ENPP3

Official Full Name

ectonucleotide pyrophosphatase/phosphodiesterase 3

Organism

Homo sapiens

GeneID

5169

Background

The protein encoded by this gene belongs to a series of ectoenzymes that are involved in hydrolysis of extracellular nucleotides. These ectoenzymes possess ATPase and ATP pyrophosphatase activities and are type II transmembrane proteins. Expression of the related rat mRNA has been found in a subset of immature glial cells and in the alimentary tract. The corresponding rat protein has been detected in the pancreas, small intestine, colon, and liver. The human mRNA is expressed in glioma cells, prostate, and uterus. Expression of the human protein has been detected in uterus, basophils, and mast cells. Two transcript variants, one protein coding and the other non-protein coding, have been found for this gene. [provided by RefSeq, Oct 2015]

Synonyms

B10; NPP3; PDNP3; CD203c; PD-IBETA;

Bio Chemical Class

Phosphoric diester hydrolase

Protein Sequence

MESTLTLATEQPVKKNTLKKYKIACIVLLALLVIMSLGLGLGLGLRKLEKQGSCRKKCFDASFRGLENCRCDVACKDRGDCCWDFEDTCVESTRIWMCNKFRCGETRLEASLCSCSDDCLQRKDCCADYKSVCQGETSWLEENCDTAQQSQCPEGFDLPPVILFSMDGFRAEYLYTWDTLMPNINKLKTCGIHSKYMRAMYPTKTFPNHYTIVTGLYPESHGIIDNNMYDVNLNKNFSLSSKEQNNPAWWHGQPMWLTAMYQGLKAATYFWPGSEVAINGSFPSIYMPYNGSVPFEERISTLLKWLDLPKAERPRFYTMYFEEPDSSGHAGGPVSARVIKALQVVDHAFGMLMEGLKQRNLHNCVNIILLADHGMDQTYCNKMEYMTDYFPRINFFYMYEGPAPRIRAHNIPHDFFSFNSEEIVRNLSCRKPDQHFKPYLTPDLPKRLHYAKNVRIDKVHLFVDQQWLAVRSKSNTNCGGGNHGYNNEFRSMEAIFLAHGPSFKEKTEVEPFENIEVYNLMCDLLRIQPAPNNGTHGSLNHLLKVPFYEPSHAEEVSKFSVCGFANPLPTESLDCFCPHLQNSTQLEQVNQMLNLTQEEITATVKVNLPFGRPRVLQKNVDHCLLYHREYVSGFGKAMRMPMWSSYTVPQLGDTSPLPPTVPDCLRADVRVPPSESQKCSFYLADKNITHGFLYPPASNRTSDSQYDALITSNLVPMYEEFRKMWDYFHSVLLIKHATERNGVNVVSGPIFDYNYDGHFDAPDEITKHLANTDVPIPTHYFVVLTSCKNKSHTPENCPGWLDVLPFIIPHRPTNVESCPEGKPEALWVEERFTAHIARVRDVELLTGLDFYQDKVQPVSEILQLKTYLPTFETTI

Open

Disease

Renal cell carcinoma

Approved Drug

Clinical Trial Drug

1 +

Discontinued Drug

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Detailed Information

ENPP3 (Ectonucleotide Pyrophosphatase/Phosphodiesterase 3) is a significant type II transmembrane protein, with its extracellular portion composed of a nuclease-like domain, a catalytic domain, and a somatomedin B-like domain. This protein primarily participates in the hydrolysis of extracellular nucleotides, metabolizing ATP, GTP, UTP, and CTP, and possesses ATPase and ATP pyrophosphatase activities. Such metabolic functions are vital in various cellular physiological activities, particularly playing key roles in immune regulation and glycosylation biosynthesis.

The expression pattern of ENPP3 varies significantly among species and tissues. In humans, this gene is highly expressed in glioma cells, the prostate, and the uterus, while its protein is predominantly found in the uterus, basophils, and mast cells. By hydrolyzing extracellular ATP, ENPP3 limits the overactivation of basophils and mast cells in inflammation, thereby alleviating chronic allergic responses. In the intestines, ENPP3 prevents ATP-induced apoptosis of plasmacytoid dendritic cells through ATP metabolism, thus maintaining the integrity of the intestinal immune barrier.

Molecular Mechanism and Multifunctionality of ENPP3

ENPP3 is capable not only of hydrolyzing ATP but also other extracellular diadenosine polyphosphates, including vasoreactive adenosine polyphosphates. Additionally, it exhibits alkaline phosphodiesterase activity and demonstrates the ability to hydrolyze nucleotide sugars such as UDP-GlcNAc and UDP-GalNAc in vitro. This broad substrate specificity enables ENPP3 to regulate glycosylation processes, indirectly affecting the modification and function of cell surface receptors and molecules. Through its regulation of metabolic networks, ENPP3 has regulatory roles in the immune system and may be involved in the pathogenesis of metabolic diseases.

Another key function of ENPP3 is its involvement in allergy regulation. By clearing extracellular ATP, it reduces autocrine activation of basophils and mast cells, offering protective effects in chronic allergic diseases. Moreover, its activity in the intestines contributes to maintaining intestinal homeostasis, inhibiting inflammation-induced cell death. These characteristics make ENPP3 an important target in inflammation and allergy research.

Figure 1 presents a hypothetical model illustrating how ENPP3 modulates glycan biosynthesis by degrading nucleotide sugars, potentially inhibiting glycosyltransferases through substrate reduction and inhibitory hydrolysis products like NMP. Figure 1. A hypothetical model of the ENPP3-mediated modulation of glycan biosynthesis. (Korekane H, et al., 2013)

Role of ENPP3 in Chronic Myeloid Leukemia

ENPP3 has been identified as a specific marker for basophils in Chronic Myeloid Leukemia (CML), a malignancy characterized by the abnormal proliferation of myeloid cells, notably marked by a significant increase in basophils. However, due to the immature and hypo granular nature of basophils in patients, traditional detection methods struggle to accurately quantify them. Research indicates that ENPP3 expression is significantly higher in basophils of CML patients compared to normal individuals, providing a novel tool for CML diagnosis and a foundation for developing targeted therapeutic strategies.

Additionally, the detection of CD203c+ vesicles in serum has shown high sensitivity and accuracy in diagnosing hypersensitivity reactions (HR) during perioperative periods. CD203c is a synonym for ENPP3, and its increased expression serves as a biomarker for diagnosing and predicting the prognosis of HR, offering new insights into early identification and management of drug hypersensitivity reactions.

Drug Development and Clinical Research Targeting ENPP3

In drug development targeting ENPP3, Xencor's XmAb-819, and Agensys's AGS-16C3 are currently the only drugs advancing to clinical trial phases.

XmAb-819 is a "2+1" bispecific antibody designed with two binding domains targeting ENPP3 and one CD3-targeting T cell binding domain. By activating T cells, XmAb-819 efficiently kills tumor cells expressing ENPP3 and activates the patient's immune system. Its bispecific structure is optimized by Xencor's XmAb platform, offering a long half-life and high stability. The drug is currently undergoing a Phase I clinical trial in patients with advanced renal cell carcinoma.

AGS-16C3F is an ADC targeting ENPP3, with its antibody conjugated to the microtubule inhibitor MMAF via a non-cleavable linker. Upon entry into tumor cells, MMAF releases active drug fragments upon cleavage, inhibiting cancer cell division and ultimately leading to cell death. Although a Phase II study in patients with metastatic renal cell carcinoma did not meet the expected efficacy, this research provided valuable insights for ADC applications in other cancers.

Future Applications of ENPP3 in Disease Treatment

As a crucial enzyme in extracellular ATP metabolism, ENPP3 possesses broad physiological functions and clinical application potential. Its regulatory role in inflammatory and allergic diseases offers possibilities for developing novel treatment methods. Additionally, as a specific marker for basophils in CML, ENPP3 can be utilized in disease diagnosis and classification, particularly for basophil quantification. While current drug research targeting ENPP3 is in its early stages, its potential in cancer immunotherapy has garnered widespread attention. Future research focusing on its structure and function is expected to develop more innovative drugs targeting ENPP3, providing new options for treating cancer, allergic diseases, and inflammatory conditions.

References:

Borza R, Salgado-Polo F, et al. Structure and function of the ecto-nucleotide pyrophosphatase/phosphodiesterase (ENPP) family: Tidying up diversity. J Biol Chem. 2022 Feb;298(2):101526.
Kabashima K, Nakashima C, et al. Biomarkers for evaluation of mast cell and basophil activation. Immunol Rev. 2018 Mar;282(1):114-120.
Korekane H, Park JY, et al. Identification of ectonucleotide pyrophosphatase/phosphodiesterase 3 (ENPP3) as a regulator of N-acetylglucosaminyltransferase GnT-IX (GnT-Vb). J Biol Chem. 2013;288(39):27912-27926.

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