Details of the Drug Transporter (DTP)

General Information of Drug Transporter (DTP) (ID: DTXD1TQ)

• DTP Name: Equilibrative nucleoside transporter 1 (SLC29A1)
• Gene Name: SLC29A1
• UniProt ID: Q99808 (S29A1_HUMAN)
• VARIDT ID: DTD0247
• Synonyms: ENT1; Equilibrative NBMPR-sensitive nucleoside transporter; Equilibrative nitrobenzylmercaptopurine riboside-sensitive nucleoside transporter; Nucleoside transporter, es-type; SLC29A1; Solute carrier family 29 member 1
• DTP Family: Equilibrative Nucleoside Transporter (ENT) Family
• Tissue Specificity: Detected in erythrocytes (at protein level).Expressed in heart, brain, mammary gland, erythrocytes andplacenta, and also in fetal liver and spleen.
• Sequence:
  MTTSHQPQDRYKAVWLIFFMLGLGTLLPWNFFMTATQYFTNRLDMSQNVSLVTAELSKDA
  QASAAPAAPLPERNSLSAIFNNVMTLCAMLPLLLFTYLNSFLHQRIPQSVRILGSLVAIL
  LVFLITAILVKVQLDALPFFVITMIKIVLINSFGAILQGSLFGLAGLLPASYTAPIMSGQ
  GLAGFFASVAMICAIASGSELSESAFGYFITACAVIILTIICYLGLPRLEFYRYYQQLKL
  EGPGEQETKLDLISKGEEPRAGKEESGVSVSNSQPTNESHSIKAILKNISVLAFSVCFIF
  TITIGMFPAVTVEVKSSIAGSSTWERYFIPVSCFLTFNIFDWLGRSLTAVFMWPGKDSRW
  LPSLVLARLVFVPLLLLCNIKPRRYLTVVFEHDAWFIFFMAAFAFSNGYLASLCMCFGPK
  KVKPAEAETAGAIMAFFLCLGLALGAVFSFLFRAIV
• Function: This transporter mediates both influx and efflux of nucleosides across the membrane (equilibrative transporter). It is sensitive (ES) to low concentrations of the inhibitor nitrobenzylmercaptopurine riboside (NBMPR) and is sodium-independent. It has a higher affinity for adenosine. Inhibited by dipyridamole and dilazep (anticancer chemotherapeutics drugs).
• Endogenous Substrate(s): Nucleosides
• TCDB ID: 2.A.57.1.1
• Gene ID: 2030
• Reactome Pathway:
  Azathioprine ADME (R-HSA-9748787)
  Transport of nucleosides and free purine and pyrimidine bases across the plasma membrane (R-HSA-83936)

Molecular Interaction Atlas (MIA) of This DTP

8 Approved Drug(s) Transported by This DTP

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Adenosine	DMM2NSK	Paroxysmal supraventricular tachycardia	BC81.Z	Approved	[9]
Clofarabine	DMCVJ86	Acute lymphoblastic leukaemia	2A85	Approved	[10]
Cytarabine	DMZD5QR	Acute lymphoblastic leukaemia	2A85	Approved	[11]
Entecavir	DM7VTQO	Hepatitis B virus infection	1E51.0	Approved	[12]
Fluorouracil	DMUM7HZ	Solid tumour/cancer	2A00-2F9Z	Approved	[13]
Mercaptopurine	DMTM2IK	Acute lymphoblastic leukaemia	2A85	Approved	[14]
Ribavirin	DMEYLH9	Hepatitis C virus infection	1E51.1	Approved	[15]
Trifluridine	DMG2YBD	Virus infection	1A24-1D9Z	Approved	[16]

1 Discontinued Drug(s) Transported by This DTP

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Tecadenoson	DM9T6MS	Atrial fibrillation	BC81.3	Discontinued in Phase 3	[17]

Molecular Expression Atlas (MEA) of This DTP

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Acute myelocytic leukaemia	2B33.1	Bone marrow	6.37E-03	-1.14E-01	-1.83E-01
Adrenocortical carcinoma	2D11.Z	Kidney	4.20E-01	-1.66E-01	-2.81E-01
Alopecia	ED70	Skin from scalp	6.01E-02	5.43E-02	1.63E-01
Alzheimer's disease	8A20	Entorhinal cortex	1.69E-03	-2.16E-01	-4.23E-01
Ankylosing spondylitis	FA92.0	Pheripheral blood	8.65E-01	4.41E-02	1.16E-01
Aortic stenosis	BB70	Calcified aortic valve	3.34E-01	1.08E-01	2.63E-01
Apnea	7A40	Hyperplastic tonsil	5.71E-01	-9.59E-02	-5.22E-01
Arthropathy	FA00-FA5Z	Peripheral blood	2.77E-01	2.22E-01	7.68E-01
Asthma	CA23	Nasal and bronchial airway	4.77E-05	-2.20E-01	-5.03E-01
Atopic dermatitis	EA80	Skin	6.37E-04	-3.52E-01	-8.78E-01
Autism	6A02	Whole blood	8.16E-01	-1.00E-01	-3.44E-01
Autoimmune uveitis	9A96	Peripheral monocyte	5.83E-01	-1.86E-01	-8.85E-01
Autosomal dominant monocytopenia	4B04	Whole blood	3.53E-01	-6.06E-01	-8.07E-01
Bacterial infection of gingival	1C1H	Gingival tissue	3.74E-11	3.78E-01	1.13E+00
Batten disease	5C56.1	Whole blood	3.78E-01	-2.50E-02	-2.13E-01
Behcet's disease	4A62	Peripheral blood	4.60E-02	2.49E-01	9.06E-01
Bipolar disorder	6A60-6A6Z	Prefrontal cortex	5.26E-01	-2.42E-01	-5.21E-01
Bladder cancer	2C94	Bladder tissue	2.91E-01	-1.35E-01	-3.75E-01
Breast cancer	2C60-2C6Z	Breast tissue	3.25E-15	-5.51E-01	-6.83E-01
Cardioembolic stroke	8B11.20	Whole blood	4.56E-05	-5.78E-01	-1.12E+00
Cervical cancer	2C77	Cervical tissue	5.59E-04	5.12E-02	2.62E-01
Childhood onset rheumatic disease	FA20.Z	Peripheral blood	9.48E-01	2.61E-01	1.95E-01
Chronic hepatitis C	1E51.1	Whole blood	4.97E-01	7.09E-02	3.66E-01
Chronic obstructive pulmonary disease	CA22	Lung tissue	3.03E-01	-1.62E-01	-3.70E-01
Chronic obstructive pulmonary disease	CA22	Small airway epithelium	3.00E-05	-5.37E-01	-8.67E-01
Chronic rhinosinusitis	CA0A	Sinus mucosa tissue	5.96E-01	4.65E-02	1.59E-01
Colon cancer	2B90	Colon tissue	8.03E-98	1.38E+00	3.31E+00
Coronary artery disease	BA80-BA8Z	Peripheral blood	8.56E-01	2.22E-02	1.01E-01
Diffuse large B-cell lymphoma	2A81	Tonsil tissue	8.60E-01	-7.50E-02	-3.77E-01
Endometriosis	GA10	Endometrium tissue	2.02E-02	2.49E-01	6.58E-01
Familial hypercholesterolemia	5C80.00	Peripheral blood	3.83E-01	2.88E-03	1.92E-02
Familial hypercholesterolemia	5C80.00	Whole blood	9.07E-01	-5.13E-02	-2.62E-01
Gastric cancer	2B72	Gastric tissue	1.98E-01	-1.35E+00	-1.06E+00
Glioblastopma	2A00.00	Nervous tissue	1.64E-10	-3.20E-01	-5.39E-01
Glioma	2A00.0Y-2A00.0Z	White matter tissue	2.53E-02	-3.90E-01	-9.15E-01
Head and neck cancer	2D42	Head and neck tissue	8.93E-08	3.80E-01	7.77E-01
HIV-associated neurocognitive impairment	8A2Y-8A2Z	White matter tissue	9.56E-01	-1.18E-01	-2.55E-01
Huntington's disease	8A01.10	Whole blood	4.91E-01	-1.02E-02	-7.68E-02
Idiopathic pulmonary fibrosis	CB03.4	Lung tissue	1.77E-02	3.13E-01	2.53E+00
Immunodeficiency	4A00-4A20	Peripheral blood	3.26E-03	9.38E-02	1.46E+00
Influenza	1.00E+30	Whole blood	3.74E-01	-1.69E-01	-3.53E-01
Interstitial cystitis	GC00.3	Bladder tissue	1.83E-01	-2.49E-01	-7.73E-01
Intracranial aneurysm	8B01.0	Intracranial artery	5.38E-01	-3.67E-01	-5.43E-01
Irritable bowel syndrome	DD91.0	Rectal colon tissue	2.64E-01	-3.41E-02	-1.67E-01
Ischemic stroke	8B11	Peripheral blood	1.62E-01	-2.59E-01	-1.18E+00
Juvenile idiopathic arthritis	FA24	Peripheral blood	8.21E-03	-5.15E-02	-1.10E-01
Lateral sclerosis	8B60.4	Cervical spinal cord	2.42E-01	2.11E-01	7.03E-01
Lateral sclerosis	8B60.4	Skin	2.36E-01	2.56E-01	9.70E-01
Liver cancer	2C12.0	Liver tissue	6.71E-02	2.97E-02	4.20E-02
Liver failure	DB99.7-DB99.8	Liver tissue	3.73E-04	3.82E-01	2.27E+00
Lung cancer	2C25	Lung tissue	4.12E-06	-2.73E-01	-5.38E-01
Lupus erythematosus	4A40	Whole blood	1.24E-01	-1.02E-01	-2.42E-01
Major depressive disorder	6A70-6A7Z	Whole blood	1.43E-01	1.55E-01	3.80E-01
Major depressive disorder	6A70-6A7Z	Hippocampus	8.91E-01	-1.25E-01	-2.70E-01
Melanoma	2C30	Skin	1.51E-02	5.48E-01	6.46E-01
Multiple myeloma	2A83.1	Bone marrow	1.24E-03	-3.01E-01	-2.00E+00
Multiple myeloma	2A83.1	Peripheral blood	5.50E-01	-1.81E-01	-6.17E-01
Multiple sclerosis	8A40	Plasmacytoid dendritic cells	7.28E-01	1.90E-01	3.49E-01
Myelodysplastic syndrome	2A36-2A3Z	Bone marrow	9.62E-01	8.38E-02	2.61E-01
Myelofibrosis	2A20.2	Whole blood	2.99E-03	-1.86E-01	-1.40E+00
Myocardial infarction	BA41-BA50	Peripheral blood	5.71E-01	1.22E-01	3.04E-01
Myopathy	8C70.6	Muscle tissue	1.80E-03	-4.27E-01	-1.93E+00
Neonatal sepsis	KA60	Whole blood	4.70E-01	-6.36E-02	-2.59E-01
Neuroectodermal tumour	2A00.11	Brain stem tissue	1.36E-06	-7.39E-01	-3.19E+00
Non-alcoholic fatty liver disease	DB92	Liver tissue	1.11E-01	1.27E-01	3.17E-01
Obesity related type 2 diabetes	5A11	Omental adipose tissue	2.89E-01	1.02E-01	4.97E-01
Olive pollen allergy	CA08.00	Peripheral blood	4.23E-02	1.73E-01	1.67E+00
Oral cancer	2B6E	Oral tissue	1.11E-01	-2.47E-01	-3.32E-01
Osteoarthritis	FA00-FA0Z	Synovial tissue	4.51E-01	6.95E-01	6.63E-01
Osteoporosis	FB83.1	Bone marrow	1.44E-01	4.08E-01	6.00E-01
Ovarian cancer	2C73	Ovarian tissue	6.07E-01	-1.75E-01	-1.70E-01
Pancreatic cancer	2C10	Pancreas	1.50E-01	2.34E-01	5.51E-01
Parkinson's disease	8A00.0	Substantia nigra tissue	4.81E-01	-4.55E-02	-3.15E-01
Pediatric respiratory syncytial virus infection	CA40.11	Peripheral blood	1.39E-02	1.78E-01	7.04E-01
Pituitary cancer	2D12	Pituitary tissue	1.32E-06	1.15E+00	2.87E+00
Pituitary gonadotrope tumour	2D12	Pituitary tissue	5.00E-06	8.99E-01	2.52E+00
Polycystic ovary syndrome	5A80.1	Vastus lateralis muscle	5.94E-02	1.48E-01	4.82E-01
Polycythemia vera	2A20.4	Whole blood	6.31E-05	-1.62E-01	-9.31E-01
Pompe disease	5C51.3	Biceps muscle	8.78E-02	-3.52E-01	-1.40E+00
Preterm birth	KA21.4Z	Myometrium	9.35E-01	3.97E-02	2.45E-01
Prostate cancer	2C82	Prostate	9.00E-03	-2.43E-01	-6.24E-01
Psoriasis	EA90	Skin	2.54E-19	-8.31E-01	-1.34E+00
Rectal cancer	2B92	Rectal colon tissue	1.74E-03	7.89E-01	1.94E+00
Renal cancer	2C90-2C91	Kidney	7.40E-02	-1.90E-01	-5.11E-01
Retinoblastoma	2D02.2	Uvea	3.82E-02	-7.36E-01	-1.94E+00
Rheumatoid arthritis	FA20	Synovial tissue	1.25E-27	1.67E+00	1.40E+01
Rhinovirus infection	CA42.1	Nasal epithelium tissue	1.92E-01	-2.60E-02	-1.02E-01
Schizophrenia	6A20	Prefrontal cortex	9.20E-02	-2.71E-01	-5.82E-01
Schizophrenia	6A20	Superior temporal cortex	6.96E-01	2.04E-03	7.09E-03
Scleroderma	4A42.Z	Whole blood	5.00E-02	3.71E-01	1.22E+00
Seizure	8A60-8A6Z	Whole blood	1.47E-01	-6.84E-02	-2.45E-01
Sensitive skin	EK0Z	Skin	6.93E-01	5.59E-03	2.75E-02
Sepsis with septic shock	1G41	Whole blood	3.60E-07	-1.10E-01	-4.55E-01
Shwachman-Diamond syndrome	3A70.0	Bone marrow	7.06E-01	8.78E-02	2.46E-01
Sickle cell disease	3A51.0-3A51.3	Peripheral blood	9.39E-02	5.85E-02	3.67E-01
Simpson golabi behmel syndrome	LD2C	Adipose tissue	3.69E-01	-1.43E-01	-5.17E-01
Sjogren's syndrome	4A43.2	Salivary gland tissue	2.97E-01	2.58E-01	7.83E-01
Skin cancer	2C30-2C3Z	Skin	4.58E-08	-4.93E-01	-8.30E-01
Thrombocythemia	3B63	Whole blood	3.34E-03	-7.29E-02	-5.37E-01
Thrombocytopenia	3B64	Whole blood	4.83E-01	3.42E-01	7.38E-01
Thyroid cancer	2D10	Thyroid	8.02E-02	-1.67E-01	-3.17E-01
Tibial muscular dystrophy	8C75	Muscle tissue	1.49E-01	-5.25E-01	-7.68E-01
Tuberous sclerosis complex	LD2D.2	Perituberal tissue	4.85E-03	-5.02E-01	-2.41E+00
Type 2 diabetes	5A11	Liver tissue	7.38E-01	7.06E-02	1.73E-01
Ureter cancer	2C92	Urothelium	8.32E-01	-2.55E-03	-1.26E-02
Uterine cancer	2C78	Endometrium tissue	9.37E-07	-3.92E-01	-7.16E-01
Vitiligo	ED63.0	Skin	6.07E-01	2.92E-02	8.11E-02

Drug Affinity of This DTP Assessed by Cell Line

Discontinued Drug(s)

Drug Name	Highest Status	Cell Line	Affinity	REF
Tecadenoson	Discontinued in Phase 3	CCRF-CEM cells-ENT1	Km = 24 microM	[17]
Tecadenoson	Discontinued in Phase 3	Oocytes-ENT1	Km = 196 microM	[17]

The Drug Therapeutic Target (DTT) Role of This DTP

• DTP DTT Name: Solute carrier family 29 member 1 (SLC29A1) DTT Info
• DTP DTT Type: Successful
• Related Disease: Angina pectoris [ICD-11: BA40]

1 Approved Drug(s) Targeting This DTP

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Lidoflazine	DMV23GL	Angina pectoris	BA40	Approved	[1]

9 Investigative Drug(s) Targeting This DTP

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
6-(4-Nitro-benzylsulfanyl)-9-phenethyl-9H-purine	DMPL5XV	Discovery agent	N.A.	Investigative	[2]
9-Benzyl-6-(4-nitro-benzylsulfanyl)-9H-purine	DMNY5P1	Discovery agent	N.A.	Investigative	[2]
Dilazep	DMOD5Y0	Discovery agent	N.A.	Investigative	[3]
KF24345	DMK6SMW	Discovery agent	N.A.	Investigative	[4]
N6-cyclopentyladenosine	DMD6AJO	Discovery agent	N.A.	Investigative	[5]
NBTGR	DMVF420	Discovery agent	N.A.	Investigative	[6]
Nitrobenzylthioinosine	DM7F3RY	Discovery agent	N.A.	Investigative	[7]
S6-nitrobenzyl mercaptopurine riboside	DMIKJNL	Discovery agent	N.A.	Investigative	[8]
[3H]nitrobenzylmercaptopurine ribonucleoside	DM5TDFQ	Discovery agent	N.A.	Investigative	[6]

References

• [1] Synthesis, flow cytometric evaluation, and identification of highly potent dipyridamole analogues as equilibrative nucleoside transporter 1 inhibit... J Med Chem. 2007 Aug 9;50(16):3906-20.
• [2] Inhibition of nucleoside transport by new analogues of 4-nitrobenzylthioinosine: replacement of the ribose moiety by substituted benzyl groups. J Med Chem. 2004 Oct 21;47(22):5441-50.
• [3] Residues Met89 and Ser160 in the human equilibrative nucleoside transporter 1 affect its affinity for adenosine, guanosine, S6-(4-nitrobenzyl)-merc... Mol Pharmacol. 2005 Mar;67(3):837-44.
• [4] Interaction of the novel adenosine uptake inhibitor 3-[1-(6,7-diethoxy-2-morpholinoquinazolin-4-yl)piperidin-4-yl]-1,6-dimethyl-2,4(1H,3H)-quinazol... J Pharmacol Exp Ther. 2004 Mar;308(3):1083-93.
• [5] Inhibition of nucleoside transport proteins by C8-alkylamine-substituted purines. J Med Chem. 2005 Jan 13;48(1):321-9.
• [6] URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Target id: 1117).
• [7] The role of human nucleoside transporters in uptake of 3'-deoxy-3'-fluorothymidine. Mol Pharmacol. 2008 Nov;74(5):1372-80.
• [8] Synthesis and biological evaluation of phloridzin analogs as human concentrative nucleoside transporter 3 (hCNT3) inhibitors. Bioorg Med Chem Lett. 2009 Feb 1;19(3):917-21.
• [9] Nitric oxide reduces adenosine transporter ENT1 gene (SLC29A1) promoter activity in human fetal endothelium from gestational diabetes. J Cell Physiol. 2006 Aug;208(2):451-60.
• [10] Cytarabine-resistant leukemia cells are moderately sensitive to clofarabine in vitro. Anticancer Res. 2014 Apr;34(4):1657-62.
• [11] FLT3 is implicated in cytarabine transport by human equilibrative nucleoside transporter 1 in pediatric acute leukemia. Oncotarget. 2016 Aug 2;7(31):49786-49799.
• [12] Multiple SLC and ABC Transporters Contribute to the Placental Transfer of Entecavir. Drug Metab Dispos. 2017 Mar;45(3):269-278.
• [13] Human equilibrative nucleoside transporter 1, as a predictor of 5-fluorouracil resistance in human pancreatic cancer. Anticancer Res. 2007 Jul-Aug;27(4B):2241-9.
• [14] PharmGKB: A worldwide resource for pharmacogenomic information. Wiley Interdiscip Rev Syst Biol Med. 2018 Jul;10(4):e1417. (ID: PA2040)
• [15] Effects of dipyridamole coadministration on the pharmacokinetics of ribavirin in healthy volunteers. Drug Metab Pharmacokinet. 2013;28(5):406-10.
• [16] Lonsurf, INN-trifluridine/tipiracil.
• [17] Transport of A1 adenosine receptor agonist tecadenoson by human and mouse nucleoside transporters: evidence for blood-brain barrier transport by murine equilibrative nucleoside transporter 1 mENT1. Drug Metab Dispos. 2013 Apr;41(4):916-22.