ENPP3 - ectonucleotide pyrophosphatase/phosphodiesterase 3 |Elisa - Clia - Antibody - Protein

Background

ENPP3, or ectonucleotide pyrophosphatase/phosphodiesterase 3, is a member of the ectonucleotide pyrophosphatase/phosphodiesterase (ENPP) family, which is involved in the hydrolysis of extracellular nucleotides and plays significant roles in cell signaling and metabolism. ENPP3, encoded by the ENPP3 gene in humans, is prominently expressed on the surface of various cell types, including epithelial cells, immune cells, and especially on mast cells and basophils. The enzyme's primary function is to hydrolyze extracellular nucleotide phosphates, such as ATP, ADP, and NAD+, producing pyrophosphate and nucleoside monophosphates as end products. These hydrolytic activities of ENPP3 influence signaling pathways that regulate inflammation, immune responses, and cellular proliferation.

The activity of ENPP3 is particularly important in the modulation of immune responses and inflammation. By controlling extracellular nucleotide levels, ENPP3 indirectly regulates purinergic signaling, which is central to processes such as cell migration, cytokine release, and response to injury. ENPP3 dysregulation is associated with a range of pathological conditions, including allergic responses, autoimmune diseases, and some cancers, making it a potential therapeutic target for intervention in these diseases.

Protein Structure

ENPP3 is a type II transmembrane glycoprotein approximately 875 amino acids in length and with a molecular weight of around 100 kDa. It has a well-defined and unique domain structure, which is crucial for its enzymatic and regulatory functions. The main structural domains include:

1. N-terminal Transmembrane Domain: This domain anchors ENPP3 to the plasma membrane. ENPP3 is a type II membrane protein, meaning that its N-terminus is embedded in the membrane, while the large C-terminal extracellular domain contains the functional regions involved in enzymatic activity.
2. Somatomedin B-like (SMB) Domain: Located just after the transmembrane segment in the extracellular region, this domain is involved in protein-protein interactions. The SMB domain aids in the interaction of ENPP3 with other extracellular matrix molecules or membrane proteins, which can influence cell adhesion and migration.
3. Catalytic Domain: The catalytic domain is essential for the enzyme's pyrophosphatase/phosphodiesterase activities, where it hydrolyzes extracellular nucleotides. The catalytic site contains key amino acid residues that are responsible for binding and cleaving phosphate bonds, producing pyrophosphate and monophosphate derivatives. This catalytic domain is conserved across the ENPP family and is central to ENPP3’s role in modulating extracellular nucleotide concentrations.
4. Nucleotide Pyrophosphatase/Phosphodiesterase Domain: This domain plays a significant role in binding to nucleotide substrates, specifically nucleotides such as ATP, ADP, and NAD+. It allows ENPP3 to perform its phosphodiesterase function by breaking the phosphodiester bonds in these molecules. The domain's structure enables substrate specificity and ensures efficient hydrolysis of extracellular nucleotides.
5. C-terminal Region: This region is involved in stabilizing the protein and may also be responsible for interactions with other regulatory proteins. The C-terminal tail of ENPP3 plays a structural role in maintaining the conformation of the extracellular domains.

The organized structure of ENPP3’s extracellular regions, with the catalytic domain adjacent to substrate-binding sites, enhances its efficiency in hydrolyzing nucleotides in the extracellular space. Glycosylation sites are also present within ENPP3, contributing to protein stability and proper folding.

Classification and Subtypes

ENPP3 belongs to the ENPP (ectonucleotide pyrophosphatase/phosphodiesterase) family, which consists of seven known members (ENPP1 to ENPP7). ENPP family members are characterized by their ability to hydrolyze nucleotides and related phosphodiester bonds, although they differ in substrate specificities, tissue distribution, and biological functions.

ENPP3 is closely related to ENPP2 (also known as autotaxin) and ENPP1. While ENPP1 and ENPP3 share functional similarities, such as hydrolysis of ATP and ADP, they differ in terms of expression patterns and precise biological roles. ENPP3 is more specifically expressed in immune cells, especially mast cells and basophils, and plays a unique role in immune response modulation.

Function and Biological Significance

ENPP3 plays crucial roles in multiple physiological processes through its hydrolysis of extracellular nucleotides and subsequent regulation of purinergic signaling. Its biological functions include:

• Modulation of Immune Responses: ENPP3 is highly expressed in immune cells, particularly in mast cells and basophils, where it regulates allergic and inflammatory responses. By hydrolyzing ATP, ENPP3 reduces extracellular ATP levels, a molecule that acts as a "danger signal" and promotes inflammation. Lower ATP levels lead to reduced purinergic receptor activation, thus modulating immune cell activation and inflammation.
• Regulation of Cell Proliferation and Migration: Through the breakdown of ATP and NAD+, ENPP3 indirectly influences cell signaling pathways that control cell migration and proliferation. This activity is particularly relevant in tissues with high cellular turnover and in response to injury.
• Vascular and Epithelial Barrier Function: By controlling extracellular nucleotide concentrations, ENPP3 influences endothelial and epithelial cell function, which is crucial for maintaining tissue barriers. Its role in barrier function is especially relevant in organs like the skin, gut, and lungs, where it helps maintain homeostasis.
• Role in Allergic Responses: ENPP3’s high expression in basophils and mast cells links it closely to allergic responses. By controlling ATP levels in the extracellular space, ENPP3 regulates mast cell degranulation and cytokine release, contributing to the development or attenuation of allergic reactions.

Clinical Issues

Altered ENPP3 expression or activity has been implicated in several pathological conditions, particularly in relation to immune dysregulation and cancer. Some key clinical issues associated with ENPP3 include:

• Allergic Diseases: Elevated ENPP3 activity in mast cells and basophils is associated with allergic diseases such as asthma and chronic urticaria. ENPP3 controls the degranulation of these cells in response to allergens, influencing the severity of allergic reactions. As such, ENPP3 has become a target of interest in research for treating allergic conditions.
• Cancer: ENPP3 is expressed in certain cancers, including colorectal and pancreatic cancers. It is thought that ENPP3 promotes tumor progression by influencing ATP-mediated purinergic signaling, which can enhance tumor cell proliferation and survival. ENPP3 may also contribute to the immunosuppressive microenvironment in tumors by degrading ATP, which otherwise would activate immune cells.
• Autoimmune Diseases: Given its role in immune modulation, dysregulated ENPP3 expression has been implicated in autoimmune diseases. Abnormal ENPP3 activity may contribute to inappropriate immune responses, leading to tissue damage, as seen in diseases such as rheumatoid arthritis and lupus.
• Fibrosis and Inflammatory Diseases: ENPP3’s regulation of extracellular nucleotide levels has a role in tissue repair and fibrosis. In chronic inflammatory diseases, elevated ENPP3 activity may contribute to fibrosis by altering the balance of purinergic signaling, potentially leading to pathological tissue remodeling and scarring.

Summary

ENPP3, or ectonucleotide pyrophosphatase/phosphodiesterase 3, is a critical enzyme that modulates extracellular nucleotide concentrations, impacting various signaling pathways involved in immune responses, inflammation, cell proliferation, and barrier integrity. Structurally, ENPP3 is a type II transmembrane glycoprotein with distinct functional domains that enable it to hydrolyze nucleotide substrates effectively. By regulating ATP and NAD+ levels in the extracellular space, ENPP3 modulates purinergic signaling, which affects immune cell activity and tissue responses to injury. Its dysregulation is implicated in several pathologies, including allergic conditions, cancer, and autoimmune diseases, making it a potential therapeutic target for controlling inflammation and pathological tissue remodeling.