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ENPP3

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All listed services and products are For Research Use Only. Do Not use in any diagnostic or therapeutic applications.

Background

Ectonucleotide pyrophosphatase/phosphodiesterase family member 3 (ENPP3), encoded by the ENPP3 gene located on chromosome 6q22.33 and also known as NPP3, CD203c, PD-1β, or gp130RB13-6, is a member of the nucleotide pyrophosphatase/phosphodiesterase (NPP) glycoprotein family. ENPP3 is a type II single-pass transmembrane glycoprotein of approximately 875 amino acids with a molecular mass of approximately 100 kDa. The extracellular portion of the enzyme is composed of two tandem somatomedin B-like domains (SMB1/2), a catalytic phosphodiesterase (PDE) domain containing a conserved zinc-binding motif, a lasso loop (LL), and a C-terminal nuclease-like (NUC) domain that lacks catalytic activity. The crystal structure of human ENPP3 has been determined, revealing the structural basis for nucleotide recognition. ENPP3 is expressed in multiple organs, including on epithelial and mucosal surfaces, and notably on basophils and mast cells. Within the hematopoietic cell compartment, ENPP3 is a cell surface marker of basophil and mast cell lineages. Activation of basophils by antigen-bound IgE leads to rapid upregulation of ENPP3 to the cell surface.

ENPP3 functions as an ectoenzyme that hydrolyzes extracellular nucleotides, thereby modulating purinergic signaling. The enzyme hydrolyzes a variety of phosphodiester and phosphosulfate bonds including deoxynucleotides, nucleotide sugars, and NAD. Its primary substrates include extracellular ATP, GTP, UTP, and CTP, with hydrolysis producing pyrophosphate and nucleoside monophosphates as end products. ENPP3 also hydrolyzes extracellular 2',3'-cGAMP (cyclic GMP-AMP), a second messenger that activates TMEM173/STING and triggers type-I interferon production. Through its nucleotide-hydrolyzing activity, ENPP3 limits mast cell and basophil responses during inflammation and during the chronic phases of allergic responses. ENPP3 is rapidly induced by IgE and antigen-mediated crosslinking of the high-affinity IgE receptor FcεRI, making it an activation marker for clinical diagnosis of allergic diseases. Recent studies have also identified ENPP3 as a hypoxia-driven enzyme that hydrolyzes cGAMP and suppresses STING–IFN signaling. These properties make ENPP3 an important research target for studies of ectonucleotide metabolism, purinergic signaling, basophil and mast cell biology, allergic inflammation, and cGAS-STING pathway regulation.

Fig. 1 Efficiency of ENPP3 under physiological pH conditions. (OA Literature) Fig. 1 ENPP3 is an efficient hydrolase of cGAMP at physiological pH.1

ENPP3 Protein Function: Roles in Extracellular Nucleotide Hydrolysis, Purinergic Signaling, and Immune Regulation

ENPP3, encoded by the ENPP3 gene, functions as a type II transmembrane ectoenzyme that regulates extracellular nucleotide levels and modulates purinergic signaling:

  • Extracellular Nucleotide Hydrolysis: ENPP3 hydrolyzes extracellular nucleotides including ATP, GTP, UTP, and CTP, producing pyrophosphate and nucleoside monophosphates as end products.
  • Purinergic Signaling Modulation: Through its nucleotide-hydrolyzing activity, ENPP3 modulates purinergic signaling and limits mast cell and basophil responses during inflammation and chronic allergic responses.
  • cGAMP Hydrolysis and STING Pathway Regulation: ENPP3 hydrolyzes extracellular 2',3'-cGAMP, a second messenger that activates the STING pathway and triggers type-I interferon production, thereby negatively regulating cGAS-STING signaling.
  • Basophil and Mast Cell Activation Marker: ENPP3 is rapidly upregulated on the surface of basophils and mast cells upon IgE- and antigen-mediated crosslinking of FcεRI, serving as an activation marker for these cell types.
  • Phosphodiesterase and Pyrophosphatase Activities: ENPP3 cleaves a variety of phosphodiester and phosphosulfate bonds including deoxynucleotides, nucleotide sugars, and NAD, with broad substrate specificity.

ENPP3 Membrane Protein Product

Creative Biolabs offers high-quality ENPP3 membrane protein products produced using optimized expression systems. These include full-length type II transmembrane protein that retains the native N-terminal cytoplasmic domain and membrane-spanning region, as well as isolated extracellular domain variants containing the SMB domains, PDE catalytic domain, and NUC domain. The extracellular domains mediate nucleotide binding and hydrolysis, making these proteins suitable for studies of ectonucleotide metabolism, substrate recognition, and catalytic mechanism characterization. All ENPP3 proteins undergo strict quality control to support consistent performance across applicable research platforms.

Custom ENPP3 Protein Product

Not finding the protein product you need? Contact us to start your one-stop custom service!

ENPP3 Stable Cell Line Product

Creative Biolabs provides custom-engineered ENPP3 stable cell lines, including overexpression and knockdown models. These cell lines are optimized for studies of extracellular nucleotide hydrolysis, purinergic signaling, basophil and mast cell activation, and cGAS-STING pathway regulation. Each cell line undergoes stringent validation to ensure stable expression profiles and consistent functional performance in diverse experimental contexts.

ENPP3 Stable Cell Line Product

Not finding the stable cell line product you need? Contact us to start your one-stop custom service!

ENPP3 Recombinant Antibody Product

High-specificity recombinant antibodies targeting ENPP3 are developed using antibody engineering technologies for research applications involving ENPP3 expression and localization. These antibodies can be used in studies of ENPP3 distribution on basophils, mast cells, and epithelial surfaces, and may also support characterization of ENPP3-mediated nucleotide hydrolysis and signaling in combination with appropriate detection reagents.

ENPP3 Recombinant Antibody Product

Not finding the recombinant antibody product you need? Contact us to start your one-stop custom service!

Product Features

  • Native Ectoenzyme Structure Preservation: Maintains the characteristic type II transmembrane topology and catalytic domain architecture essential for nucleotide hydrolysis and substrate recognition studies.
  • Purinergic Signaling Research Compatibility: Optimized reagent series for studies of extracellular nucleotide metabolism, basophil and mast cell biology, and allergic inflammation research.
  • High Specificity for ENPP3: Minimizes non-specific cross-reactivity with other NPP family members including ENPP1, ENPP2, and ENPP4-7.
  • Comprehensive Customization Support: Facilitates end-to-end development of customized proteins, antibodies and stable cell lines to address ectonucleotide metabolism and purinergic signaling research demands.

Custom ENPP3 Research Services

Beyond catalog products, Creative Biolabs offers specialized custom services for ENPP3 research:

  • Custom ENPP3 Protein Production: Tailored expression of mutant and tagged ENPP3 constructs for nucleotide hydrolysis and substrate specificity studies.
  • Custom Antibody Development: Generation of ENPP3-specific antibodies for immunostaining, flow cytometry, and protein detection applications.
  • Stable Cell Line Engineering: Construction of ENPP3-modified cell models for purinergic signaling, basophil activation, and cGAS-STING pathway research.
  • Functional Assay Development: Custom design of nucleotide hydrolysis, phosphodiesterase activity, and signaling pathway detection workflows.

Frequently Asked Questions (FAQs)

  1. What is the primary function of ENPP3?

    ENPP3 is a type II transmembrane ectoenzyme that hydrolyzes extracellular nucleotides including ATP, GTP, UTP, and CTP, modulating purinergic signaling and regulating basophil and mast cell responses.

  2. Why is ENPP3 a significant research target?

    ENPP3 plays key roles in extracellular nucleotide metabolism, purinergic signaling, and allergic inflammation. It is an activation marker for basophils and mast cells and has been identified as a regulator of the cGAS-STING pathway through cGAMP hydrolysis.

  3. Are Creative Biolabs' ENPP3 products suitable for clinical use?

    No, all ENPP3 products and services are strictly for research use only, not intended for clinical diagnosis or treatment.

  4. What types of ENPP3 products does Creative Biolabs offer?

    Offerings include full-length ENPP3 transmembrane proteins, extracellular domain variants, specific detection antibodies, and custom stable cell lines for nucleotide metabolism and purinergic signaling research.

  5. How are ENPP3 proteins validated for activity?

    ENPP3 proteins are validated via nucleotide hydrolysis assays, phosphodiesterase activity assays, and relevant functional characterization in applicable research platforms.

Reference
  1. Mardjuki, R., et al. "Identification of the Extracellular Membrane Protein ENPP3 as a Major cGAMP Hydrolase and Innate Immune Checkpoint." Cell Reports 43.5 (2024): 114209. Under Open Access license CC BY 4.0, without modification. https://doi.org/10.1016/j.celrep.2024.114209
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