: 5.68), [nasal mucosa goblet cells](/details-cell/CL0002480) (CSI: 3.59), and [club cells](/details-cell/CL0000158) (CSI: 3.27). This consistent high expression across various secretory and ciliated lineages, such as [lung ciliated cells](/details-cell/CL1000271) and [tracheal goblet cells](/details-cell/CL1000329), suggests its function is central to maintaining the epithelial barrier and orchestrating responses to environmental stimuli in the airways. In addition to its prominent role in epithelial biology, [ALOX15](/details-gene/246) is also significantly expressed in antigen-presenting [dendritic cells](/details-cell/CL0000451) (CSI: 3.60). This suggests a dual function for the gene, contributing not only to epithelial barrier integrity but also to the modulation of immune responses within mucosal tissues. The enzyme's activity in these cells likely contributes to the generation of lipid mediators that regulate local inflammation and immune cell communication. The pattern of expression highlights [ALOX15](/details-gene/246) as a key enzyme at the host-environment interface. ## Pathways and Molecular Function [ALOX15](/details-gene/246) functions primarily as a lipoxygenase, with demonstrated [arachidonate 15-lipoxygenase activity](/details-cell/GO:0050473) and [linoleate 13s-lipoxygenase activity](/details-cell/GO:0016165). Its molecular function requires [iron ion binding](/details-cell/GO:0005506) for catalysis. The enzyme is a central component of the [arachidonate metabolism](/details-cell/R-HSA-2142753) pathway, converting arachidonic acid into 15-hydroperoxyeicosatetraenoic acid (15-HpETE), a precursor to a wide array of signaling molecules. The biological processes involving [ALOX15](/details-gene/246) are extensive and centered on lipid signaling in inflammation and immunity. It is a critical enzyme in the [biosynthesis of specialized pro-resolving mediators (SPMs)](/details-cell/R-HSA-9018678), including lipoxins, resolvins, and protectins. These molecules are essential for the active resolution of inflammation, contributing to processes like [apoptotic cell clearance](/details-cell/GO:0043277) and [wound healing](/details-cell/GO:0042060). Consistent with its expression in dendritic cells, [ALOX15](/details-gene/246) is implicated in the [negative regulation of the adaptive immune response](/details-cell/GO:0002820) and is involved in [cytokine signaling in the immune system](/details-cell/R-HSA-1280215), particularly downstream of IL-4 and IL-13 signaling ([R-HSA-6785807](https://reactome.org/content/detail/R-HSA-6785807)). Studies have shown that its promoter contains binding sites for regulatory factors induced by IL-13, directly linking it to type 2 immunity ([Link](https://doi.org/10.1023/a:1006813009006)). Cellularly, the protein is found in the [cytosol](/details-cell/GO:0005829) and can translocate to the [plasma membrane](/details-cell/GO:0005886) in a calcium-dependent manner ([Link](https://pubmed.ncbi.nlm.nih.gov/9414270/)). It also associates with [lipid droplets](/details-cell/GO:0005811), suggesting a role in lipid droplet metabolism within macrophages ([Link](https://doi.org/10.1194/jlr.m900081-jlr200)). ## Research Directions The expression and functional data for [ALOX15](/details-gene/246) position it as a critical regulator of mucosal inflammation and resolution. Its high specificity for respiratory epithelial cells and select immune cells makes it a compelling subject for further investigation in both homeostasis and disease. **Proposed Hypotheses:** 1. Given its high expression in airway secretory and ciliated cells and its role in producing anti-inflammatory lipid mediators, we hypothesize that [ALOX15](/details-gene/246) is essential for maintaining airway mucosal homeostasis. Its downregulation or dysfunction may lead to an exaggerated inflammatory response to allergens or pathogens, contributing to the pathophysiology of chronic inflammatory lung diseases like asthma or chronic obstructive pulmonary disease (COPD). 2. The significant expression of [ALOX15](/details-gene/246) in [dendritic cells](/details-cell/CL0000451) suggests a direct role in shaping adaptive immunity. We hypothesize that dendritic cell-derived, [ALOX15](/details-gene/246)-dependent SPMs are critical for promoting the resolution of inflammation and inducing T-cell tolerance at mucosal surfaces. A deficiency in this pathway could result in a failure to resolve inflammation and a shift towards chronic immune activation. **Experimental Approach:** To test the first hypothesis regarding the role of [ALOX15](/details-gene/246) in airway epithelial cells, a robust *in vitro* model could be employed. Primary human bronchial epithelial cells could be cultured at an air-liquid interface to form a differentiated, mucociliary epithelium. Using CRISPR-Cas9 or siRNA to specifically knock down [ALOX15](/details-gene/246), these cultures would then be challenged with an inflammatory stimulus relevant to asthma, such as interleukin-13 (IL-13). The impact of [ALOX15](/details-gene/246) loss could be assessed by measuring the secretion of pro-inflammatory cytokines (e.g., IL-6, TSLP) via ELISA, quantifying mucin gene expression (e.g., *MUC5AC*) by qPCR, and performing lipidomic analysis by mass spectrometry to confirm the loss of 15-HETE and downstream SPM production. This would directly test whether [ALOX15](/details-gene/246) is required to restrain inflammatory responses in the airway epithelium. **Therapeutic Potential:** [ALOX15](/details-gene/246) represents a promising therapeutic target, primarily through strategies aimed at **activation** or supplementation of its products. As the enzyme produces pro-resolving mediators, small-molecule activators of [ALOX15](/details-gene/246) could be developed to enhance the resolution of inflammation in chronic inflammatory diseases. Alternatively, the stable synthetic analogues of its downstream products (e.g., resolvins, lipoxins) are already being investigated as "resolution pharmacology" agents. Given its enzymatic nature and well-defined active site, [ALOX15](/details-gene/246) is a druggable target. Such therapies could offer a novel approach that promotes the natural termination of inflammation rather than simply blocking pro-inflammatory pathways.

Genular Protein ID: 1151080486

Symbol: LOX15_HUMAN

Name: Arachidonate 15-lipoxygenase

UniProtKB Accession Codes:

P16050 A8K2P4 B7ZA11 Q8N6R7 Q99657

Database IDs:

AGR 1 AlphaFoldDB 1 Antibodypedia 1 BRENDA 2 Bgee 1 BindingDB 1 BioCyc 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 1 CDD 1 CTD 1 ChEBI 86 ChEMBL 1 DIP 1 DMDM 1 DNASU 1 DisGeNET 1 DisProt 1 DrugBank 5 DrugCentral 1 EC 3 EMBL 8 Ensembl 3 GO 35 Gene3D 2 GeneCards 1 GeneTree 1 GeneWiki 1 GenomeRNAi 1 GuidetoPHARMACOLOGY 1 HGNC 1 HOGENOM 1 HPA 1 InParanoid 1 IntAct 1 InterPro 9 KEGG 1 MANE-Select 1 MIM 1 MassIVE 1 MetOSite 1 NCBI Taxonomy 1 OMA 1 OpenTargets 1 OrthoDB 1 PANTHER 2 PIR 1 PRINTS 2 PRO 1 PROSITE 4 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 2 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 2 RNAct 1 Reactome 10 RefSeq 1 Rhea 54 SABIO-RK 1 SIGNOR 1 SMART 1 SMR 1 STRING 1 SUPFAM 2 SignaLink 1 SwissLipids 1 TreeFam 1 UCSC 1 UniPathway 1 VEuPathDB 1 eggNOG 1 iPTMnet 1 jPOST 1 neXtProt 1

Citations:

PubMed ID: 3202857

Title: Molecular cloning and primary structure of human 15-lipoxygenase.

PubMed ID: 3202857

DOI: 10.1016/s0006-291x(88)80271-7

PubMed ID: 9224951

Title: Characterization and sequence of an additional 15-lipoxygenase transcript and of the human gene.

PubMed ID: 9224951

DOI: 10.1016/s0167-4781(97)00005-5

PubMed ID: 14702039

Title: Complete sequencing and characterization of 21,243 full-length human cDNAs.

PubMed ID: 14702039

DOI: 10.1038/ng1285

PubMed ID: 16625196

Title: DNA sequence of human chromosome 17 and analysis of rearrangement in the human lineage.

PubMed ID: 16625196

DOI: 10.1038/nature04689

PubMed ID: 15489334

Title: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).

PubMed ID: 15489334

DOI: 10.1101/gr.2596504

PubMed ID: 9700053

Title: Human 15-lipoxygenase gene promoter: analysis and identification of DNA binding sites for IL-13-induced regulatory factors in monocytes.

PubMed ID: 9700053

DOI: 10.1023/a:1006813009006

PubMed ID: 3356688

Title: Arachidonate 15-lipoxygenase (omega-6 lipoxygenase) from human leukocytes. Purification and structural homology to other mammalian lipoxygenases.

PubMed ID: 3356688

DOI: 10.1016/s0021-9258(18)60719-7

PubMed ID: 1662607

Title: Purification of two forms of arachidonate 15-lipoxygenase from human leukocytes.

PubMed ID: 1662607

DOI: 10.1111/j.1432-1033.1991.tb16495.x

PubMed ID: 1944593

Title: A primary determinant for lipoxygenase positional specificity.

PubMed ID: 1944593

DOI: 10.1038/354149a0

PubMed ID: 8334154

Title: Overexpression, purification and characterization of human recombinant 15-lipoxygenase.

PubMed ID: 8334154

DOI: 10.1016/0005-2760(93)90085-n

PubMed ID: 9414270

Title: Membrane translocation of 15-lipoxygenase in hematopoietic cells is calcium-dependent and activates the oxygenase activity of the enzyme.

PubMed ID: 9414270

PubMed ID: 11418015

Title: Evaluation of the activity and localization of 15-lipoxygenase-1 after introduction into human colorectal carcinoma Caco-2 cells.

PubMed ID: 11418015

DOI: 10.1054/plef.2001.0263

PubMed ID: 17052953

Title: Interaction of human 15-lipoxygenase-1 with phosphatidylinositol bisphosphates results in increased enzyme activity.

PubMed ID: 17052953

DOI: 10.1016/j.bbalip.2006.09.007

PubMed ID: 18755188

Title: Reciprocal regulation of 12- and 15-lipoxygenases by UV-irradiation in human keratinocytes.

PubMed ID: 18755188

DOI: 10.1016/j.febslet.2008.08.017

PubMed ID: 19528634

Title: 15(S)-Lipoxygenase-1 associates with neutral lipid droplets in macrophage foam cells: evidence of lipid droplet metabolism.

PubMed ID: 19528634

DOI: 10.1194/jlr.m900081-jlr200

PubMed ID: 21831839

Title: 15-Lipoxygenase 1 interacts with phosphatidylethanolamine-binding protein to regulate MAPK signaling in human airway epithelial cells.

PubMed ID: 21831839

DOI: 10.1073/pnas.1018075108

PubMed ID: 23242647

Title: Biosynthesis, isolation, and NMR analysis of leukotriene A epoxides: substrate chirality as a determinant of the cis or trans epoxide configuration.

PubMed ID: 23242647

DOI: 10.1194/jlr.m033746

PubMed ID: 24282679

Title: Functional characterization of genetic enzyme variations in human lipoxygenases.

PubMed ID: 24282679

DOI: 10.1016/j.redox.2013.11.001

PubMed ID: 25293588

Title: Lipoxygenase-catalyzed transformation of epoxy fatty acids to hydroxy-endoperoxides: a potential P450 and lipoxygenase interaction.

PubMed ID: 25293588

DOI: 10.1194/jlr.m054072

PubMed ID: 32404334

Title: 15-Lipoxygenase-1 biosynthesis of 7S,14S-diHDHA implicates 15-lipoxygenase-2 in biosynthesis of resolvin D5.

PubMed ID: 32404334

DOI: 10.1194/jlr.ra120000777

PubMed ID: 17959182

Title: A near null variant of 12/15-LOX encoded by a novel SNP in ALOX15 and the risk of coronary artery disease.

PubMed ID: 17959182

DOI: 10.1016/j.atherosclerosis.2007.09.003

Sequence Information:

  • Length: 662
  • Mass: 74804
  • Checksum: 9ACF7FE7863A045C
  • Sequence:
    • MGLYRIRVST GASLYAGSNN QVQLWLVGQH GEAALGKRLW PARGKETELK VEVPEYLGPL 
LFVKLRKRHL LKDDAWFCNW ISVQGPGAGD EVRFPCYRWV EGNGVLSLPE GTGRTVGEDP 
QGLFQKHREE ELEERRKLYR WGNWKDGLIL NMAGAKLYDL PVDERFLEDK RVDFEVSLAK 
GLADLAIKDS LNVLTCWKDL DDFNRIFWCG QSKLAERVRD SWKEDALFGY QFLNGANPVV 
LRRSAHLPAR LVFPPGMEEL QAQLEKELEG GTLFEADFSL LDGIKANVIL CSQQHLAAPL 
VMLKLQPDGK LLPMVIQLQL PRTGSPPPPL FLPTDPPMAW LLAKCWVRSS DFQLHELQSH 
LLRGHLMAEV IVVATMRCLP SIHPIFKLII PHLRYTLEIN VRARTGLVSD MGIFDQIMST 
GGGGHVQLLK QAGAFLTYSS FCPPDDLADR GLLGVKSSFY AQDALRLWEI IYRYVEGIVS 
LHYKTDVAVK DDPELQTWCR EITEIGLQGA QDRGFPVSLQ ARDQVCHFVT MCIFTCTGQH 
ASVHLGQLDW YSWVPNAPCT MRLPPPTTKD ATLETVMATL PNFHQASLQM SITWQLGRRQ 
PVMVAVGQHE EEYFSGPEPK AVLKKFREEL AALDKEIEIR NAKLDMPYEY LRPSVVENSV 
AI