ENTPD1

Official Full Name

ectonucleoside triphosphate diphosphohydrolase 1

Organism

Homo sapiens

GeneID

953

Background

The protein encoded by this gene is a plasma membrane protein that hydrolyzes extracellular ATP and ADP to AMP. Inhibition of this protein's activity may confer anticancer benefits. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2015]

Synonyms

CD39; SPG64; ATP-DPH; ATPDase; NTPDase-1;

Bio Chemical Class

Acid anhydride hydrolase

Protein Sequence

MEDTKESNVKTFCSKNILAILGFSSIIAVIALLAVGLTQNKALPENVKYGIVLDAGSSHTSLYIYKWPAEKENDTGVVHQVEECRVKGPGISKFVQKVNEIGIYLTDCMERAREVIPRSQHQETPVYLGATAGMRLLRMESEELADRVLDVVERSLSNYPFDFQGARIITGQEEGAYGWITINYLLGKFSQKTRWFSIVPYETNNQETFGALDLGGASTQVTFVPQNQTIESPDNALQFRLYGKDYNVYTHSFLCYGKDQALWQKLAKDIQVASNEILRDPCFHPGYKKVVNVSDLYKTPCTKRFEMTLPFQQFEIQGIGNYQQCHQSILELFNTSYCPYSQCAFNGIFLPPLQGDFGAFSAFYFVMKFLNLTSEKVSQEKVTEMMKKFCAQPWEEIKTSYAGVKEKYLSEYCFSGTYILSLLLQGYHFTADSWEHIHFIGKIQGSDAGWTLGYMLNLTNMIPAEQPLSTPLSHSTYVFLMVLFSLVLFTVAIIGLLIFHKPSYFWKDMV

Open

Disease

Lymphoma, Solid tumour/cancer

Approved Drug

Clinical Trial Drug

3 +

Discontinued Drug

Cat.No.	Product Name	Price

Cat.No.	Product Name	Price

Cat.No.	Product Name	Price

Cat.No.	Product Name	Tag	Price

Cat.No.	Product Name	Price

Detailed Information

An essential enzyme in the metabolism of purine nucleotides, CD39 is produced by the ENTPD1 gene. Comprising the plasma membrane, CD39 hydrolyzes extracellular ATP and ADP into AMP, therefore controlling nucleotide levels in the extracellular space. Maintaining homeostasis in several physiological processes like inflammation, platelet aggregation, and immunological response depends on this enzymatic activity. Particularly in the framework of cancer immunology, we investigate in this paper the structure, purpose, and ramifications of CD39.

CD39's Mechanism and Structural Integrity

Calcium- and magnesium-dependent ectoenzyme CD39 catalyzes the hydrolysis of both triphosphate and diphosphate nucleotides (NTPs and NDPs). The initial step of purine metabolism, it convert ATP and ADP into AMP. Structurally, CD39 boasts two transmembrane domains, a sizable extracellular loop, and intracellular N- and C-terminal ends. Important for the stability and activity of the enzyme, the extracellular region lets CD39 connect with other enzymes, including CD73 another ectoenzyme that further hydrolyzes AMP to adenosine. It also features many glycosylation sites.

This figure illustrates the effects of targeting CD39 on T cells, showing how CD39 or CD73 blockade influences the suppressive activity of Treg cells, enhances effector and cytotoxic functions in CD8 T cells, and increases cytokine production in CD4 T cells, thereby promoting B cell differentiation. Figure 1. Effects of targeting CD39 on T cells. (London M, et al., 2020)

On the surface of many different cells—including T cells, natural killer (NK) cells, endothelial cells, and neurons—CD39 is expressed. This widespread suggests its participation in the control of inflammation and immunological responses. Functionally, by degrading ATP and ADP, CD39 controls purinergic signaling by thereby lowering their capacity to activate purinergic receptors. Both of these are vital in disease states like cancer, this helps regulate inflammation and immunological responses.

CD39 in Cancer Immunology: a Double-Edged Sword

In the tumor microenvironment (TME), CD39 controls immune reactions in a multifarious way. Purinergic receptors such as P2X and P2Y receptors are known to activate immune cells by extracellular ATP (eATP). This activation can cause inflammation and immunological reactions meant for cancer attacks. But by turning ATP into AMP and hence lowering immune cell activation, CD39's enzymatic activity inhibits the pro-inflammatory impact of ATP.

Significant immunosuppressive effects follow from CD73's additional conversion of the AMP produced by CD39 into adenosine. Adenosine reduces the activation, survival, and activity of anti-tumor T lymphocytes especially in high quantities within the TME. It also encourages the activation of immune response suppressing regulatory T cells (Tregs). Furthermore, by activating adenosine receptors on tumor cells, adenosine can induce cancer cell motility and metastases. First lowering ATP levels and subsequently producing adenosine, this combined action of CD39 and CD73 produces an immunosuppressive milieu that inhibits strong anti-tumor immunity.

CD39 has so become a potential target for cancer immunotherapy rather nicely. Reducing CD39 could help to stop ATP from hydrolysing, hence raising extracellular ATP levels. This would increase immune cell activation and thereby raise the efficacy of immunotherapies depending on the immune system to target cancer cells.

Challenges and Therapeutic Potential

Targeting CD39 for therapeutic benefit in cancer shows great promise. By raising extracellular ATP levels, inhibiting CD39 may stimulate immune cells including T cells and NK cells, hence producing more robust anti-tumor immune responses. Furthermore, inhibiting CD39 might help to lower the adenosine accumulation in the TME, so reversing the immunosuppressive actions impeding the immune system's capacity to combat cancer.

This therapeutic approach has certain difficulties, though. Among several physiological functions, CD39 is crucial in controlling blood flow and stopping too-strong platelet aggregation. Inhibition of CD39 might cause adverse effects including compromised vascular function or higher risk of thrombosis. Moreover, CD39 controls purine metabolism in many tissues, therefore its blockage may have unanticipated effects on tissue homeostasis and normal immune response.

Given these complications, focusing on CD39 calls for rigorous evaluation of its larger physiological functions. Effective treatments will have to minimize possible detrimental effects on normal physiological processes while selectively blocking CD39's immunosuppressive actions in the TME.

References:

Timperi E, Barnaba V. CD39 Regulation and Functions in T Cells. Int J Mol Sci. 2021 Jul 28;22(15):8068.
Moesta AK, Li XY, Smyth MJ. Targeting CD39 in cancer. Nat Rev Immunol. 2020 Dec;20(12):739-755.

Quick Inquiry

Interested in learning more?

Contact us today for a free consultation with the scientific team and discover how Creative Biogene can be a valuable resource and partner for your organization.

Request a quote today!

Inquiry