Ecto-5'-Nucleotidase | Adenosine turnover | IUPHAR Guide to IMMUNOPHARMACOLOGY

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Ecto-5'-Nucleotidase

  Target has curated data in GtoImmuPdb

Target id: 1232

Nomenclature: Ecto-5'-Nucleotidase

Abbreviated Name: NT5E

Systematic Nomenclature: CD73

Family: Adenosine turnover

Annotation status:  image of a grey circle Awaiting annotation/under development. Please contact us if you can help with annotation.  » Email us

Gene and Protein Information
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - - NT5E 5'-nucleotidase ecto
Mouse - - Nt5e 5' nucleotidase
Rat - - Nt5e 5' nucleotidase
Previous and Unofficial Names
eN | eNT | NT5 | 5' nucleotidase (CD73) | ecto-5'-nucleotidase | 5'-nucleotidase, ecto (CD73) | 5' nucleotidase, ecto | 5' nucleotidase
Database Links
BRENDA
CATH/Gene3D
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Enzyme
KEGG Gene
OMIM
SynPHARM
UniProtKB
Wikipedia
Enzyme Reaction
EC Number: 3.1.3.5
Rank order of affinity (Human)
adenosine 5'-monophosphate, 5'-GMP, 5'-inosine monophosphate, 5'-UMP > 5'-dAMP, 5'-dGMP

Download all structure-activity data for this target as a CSV file

Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Parameter Reference
PSB-0963 Rn Inhibition 6.8 pKi 2
pKi 6.8 (Ki 1.5x10-7 M) [2]
Antibodies
Key to terms and symbols Click column headers to sort
Antibody Sp. Action Affinity Parameter Reference
oleclumab Hs Binding 11.4 pKd 4
pKd 11.4 (Kd 4.2x10-12 M) [4]
Immunopharmacology Comments
Via the conversion of ADP/ATP to AMP (CD39; ENTPD1) and AMP to adenosine (CD73; NT5E) these ectonucleotidase enzymes are crucial to the regulation of purinergic signals delivered to immune cells [1]. Increased adenosine levels are reported in tumours, and drives a shift to an anti-inflammatory environment which can promote tumour growth [12]. Increasing evidence validates both of these enzymes as potential druggable targets in cancer [3,5,10].
CD73 is immunosuppressive and pro-metastatic. CD73 on tumour cells, increases extracellular adenosine levels which inhibits the function of tumour-reactive CD8+ cells via A2A adenosine receptors, and enhances tumour cell invasion and chemotaxis (the latter via A2B adenosine receptors) [10].

Anti-CD73 mAbs that target this adenosine-driven immunosuppressive pathway are being expolited for their potential to promote anti-tumour immune responses across a wide range of tumours. Bristol-Myers Squibb, MedImmune and Innate Pharma (preclinical) have ongoing anti-CD73 immuno-oncology programmes (September 2017).
Examples of clinical evaluations of anti-CD73 mAbs in patients with advanced solid tumours: MedImmune's oleclumab (MEDI9447) is being evaluated alone and in combination with anti PD-L1 mAb durvalumab (MEDI4736) in Phase 1 clinical trial NCT02503774. Bristol-Myers' BMS-986179 is being tested in combination with the anti-PD-1 mAb nivolumab (BMS-936558) in Phase 1/2 trial NCT02754141.
Immuno Process Associations
Immuno Process:  Chemotaxis & migration
GO Annotations:  Associated to 1 GO processes
GO:0007159 leukocyte cell-cell adhesion IDA
Immuno Process:  Inflammation
GO Annotations:  Associated to 1 GO processes, IEA only
click arrow to show/hide IEA associations
GO:0050728 negative regulation of inflammatory response IEA
Immuno Process:  Immune regulation
GO Annotations:  Associated to 1 GO processes, IEA only
click arrow to show/hide IEA associations
GO:0050728 negative regulation of inflammatory response IEA
General Comments
CD73 is membrane-bound extracellular enzyme that, together with CD39, plays a major role in promoting immunosuppression through the pathway that degrades adenosine triphosphate (ATP) into adenosine. CD73 performs the terminal catalytic step in conversion to adenosine. It is overexpressed in several cancer types, and this has been linked with poor prognosis in certain cancers [6-9,11,13]. Adenosine accumulation driven by this pathway in the tumour microenvironment causes immune suppression, is pro-angiogenic and stimulates tumour metastasis.

References

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1. Antonioli L, Pacher P, Vizi ES, Haskó G. (2013) CD39 and CD73 in immunity and inflammation. Trends Mol Med, 19 (6): 355-67. [PMID:23601906]

2. Baqi Y, Lee SY, Iqbal J, Ripphausen P, Lehr A, Scheiff AB, Zimmermann H, Bajorath J, Müller CE. (2010) Development of potent and selective inhibitors of ecto-5'-nucleotidase based on an anthraquinone scaffold. J. Med. Chem., 53 (5): 2076-86. [PMID:20146483]

3. Bastid J, Cottalorda-Regairaz A, Alberici G, Bonnefoy N, Eliaou JF, Bensussan A. (2013) ENTPD1/CD39 is a promising therapeutic target in oncology. Oncogene, 32 (14): 1743-51. [PMID:22751118]

4. Geoghegan JC, Diedrich G, Lu X, Rosenthal K, Sachsenmeier KF, Wu H, Dall'Acqua WF, Damschroder MM. (2016) Inhibition of CD73 AMP hydrolysis by a therapeutic antibody with a dual, non-competitive mechanism of action. MAbs, 8 (3): 454-67. [PMID:26854859]

5. Häusler SF, Del Barrio IM, Diessner J, Stein RG, Strohschein J, Hönig A, Dietl J, Wischhusen J. (2014) Anti-CD39 and anti-CD73 antibodies A1 and 7G2 improve targeted therapy in ovarian cancer by blocking adenosine-dependent immune evasion. Am J Transl Res, 6 (2): 129-39. [PMID:24489992]

6. Leclerc BG, Charlebois R, Chouinard G, Allard B, Pommey S, Saad F, Stagg J. (2016) CD73 Expression Is an Independent Prognostic Factor in Prostate Cancer. Clin. Cancer Res., 22 (1): 158-66. [PMID:26253870]

7. Loi S, Pommey S, Haibe-Kains B, Beavis PA, Darcy PK, Smyth MJ, Stagg J. (2013) CD73 promotes anthracycline resistance and poor prognosis in triple negative breast cancer. Proc. Natl. Acad. Sci. U.S.A., 110 (27): 11091-6. [PMID:23776241]

8. Lu XX, Chen YT, Feng B, Mao XB, Yu B, Chu XY. (2013) Expression and clinical significance of CD73 and hypoxia-inducible factor-1α in gastric carcinoma. World J. Gastroenterol., 19 (12): 1912-8. [PMID:23569336]

9. Ren ZH, Lin CZ, Cao W, Yang R, Lu W, Liu ZQ, Chen YM, Yang X, Tian Z, Wang LZ et al.. (2016) CD73 is associated with poor prognosis in HNSCC. Oncotarget, 7 (38): 61690-61702. [PMID:27557512]

10. Stagg J. (2012) The double-edge sword effect of anti-CD73 cancer therapy. Oncoimmunology, 1 (2): 217-218. [PMID:22720247]

11. Wang H, Lee S, Nigro CL, Lattanzio L, Merlano M, Monteverde M, Matin R, Purdie K, Mladkova N, Bergamaschi D et al.. (2012) NT5E (CD73) is epigenetically regulated in malignant melanoma and associated with metastatic site specificity. Br. J. Cancer, 106 (8): 1446-52. [PMID:22454080]

12. Wang L, Fan J, Thompson LF, Zhang Y, Shin T, Curiel TJ, Zhang B. (2011) CD73 has distinct roles in nonhematopoietic and hematopoietic cells to promote tumor growth in mice. J. Clin. Invest., 121 (6): 2371-82. [PMID:21537079]

13. Wu XR, He XS, Chen YF, Yuan RX, Zeng Y, Lian L, Zou YF, Lan N, Wu XJ, Lan P. (2012) High expression of CD73 as a poor prognostic biomarker in human colorectal cancer. J Surg Oncol, 106 (2): 130-7. [PMID:22287455]

Contributors

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How to cite this page

Detlev Boison.
Adenosine turnover: Ecto-5'-Nucleotidase. Last modified on 20/09/2017. Accessed on 19/03/2019. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetoimmunopharmacology.org/GRAC/ObjectDisplayForward?objectId=1232.