Details for: CYP26A1

Gene ID: 1592

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: CYP26A1

Ensembl ID: ENSG00000095596

Description: cytochrome P450 family 26 subfamily A member 1

Selected Context(s):  Overall

Cell Significance Landscape

Contexts:

Associated with

Significant Cells

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

  • Mueller cell CL0000636
    CSI 4.83
    rCSI 11.02%
    PRS 97.97
  • ionocyte CL0005006
    CSI 4.78
    rCSI 5.13%
    PRS 99.31
  • secretory cell CL0000151
    CSI 4.37
    rCSI 4.56%
    PRS 99.15
  • pulmonary ionocyte CL0017000
    CSI 4.16
    rCSI 5.07%
    PRS 99.35
  • respiratory suprabasal cell CL4033048
    CSI 3.6
    rCSI 4.62%
    PRS 99.62
  • respiratory basal cell CL0002633
    CSI 3.3
    rCSI 3.42%
    PRS 99.5
  • neuroblast (sensu Nematoda and Protostomia) CL0000338
    CSI 2.58
    rCSI 2.97%
    PRS 97.87
  • glioblast CL0000030
    CSI 2.27
    rCSI 3.62%
    PRS 97.83
  • club cell CL0000158
    CSI 2.18
    rCSI 3.19%
    PRS 99.29
  • decidual natural killer cell, human CL0002343
    CSI 0.93
    rCSI 9.46%
    PRS 99.04
  • basal cell of epithelium of trachea CL1000348
    CSI 0.83
    rCSI 5.84%
    PRS 99.23

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

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  • Node Color (Target Cell CSI, relative to current network):
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  • 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 [CYP26A1](/details-gene/1592) encodes Cytochrome P450 26A1, a key enzyme in the catabolism of all-trans retinoic acid (RA), a potent signaling molecule derived from vitamin A. Functionally, it acts as a hydroxylase, specifically metabolizing RA to control its local concentration and prevent excessive signaling ([Link](https://pubmed.ncbi.nlm.nih.gov/9228017/)). This role is critical for regulating processes such as embryonic development, particularly of the nervous system and kidneys, and maintaining cellular differentiation. Expression data from the **Overall** context indicates that [CYP26A1](/details-gene/1592) is a highly significant gene in specialized cell types, including retinal [Mueller cell](/details-cell/CL0000636) and various respiratory epithelial cells like [pulmonary ionocyte](/details-cell/CL0017000), suggesting its primary function is to establish precise RA gradients essential for the homeostasis of these tissues. Dysregulation of this gene is associated with developmental abnormalities ([Link](https://omim.org/entry/602239)). ## Cellular Roles and Expression Landscape The expression profile of [CYP26A1](/details-gene/1592) points to a specialized role in maintaining local environments by clearing retinoic acid, rather than a ubiquitous function. **Overall**, its significance is highest in a distinct set of cell types responsible for sensory function, epithelial barriers, and neural development. - **Ocular and Neural Tissues:** The gene's highest significance is observed in the [Mueller cell](/details-cell/CL0000636) of the retina (CSI: 4.83). Mueller cells are principal glial cells of the retina, providing structural and metabolic support to neurons. The prominent role of [CYP26A1](/details-gene/1592) here suggests it is critical for protecting retinal neurons from potentially teratogenic or toxic levels of RA, thereby maintaining retinal integrity. Its significance in [glioblast](/details-cell/CL0000030) and [neuroblast (sensu Nematoda and Protostomia)](/details-cell/CL0000338) is consistent with its established role in nervous system development ([Link](https://www.ebi.ac.uk/QuickGO/term/GO:0007417)). - **Respiratory Epithelium:** A second major site of high significance for [CYP26A1](/details-gene/1592) is the respiratory tract. It is a key marker for specialized epithelial cells including [ionocyte](/details-cell/CL0005006), [pulmonary ionocyte](/details-cell/CL0017000), [respiratory suprabasal cell](/details-cell/CL4033048), [respiratory basal cell](/details-cell/CL0002633), and [club cell](/details-cell/CL0000158). This pattern suggests that precise control of RA signaling is fundamental for the maintenance, differentiation, and function of the airway epithelial barrier. - **Other Specialized Cells:** The gene also shows relevance in [secretory cell](/details-cell/CL0000151) and [decidual natural killer cell, human](/details-cell/CL0002343), indicating a context-specific role in glandular tissues and the unique immune environment of the maternal-fetal interface. ## Pathways and Molecular Function [CYP26A1](/details-gene/1592) is an enzyme located in the '[endoplasmic reticulum membrane](/details-go/GO:0005789)' that plays a central role in vitamin A metabolism and retinoic acid signaling. - **Molecular Function:** Its primary enzymatic activity is '[retinoic acid 4-hydroxylase activity](/details-go/GO:0008401)', which includes both '[all-trans retinoic acid 4-hydrolase activity](/details-go/GO:0062182)' and '[all-trans retinoic acid 18-hydroxylase activity](/details-go/GO:0062183)'. As a member of the cytochrome P450 family, it relies on '[heme binding](/details-go/GO:0020037)' and '[iron ion binding](/details-go/GO:0005506)' to carry out its monooxygenase activity. - **Biological Process:** By metabolizing RA, [CYP26A1](/details-gene/1592) is a key executor of the '[retinoic acid catabolic process](/details-go/GO:0034653)'. This function serves as a '[negative regulation of retinoic acid receptor signaling pathway](/details-go/GO:0048387)', effectively acting as a brake on RA-induced gene expression. This regulatory role is fundamental to developmental processes such as '[central nervous system development](/details-go/GO:0007417)' and '[kidney development](/details-go/GO:0001822)'. - **Reactome Pathways:** Its function is annotated within broader metabolic pathways like '[Biological oxidations](/details-pathway/R-HSA-211859)' and '[Metabolism of vitamins](/details-pathway/R-HSA-211916)'. More specifically, it is a crucial component of the '[RA biosynthesis pathway](/details-pathway/R-HSA-5365859)' and the overarching '[Signaling by retinoic acid](/details-pathway/R-HSA-5362517)' pathway, highlighting its role as a gatekeeper of this signaling cascade. ## Research Directions The highly specific expression pattern of [CYP26A1](/details-gene/1592) and its critical function in degrading a potent morphogen suggest that its dysregulation could be a key factor in developmental disorders and epithelial diseases. **Testable Hypotheses:** 1. Given its high significance in multiple respiratory epithelial cell types, dysregulation of [CYP26A1](/details-gene/1592) contributes to pathological epithelial remodeling in chronic lung diseases (e.g., COPD or asthma) by disrupting the local RA gradients required for proper cellular differentiation and barrier function. 2. In the retina, loss-of-function mutations or downregulation of [CYP26A1](/details-gene/1592) in [Mueller cell](/details-cell/CL0000636) leads to RA overexposure and subsequent photoreceptor degeneration or developmental retinopathies. **Proposed Experimental Approach:** To test the hypothesis regarding its role in the respiratory epithelium, a valuable experiment would be to use an air-liquid interface (ALI) culture model of primary human bronchial epithelial cells. 1. Use CRISPR-Cas9 or shRNA to achieve stable knockdown of [CYP26A1](/details-gene/1592) in bronchial basal stem cells. 2. Induce differentiation of both control and knockdown cells in ALI culture over several weeks. 3. Assess the impact on epithelial architecture and cellular composition using immunofluorescence staining for lineage markers (e.g., FOXJ1 for ciliated cells, MUC5AC for goblet cells, KRT5 for basal cells). 4. Perform single-cell RNA sequencing at different time points to comprehensively map the altered differentiation trajectories and identify dysregulated gene networks downstream of RA signaling. **Therapeutic Potential:** [CYP26A1](/details-gene/1592) represents a highly attractive therapeutic target. As an enzyme that degrades a pro-differentiation and growth-inhibitory signal (RA), its **inhibition** is a promising strategy in certain cancers. In malignancies like acute promyelocytic leukemia or some breast and colon carcinomas, tumor cells can overexpress [CYP26A1](/details-gene/1592) to create an RA-depleted microenvironment, thereby evading differentiation signals and promoting proliferation ([Link](https://pubmed.ncbi.nlm.nih.gov/9716180/)). Specific inhibitors of [CYP26A1](/details-gene/1592) could be used in combination with RA-based therapies to restore intracellular RA levels, induce differentiation, and halt tumor growth. The enzyme's high substrate specificity suggests that potent and selective inhibitors could be developed with a favorable therapeutic window.

Genular Protein ID: 1311924124

Symbol: CP26A_HUMAN

Name: Cytochrome P450 26A1

UniProtKB Accession Codes:

O43174 B3KNI4 Q5VXH9 Q5VXI0

Database IDs:

AGR 1 AlphaFoldDB 1 Antibodypedia 1 Bgee 1 BindingDB 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 2 CDD 1 CTD 1 ChEBI 24 ChEMBL 1 ChiTaRS 1 DNASU 1 DisGeNET 1 DrugBank 3 DrugCentral 1 EMBL 5 Ensembl 2 ExpressionAtlas 1 GO 19 Gene3D 1 GeneCards 1 GeneTree 1 GeneWiki 1 GenomeRNAi 1 GuidetoPHARMACOLOGY 1 HGNC 1 HOGENOM 1 HPA 1 InParanoid 1 IntAct 1 InterPro 4 KEGG 1 MANE-Select 1 MIM 1 MassIVE 1 NCBI Taxonomy 1 OMA 1 OpenTargets 1 OrthoDB 1 PANTHER 2 PRINTS 2 PRO 1 PROSITE 1 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 1 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 2 RNAct 1 Reactome 2 RefSeq 2 Rhea 12 SABIO-RK 1 SIGNOR 1 SMR 1 STRING 1 SUPFAM 1 SwissLipids 1 TreeFam 1 UCSC 1 VEuPathDB 1 eggNOG 1 iPTMnet 1 jPOST 1 neXtProt 1

Citations:

PubMed ID: 9228017

Title: cDNA cloning of human retinoic acid-metabolizing enzyme (hP450RAI) identifies a novel family of cytochromes P450.

PubMed ID: 9228017

DOI: 10.1074/jbc.272.30.18538

PubMed ID: 9716180

Title: Human retinoic acid (RA) 4-hydroxylase (CYP26) is highly specific for all-trans-RA and can be induced through RA receptors in human breast and colon carcinoma cells.

PubMed ID: 9716180

PubMed ID: 14702039

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

PubMed ID: 14702039

DOI: 10.1038/ng1285

PubMed ID: 15164054

Title: The DNA sequence and comparative analysis of human chromosome 10.

PubMed ID: 15164054

DOI: 10.1038/nature02462

PubMed ID: 9826557

Title: Expression of cytochrome P450RAI (CYP26) in human fetal hepatic and cephalic tissues.

PubMed ID: 9826557

DOI: 10.1006/bbrc.1998.9659

PubMed ID: 22020119

Title: Comparison of the function and expression of CYP26A1 and CYP26B1, the two retinoic acid hydroxylases.

PubMed ID: 22020119

DOI: 10.1016/j.bcp.2011.10.007

PubMed ID: 26937021

Title: Identification of tazarotenic acid as the first xenobiotic substrate of human retinoic acid hydroxylase CYP26A1 and CYP26B1.

PubMed ID: 26937021

DOI: 10.1124/jpet.116.232637

Sequence Information:

  • Length: 497
  • Mass: 56199
  • Checksum: 834318FA493E76D4
  • Sequence:
    • MGLPALLASA LCTFVLPLLL FLAAIKLWDL YCVSGRDRSC ALPLPPGTMG FPFFGETLQM 
VLQRRKFLQM KRRKYGFIYK THLFGRPTVR VMGADNVRRI LLGEHRLVSV HWPASVRTIL 
GSGCLSNLHD SSHKQRKKVI MRAFSREALE CYVPVITEEV GSSLEQWLSC GERGLLVYPE 
VKRLMFRIAM RILLGCEPQL AGDGDSEQQL VEAFEEMTRN LFSLPIDVPF SGLYRGMKAR 
NLIHARIEQN IRAKICGLRA SEAGQGCKDA LQLLIEHSWE RGERLDMQAL KQSSTELLFG 
GHETTASAAT SLITYLGLYP HVLQKVREEL KSKGLLCKSN QDNKLDMEIL EQLKYIGCVI 
KETLRLNPPV PGGFRVALKT FELNGYQIPK GWNVIYSICD THDVAEIFTN KEEFNPDRFM 
LPHPEDASRF SFIPFGGGLR SCVGKEFAKI LLKIFTVELA RHCDWQLLNG PPTMKTSPTV 
YPVDNLPARF THFHGEI