Details of the Drug Transporter (DTP)

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

• DTP Name: Excitatory amino acid transporter 3 (SLC1A1)
• Gene Name: SLC1A1
• UniProt ID: P43005 (EAA3_HUMAN)
• VARIDT ID: DTD0129
• Synonyms: DCBXA; EAAC1; EAAT3; Excitatory amino-acid carrier 1; Neuronal and epithelial glutamate transporter; SCZD18; SLC1A1; Sodium-dependent glutamate/aspartate transporter 3; Solute carrier family 1 member 1
• DTP Family: Dicarboxylate/Amino Acid:Cation (Na(+) Or H(+)) Symporter (DAACS) Family
• Tissue Specificity: Expressed in all tissues tested includingliver, muscle, testis, ovary, retinoblastoma cell line, neuronsand brain (in which there was dense expression in substantianigra, red nucleus, hippocampus and in cerebral cortical layers).
• Sequence:
  MGKPARKGCEWKRFLKNNWVLLSTVAAVVLGITTGVLVREHSNLSTLEKFYFAFPGEILM
  RMLKLIILPLIISSMITGVAALDSNVSGKIGLRAVVYYFCTTLIAVILGIVLVVSIKPGV
  TQKVGEIARTGSTPEVSTVDAMLDLIRNMFPENLVQACFQQYKTKREEVKPPSDPEMNMT
  EESFTAVMTTAISKNKTKEYKIVGMYSDGINVLGLIVFCLVFGLVIGKMGEKGQILVDFF
  NALSDATMKIVQIIMCYMPLGILFLIAGKIIEVEDWEIFRKLGLYMATVLTGLAIHSIVI
  LPLIYFIVVRKNPFRFAMGMAQALLTALMISSSSATLPVTFRCAEENNQVDKRITRFVLP
  VGATINMDGTALYEAVAAVFIAQLNDLDLGIGQIITISITATSASIGAAGVPQAGLVTMV
  IVLSAVGLPAEDVTLIIAVDWLLDRFRTMVNVLGDAFGTGIVEKLSKKELEQMDVSSEVN
  IVNPFALESTILDNEDSDTKKSYVNGGFAVDKSDTISFTQTSQF
• Function: This sodium-dependent, high-affinity amino acid transporter functions as a symporter and mediates the uptake of L-glutamate and also L-aspartate and D-aspartate. Can also transport L-cysteine. Mediates Cl(-) flux that is not coupled to amino acid transport; this avoids the accumulation of negative charges due to aspartate and Na(+) symport. Plays an important role in L-glutamate and L-aspartate reabsorption in renal tubuli. Plays a redundant role in the rapid removal of released glutamate from the synaptic cleft, which is essential for terminating the postsynaptic action of glutamate.
• Endogenous Substrate(s): Cysteine; Potassium ions; Li+; Na+; Aspartate
• TCDB ID: 2.A.23.2.3
• Gene ID: 6505
• KEGG Pathway:
  Synaptic vesicle cycle (hsa04721)
  Glutamatergic synapse (hsa04724)
  Protein digestion and absorption (hsa04974)
• Reactome Pathway:
  Transport of inorganic cations/anions and amino acids/oligopeptides (R-HSA-425393)
  Defective SLC1A1 is implicated in schizophrenia 18 (SCZD18) and dicarboxylic aminoaciduria (DCBXA) (R-HSA-5619067)
  Glutamate Neurotransmitter Release Cycle (R-HSA-210500)

Molecular Interaction Atlas (MIA) of This DTP

1 Approved Drug(s) Transported by This DTP

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
L-Glutamic Acid	DM4PUDW	Schizophrenia	6A20	Approved	[6]

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	3.25E-01	-4.27E-03	-2.17E-02
Adrenocortical carcinoma	2D11.Z	Kidney	3.97E-04	4.90E-01	9.17E-01
Alopecia	ED70	Skin from scalp	1.21E-02	1.28E-01	7.07E-01
Alzheimer's disease	8A20	Entorhinal cortex	1.55E-08	-4.68E-01	-8.91E-01
Ankylosing spondylitis	FA92.0	Pheripheral blood	2.19E-01	-5.79E-02	-5.56E-01
Aortic stenosis	BB70	Calcified aortic valve	2.01E-02	7.26E-01	1.72E+00
Apnea	7A40	Hyperplastic tonsil	3.86E-03	1.10E+00	3.31E+00
Arthropathy	FA00-FA5Z	Peripheral blood	7.47E-01	-5.64E-02	-5.30E-01
Asthma	CA23	Nasal and bronchial airway	1.05E-02	-7.06E-02	-8.44E-02
Atopic dermatitis	EA80	Skin	5.57E-03	-7.36E-02	-3.48E-01
Autism	6A02	Whole blood	9.43E-01	5.05E-04	4.05E-03
Autoimmune uveitis	9A96	Peripheral monocyte	7.34E-01	9.47E-02	5.65E-01
Autosomal dominant monocytopenia	4B04	Whole blood	4.80E-01	5.39E-02	3.45E-01
Bacterial infection of gingival	1C1H	Gingival tissue	4.81E-09	5.02E-01	1.04E+00
Batten disease	5C56.1	Whole blood	2.92E-01	9.57E-02	6.85E-01
Behcet's disease	4A62	Peripheral blood	8.99E-01	-1.58E-03	-9.60E-03
Bipolar disorder	6A60-6A6Z	Prefrontal cortex	2.67E-02	-9.28E-02	-4.11E-01
Bladder cancer	2C94	Bladder tissue	6.27E-03	-6.16E-01	-1.88E+00
Breast cancer	2C60-2C6Z	Breast tissue	1.40E-40	3.91E-01	8.56E-01
Cardioembolic stroke	8B11.20	Whole blood	8.46E-02	1.09E-01	6.10E-01
Cervical cancer	2C77	Cervical tissue	3.47E-01	-6.08E-02	-1.20E-01
Childhood onset rheumatic disease	FA20.Z	Peripheral blood	6.98E-01	-1.70E-02	-9.97E-02
Chronic hepatitis C	1E51.1	Whole blood	4.68E-01	5.81E-02	4.90E-01
Chronic obstructive pulmonary disease	CA22	Lung tissue	3.53E-01	-1.69E-01	-2.68E-01
Chronic obstructive pulmonary disease	CA22	Small airway epithelium	2.95E-01	-8.33E-02	-1.70E-01
Chronic rhinosinusitis	CA0A	Sinus mucosa tissue	6.81E-01	-1.43E-01	-3.11E-01
Colon cancer	2B90	Colon tissue	1.53E-45	-1.74E+00	-1.75E+00
Coronary artery disease	BA80-BA8Z	Peripheral blood	2.91E-01	-2.72E-01	-8.41E-01
Diffuse large B-cell lymphoma	2A81	Tonsil tissue	5.01E-01	-7.35E-02	-2.68E-01
Endometriosis	GA10	Endometrium tissue	1.77E-03	1.96E+00	1.62E+00
Familial hypercholesterolemia	5C80.00	Peripheral blood	6.34E-01	-1.33E-01	-1.64E+00
Familial hypercholesterolemia	5C80.00	Whole blood	4.61E-02	-1.33E-01	-9.86E-01
Gastric cancer	2B72	Gastric tissue	7.74E-01	3.08E-01	2.48E-01
Glioblastopma	2A00.00	Nervous tissue	1.81E-73	-1.37E+00	-1.52E+00
Glioma	2A00.0Y-2A00.0Z	White matter tissue	7.53E-01	-3.22E-01	-4.08E-01
Head and neck cancer	2D42	Head and neck tissue	4.34E-22	-1.19E+00	-1.62E+00
HIV-associated neurocognitive impairment	8A2Y-8A2Z	White matter tissue	4.16E-01	-3.09E-01	-3.86E-01
Huntington's disease	8A01.10	Whole blood	6.96E-01	-1.18E-02	-8.97E-02
Idiopathic pulmonary fibrosis	CB03.4	Lung tissue	2.99E-03	-1.14E+00	-2.44E+00
Immunodeficiency	4A00-4A20	Peripheral blood	6.21E-01	1.77E-01	5.29E-01
Influenza	1.00E+30	Whole blood	4.58E-01	1.30E-01	6.88E-01
Interstitial cystitis	GC00.3	Bladder tissue	3.61E-01	1.51E-01	1.09E+00
Intracranial aneurysm	8B01.0	Intracranial artery	1.62E-04	7.35E-01	2.94E+00
Irritable bowel syndrome	DD91.0	Rectal colon tissue	8.24E-01	-1.11E-01	-2.00E-01
Ischemic stroke	8B11	Peripheral blood	5.49E-01	2.04E-02	1.83E-01
Juvenile idiopathic arthritis	FA24	Peripheral blood	9.28E-02	7.81E-02	3.98E-01
Lateral sclerosis	8B60.4	Cervical spinal cord	6.33E-02	-3.18E-01	-6.14E-01
Lateral sclerosis	8B60.4	Skin	3.23E-02	-3.82E-01	-4.89E+00
Liver cancer	2C12.0	Liver tissue	3.44E-24	-1.69E+00	-2.34E+00
Liver failure	DB99.7-DB99.8	Liver tissue	1.18E-07	-1.97E+00	-4.76E+00
Lung cancer	2C25	Lung tissue	1.59E-89	-2.12E+00	-2.65E+00
Lupus erythematosus	4A40	Whole blood	4.15E-01	6.85E-03	2.53E-02
Major depressive disorder	6A70-6A7Z	Whole blood	1.83E-01	5.17E-02	2.54E-01
Major depressive disorder	6A70-6A7Z	Hippocampus	2.25E-01	-8.36E-02	-4.04E-01
Melanoma	2C30	Skin	6.25E-02	-2.40E-01	-2.81E-01
Multiple myeloma	2A83.1	Bone marrow	2.44E-01	-1.40E-01	-7.10E-01
Multiple myeloma	2A83.1	Peripheral blood	8.61E-02	2.96E-02	4.51E-01
Multiple sclerosis	8A40	Plasmacytoid dendritic cells	9.62E-01	-1.95E-02	-8.16E-02
Myelodysplastic syndrome	2A36-2A3Z	Bone marrow	6.27E-01	2.69E-02	2.12E-01
Myelofibrosis	2A20.2	Whole blood	1.06E-01	-4.12E-02	-3.76E-01
Myocardial infarction	BA41-BA50	Peripheral blood	2.84E-01	-7.03E-02	-1.61E-01
Myopathy	8C70.6	Muscle tissue	6.41E-02	-1.49E-01	-7.60E-01
Neonatal sepsis	KA60	Whole blood	9.61E-01	-1.10E-02	-7.21E-02
Neuroectodermal tumour	2A00.11	Brain stem tissue	6.32E-02	-5.18E-01	-1.13E+00
Non-alcoholic fatty liver disease	DB92	Liver tissue	6.12E-03	8.87E-01	1.65E+00
Obesity related type 2 diabetes	5A11	Omental adipose tissue	9.52E-01	-8.36E-02	-3.26E-01
Olive pollen allergy	CA08.00	Peripheral blood	4.25E-01	-1.20E-01	-7.25E-01
Oral cancer	2B6E	Oral tissue	1.42E-01	-1.74E-01	-3.15E-01
Osteoarthritis	FA00-FA0Z	Synovial tissue	1.55E-01	1.75E-01	1.94E-01
Osteoporosis	FB83.1	Bone marrow	3.15E-01	-4.14E-01	-2.07E+00
Ovarian cancer	2C73	Ovarian tissue	1.30E-04	6.90E-01	1.55E+00
Pancreatic cancer	2C10	Pancreas	3.51E-02	7.07E-01	7.24E-01
Parkinson's disease	8A00.0	Substantia nigra tissue	2.07E-01	-1.98E-01	-4.66E-01
Pediatric respiratory syncytial virus infection	CA40.11	Peripheral blood	3.53E-02	-1.28E-01	-9.70E-01
Pituitary cancer	2D12	Pituitary tissue	3.35E-05	-1.30E+00	-3.57E+00
Pituitary gonadotrope tumour	2D12	Pituitary tissue	2.59E-08	-1.63E+00	-6.22E+00
Polycystic ovary syndrome	5A80.1	Vastus lateralis muscle	3.80E-01	-9.01E-02	-5.97E-01
Polycythemia vera	2A20.4	Whole blood	4.10E-01	-6.85E-03	-5.15E-02
Pompe disease	5C51.3	Biceps muscle	7.95E-02	-1.38E-01	-5.57E-01
Preterm birth	KA21.4Z	Myometrium	9.10E-01	-2.65E-01	-5.03E-01
Prostate cancer	2C82	Prostate	9.73E-01	-3.57E-02	-4.65E-02
Psoriasis	EA90	Skin	1.62E-07	1.81E-01	6.26E-01
Rectal cancer	2B92	Rectal colon tissue	5.72E-04	-1.34E+00	-2.60E+00
Renal cancer	2C90-2C91	Kidney	1.67E-01	-1.99E-01	-2.07E-01
Retinoblastoma	2D02.2	Uvea	1.11E-04	-1.22E+00	-1.89E+00
Rheumatoid arthritis	FA20	Synovial tissue	1.62E-01	-2.61E-02	-3.11E-02
Rhinovirus infection	CA42.1	Nasal epithelium tissue	7.88E-01	-1.25E-01	-3.98E-01
Schizophrenia	6A20	Prefrontal cortex	1.89E-02	-4.76E-01	-2.94E-01
Schizophrenia	6A20	Superior temporal cortex	9.47E-01	7.41E-02	1.85E-01
Scleroderma	4A42.Z	Whole blood	2.20E-03	1.04E-01	1.65E+00
Seizure	8A60-8A6Z	Whole blood	9.67E-02	5.16E-02	4.81E-01
Sensitive skin	EK0Z	Skin	7.17E-01	-2.62E-02	-1.50E-01
Sepsis with septic shock	1G41	Whole blood	6.03E-01	-1.22E-02	-8.01E-02
Shwachman-Diamond syndrome	3A70.0	Bone marrow	5.78E-01	5.11E-02	3.10E-01
Sickle cell disease	3A51.0-3A51.3	Peripheral blood	1.80E-01	1.80E-01	7.32E-01
Simpson golabi behmel syndrome	LD2C	Adipose tissue	8.74E-02	6.60E-01	2.28E+00
Sjogren's syndrome	4A43.2	Salivary gland tissue	6.87E-02	5.67E-01	1.70E+00
Skin cancer	2C30-2C3Z	Skin	1.57E-02	-2.22E-01	-7.25E-01
Thrombocythemia	3B63	Whole blood	1.87E-01	-5.49E-02	-4.47E-01
Thrombocytopenia	3B64	Whole blood	6.87E-01	1.15E-01	8.60E-01
Thyroid cancer	2D10	Thyroid	5.06E-44	-1.59E+00	-2.54E+00
Tibial muscular dystrophy	8C75	Muscle tissue	1.88E-06	-4.50E-01	-1.56E+00
Tuberous sclerosis complex	LD2D.2	Perituberal tissue	1.99E-02	-9.96E-01	-2.94E+00
Type 2 diabetes	5A11	Liver tissue	9.60E-01	1.32E-01	5.61E-01
Ureter cancer	2C92	Urothelium	3.35E-01	8.68E-02	7.91E-01
Uterine cancer	2C78	Endometrium tissue	6.10E-09	-4.06E-01	-2.73E-01
Vitiligo	ED63.0	Skin	3.05E-01	4.27E-02	1.80E-01

Drug Affinity of This DTP Assessed by Cell Line

Approved Drug(s)

Drug Name	Highest Status	Cell Line	Affinity	REF
L-Glutamic Acid	Approved	Human embryonic kidney cells (HEK293)-EAAT3	Km = 9.9 microM	[7]
L-Glutamic Acid	Approved	Human embryonic kidney cells (HEK293)-EAAT3	Km = 25.0 microM	[8]

The Drug Therapeutic Target (DTT) Role of This DTP

• DTP DTT Name: Excitatory amino acid transporter 3 (SLC1A1) DTT Info
• DTP DTT Type: Literature-reported

5 Investigative Drug(s) Targeting This DTP

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
D-aspartic acid	DM7Z892	Discovery agent	N.A.	Investigative	[1]
DL-TBOA	DM2HGNU	Discovery agent	N.A.	Investigative	[2]
L-beta-BA	DMENM1B	Discovery agent	N.A.	Investigative	[3]
NBI-59159	DM7S5Y4	Discovery agent	N.A.	Investigative	[4]
[3H]ETB-TBOA	DMWGY61	Discovery agent	N.A.	Investigative	[5]

References

• [1] 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: 870).
• [2] Syntheses of optically pure beta-hydroxyaspartate derivatives as glutamate transporter blockers. Bioorg Med Chem Lett. 2000 Nov 6;10(21):2407-10.
• [3] The substituted aspartate analogue L-beta-threo-benzyl-aspartate preferentially inhibits the neuronal excitatory amino acid transporter EAAT3. Neuropharmacology. 2005 Nov;49(6):850-61.
• [4] Ligands targeting the excitatory amino acid transporters (EAATs). Curr Top Med Chem. 2006;6(17):1897-906.
• [5] Characterization of the tritium-labeled analog of L-threo-beta-benzyloxyaspartate binding to glutamate transporters. Mol Pharmacol. 2007 Jan;71(1):294-302.
• [6] Loss-of-function mutations in the glutamate transporter SLC1A1 cause human dicarboxylic aminoaciduria. J Clin Invest. 2011 Jan;121(1):446-53.
• [7] Stereoselective chemoenzymatic synthesis of the four stereoisomers of l-2-(2-carboxycyclobutyl)glycine and pharmacological characterization at human excitatory amino acid transporter subtypes 1, 2, and 3. J Med Chem. 2006 Nov 2;49(22):6532-8.
• [8] Chemoenzymatic synthesis of a series of 4-substituted glutamate analogues and pharmacological characterization at human glutamate transporters subtypes 1-3. J Med Chem. 2005 Dec 15;48(25):7980-92.