Details of Drug-Metabolizing Enzyme (DME)

General Information of Drug-Metabolizing Enzyme (DME) (ID: DE4EGMZ)

• DME Name: Dihydrofolate reductase (DHFR)
• Synonyms: Tetrahydrofolate:NADP+ oxidoreductase; 5,6,7,8-tetrahydrofolate:NADP+ oxidoreductase; 7,8-dihydrofolate reductase; DHFR
• Gene Name: DHFR
• UniProt ID: DYR_HUMAN
• INTEDE ID: DME0141
• Gene ID: 1719
• EC Number:
  EC: 1.5.1.3
  Oxidoreductase
  CH-NH donor oxidoreductase
  NAD/NADP acceptor oxidoreductase
  EC: 1.5.1.3
• Lineage:
  Species: Homo sapiens
  Kingdom: Metazoa
  Phylum: Chordata
  Class: Mammalia
  Order: Primates
  Family: Hominidae
  Genus: Homo
  Species: Homo sapiens
• Sequence:
  MVGSLNCIVAVSQNMGIGKNGDLPWPPLRNEFRYFQRMTTTSSVEGKQNLVIMGKKTWFS
  IPEKNRPLKGRINLVLSRELKEPPQGAHFLSRSLDDALKLTEQPELANKVDMVWIVGGSS
  VYKEAMNHPGHLKLFVTRIMQDFESDTFFPEIDLEKYKLLPEYPGVLSDVQEEKGIKYKF
  EVYEKND
• Function: This enzyme converts dihydrofolate into tetrahydrofolate, a methyl group shuttle required for the de novo synthesis of pyrimidines, thymidylic acid, and certain amino acids.
• KEGG Pathway:
  Antifolate resistance (hsa01523)
  Folate biosynthesis (hsa00790)
  Metabolic pathways (hsa01100)
  One carbon pool by folate (hsa00670)
• Reactome Pathway:
  Metabolism of folate and pterines (R-HSA-196757)
  Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation (R-HSA-1474151)
  G1/S-Specific Transcription (R-HSA-69205)

Molecular Interaction Atlas (MIA) of This DME

2 Approved Drug(s) Metabolized by This DME

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Folic acid	DMEMBJC	Folate-deficiency anemia	3A02.Y	Approved	[11]
Methotrexate	DM2TEOL	leukaemia	2A60-2B33	Approved	[12]

Molecular Expression Atlas (MEA) of This DME

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Acute myelocytic leukaemia	2B33.1	Bone marrow	8.87E-16	-5.39E-01	-8.56E-01
Alopecia	ED70	Skin from scalp	9.82E-02	-3.11E-02	-1.85E-01
Alzheimer's disease	8A20	Entorhinal cortex	9.97E-06	2.63E-01	6.12E-01
Ankylosing spondylitis	FA92.0	Pheripheral blood	8.14E-02	2.67E-01	8.72E-01
Aortic stenosis	BB70	Calcified aortic valve	2.25E-01	3.23E-01	8.44E-01
Apnea	7A40	Hyperplastic tonsil	1.94E-02	2.32E-01	1.04E+00
Arthropathy	FA00-FA5Z	Peripheral blood	3.04E-01	-1.31E-01	-6.30E-01
Asthma	CA23	Nasal and bronchial airway	2.56E-06	6.64E-01	9.73E-01
Atopic dermatitis	EA80	Skin	4.55E-03	3.10E-01	9.20E-01
Autism	6A02	Whole blood	7.53E-01	7.30E-02	2.57E-01
Autoimmune uveitis	9A96	Peripheral monocyte	6.45E-02	-2.60E-01	-1.20E+00
Autosomal dominant monocytopenia	4B04	Whole blood	3.70E-02	6.97E-01	1.57E+00
Bacterial infection of gingival	1C1H	Gingival tissue	6.64E-04	-1.72E-01	-4.23E-01
Batten disease	5C56.1	Whole blood	1.03E-01	-2.05E-01	-2.28E+00
Behcet's disease	4A62	Peripheral blood	9.77E-01	1.72E-01	4.75E-01
Bipolar disorder	6A60-6A6Z	Prefrontal cortex	2.21E-01	4.78E-02	1.44E-01
Bladder cancer	2C94	Bladder tissue	5.11E-06	9.72E-01	3.88E+00
Breast cancer	2C60-2C6Z	Breast tissue	1.40E-12	3.01E-01	4.46E-01
Cardioembolic stroke	8B11.20	Whole blood	1.25E-01	-1.60E-01	-4.69E-01
Cervical cancer	2C77	Cervical tissue	2.51E-09	1.23E+00	2.60E+00
Childhood onset rheumatic disease	FA20.Z	Peripheral blood	9.39E-01	6.99E-02	1.76E-01
Chronic hepatitis C	1E51.1	Whole blood	7.12E-01	6.17E-03	1.83E-02
Chronic obstructive pulmonary disease	CA22	Lung tissue	3.71E-02	-2.26E-01	-6.77E-01
Chronic obstructive pulmonary disease	CA22	Small airway epithelium	7.33E-02	-5.51E-02	-1.97E-01
Chronic rhinosinusitis	CA0A	Sinus mucosa tissue	5.89E-04	7.54E-01	2.94E+00
Colon cancer	2B90	Colon tissue	1.35E-17	4.30E-01	8.72E-01
Coronary artery disease	BA80-BA8Z	Peripheral blood	6.64E-01	-9.22E-02	-1.92E-01
Diffuse large B-cell lymphoma	2A81	Tonsil tissue	8.86E-01	3.80E-01	6.35E-01
Endometriosis	GA10	Endometrium tissue	3.09E-04	-7.24E-01	-9.75E-01
Familial hypercholesterolemia	5C80.00	Peripheral blood	6.44E-01	1.97E-01	4.47E-01
Familial hypercholesterolemia	5C80.00	Whole blood	8.87E-01	4.63E-02	2.65E-01
Gastric cancer	2B72	Gastric tissue	3.18E-02	1.13E+00	2.64E+00
Glioblastopma	2A00.00	Nervous tissue	1.13E-151	1.18E+00	2.03E+00
Glioma	2A00.0Y-2A00.0Z	Brain stem tissue	2.39E-02	2.70E-01	2.69E+00
Glioma	2A00.0Y-2A00.0Z	White matter tissue	2.33E-01	-3.39E-01	-3.39E-01
Head and neck cancer	2D42	Head and neck tissue	6.81E-11	3.91E-01	8.03E-01
HIV-associated neurocognitive impairment	8A2Y-8A2Z	White matter tissue	4.25E-01	1.21E-01	2.46E-01
Huntington's disease	8A01.10	Whole blood	2.35E-01	-8.25E-02	-4.29E-01
Idiopathic pulmonary fibrosis	CB03.4	Lung tissue	4.18E-02	4.27E-01	1.03E+00
Immunodeficiency	4A00-4A20	Peripheral blood	1.49E-03	3.99E-01	2.06E+00
Influenza	1E30	Whole blood	5.88E-01	2.27E-01	9.82E-01
Interstitial cystitis	GC00.3	Bladder tissue	3.39E-01	2.16E-01	7.33E-01
Intracranial aneurysm	8B01.0	Intracranial artery	6.72E-01	7.70E-03	2.14E-02
Irritable bowel syndrome	DD91.0	Rectal colon tissue	2.12E-01	-4.70E-02	-1.30E-01
Ischemic stroke	8B11	Peripheral blood	4.52E-01	2.72E-02	7.98E-02
Juvenile idiopathic arthritis	FA24	Peripheral blood	7.67E-01	7.31E-03	2.26E-02
Lateral sclerosis	8B60.4	Skin	9.36E-01	-1.75E-02	-2.87E-02
Lateral sclerosis	8B60.4	Cervical spinal cord	2.32E-02	-1.87E-01	-9.31E-01
Liver cancer	2C12.0	Liver tissue	6.78E-02	-4.27E-01	-6.43E-01
Liver failure	DB99.7-DB99.8	Liver tissue	4.60E-01	-2.74E-01	-8.39E-01
Lung cancer	2C25	Lung tissue	1.50E-76	8.84E-01	2.11E+00
Lupus erythematosus	4A40	Whole blood	1.39E-06	1.82E-01	4.16E-01
Major depressive disorder	6A70-6A7Z	Hippocampus	7.55E-01	-1.21E-01	-3.63E-01
Major depressive disorder	6A70-6A7Z	Whole blood	3.22E-01	-5.01E-02	-1.75E-01
Melanoma	2C30	Skin	2.71E-01	4.84E-02	6.79E-02
Multiple myeloma	2A83.1	Peripheral blood	3.92E-01	-1.16E-01	-1.02E-01
Multiple myeloma	2A83.1	Bone marrow	3.32E-05	4.72E-01	2.60E+00
Multiple sclerosis	8A40	Plasmacytoid dendritic cells	2.52E-01	-3.40E-01	-8.69E-01
Myelodysplastic syndrome	2A36-2A3Z	Bone marrow	6.08E-02	-1.75E-01	-3.44E-01
Myelofibrosis	2A20.2	Whole blood	6.39E-03	8.89E-01	5.14E+00
Myocardial infarction	BA41-BA50	Peripheral blood	9.29E-01	1.29E-01	2.48E-01
Myopathy	8C70.6	Muscle tissue	2.17E-01	3.08E-02	4.68E-02
Neonatal sepsis	KA60	Whole blood	5.12E-07	3.15E-01	8.34E-01
Neuroectodermal tumour	2A00.11	Brain stem tissue	1.53E-08	1.78E+00	4.59E+00
Non-alcoholic fatty liver disease	DB92	Liver tissue	7.10E-01	1.43E-01	4.11E-01
Obesity related type 2 diabetes	5A11	Omental adipose tissue	5.01E-01	1.43E-01	4.08E-01
Olive pollen allergy	CA08.00	Peripheral blood	1.31E-01	9.17E-02	7.74E-01
Oral cancer	2B6E	Oral tissue	4.93E-01	9.02E-02	1.89E-01
Osteoarthritis	FA00-FA0Z	Synovial tissue	4.75E-01	5.57E-01	6.31E-01
Osteoporosis	FB83.1	Bone marrow	1.94E-02	-1.19E+00	-1.47E+00
Ovarian cancer	2C73	Ovarian tissue	2.32E-07	1.29E+00	4.41E+00
Pancreatic cancer	2C10	Pancreas	3.20E-04	9.88E-01	1.27E+00
Parkinson's disease	8A00.0	Substantia nigra tissue	1.82E-02	2.82E-01	1.23E+00
Pediatric respiratory syncytial virus infection	CA40.11	Peripheral blood	6.58E-04	3.16E-01	9.54E-01
Pituitary cancer	2D12	Pituitary tissue	2.29E-01	-4.65E-02	-1.06E-01
Pituitary gonadotrope tumour	2D12	Pituitary tissue	6.45E-01	-3.35E-02	-6.35E-02
Polycystic ovary syndrome	5A80.1	Vastus lateralis muscle	2.58E-01	2.09E-01	5.95E-01
Polycythemia vera	2A20.4	Whole blood	3.21E-01	5.71E-02	3.38E-01
Pompe disease	5C51.3	Biceps muscle	4.01E-01	-6.49E-02	-1.47E-01
Preterm birth	KA21.4Z	Myometrium	2.64E-01	1.62E-01	4.64E-01
Prostate cancer	2C82	Prostate	7.84E-07	1.32E+00	1.98E+00
Psoriasis	EA90	Skin	1.68E-28	9.65E-01	1.77E+00
Rectal cancer	2B92	Rectal colon tissue	3.19E-01	1.59E-01	5.51E-01
Renal cancer	2C90-2C91	Kidney	1.96E-01	1.31E-02	2.36E-02
Retinoblastoma	2D02.2	Uvea	3.85E-06	1.08E+00	2.50E+00
Rheumatoid arthritis	FA20	Synovial tissue	1.08E-02	3.79E-01	1.46E+00
Rhinovirus infection	CA42.1	Nasal epithelium tissue	1.81E-01	-6.23E-02	-2.07E-01
Schizophrenia	6A20	Prefrontal cortex	2.12E-01	1.36E-01	4.00E-01
Schizophrenia	6A20	Superior temporal cortex	6.09E-01	-4.58E-02	-3.25E-01
Scleroderma	4A42.Z	Whole blood	2.54E-01	8.17E-02	3.39E-01
Seizure	8A60-8A6Z	Whole blood	5.52E-01	7.55E-02	1.22E-01
Sensitive skin	EK0Z	Skin	2.40E-01	2.05E-01	1.27E+00
Sepsis with septic shock	1G41	Whole blood	7.65E-25	4.43E-01	1.13E+00
Shwachman-Diamond syndrome	3A70.0	Bone marrow	1.75E-02	-2.07E-01	-8.17E-01
Sickle cell disease	3A51.0-3A51.3	Peripheral blood	7.19E-01	8.93E-03	1.06E-01
Simpson golabi behmel syndrome	LD2C	Adipose tissue	3.44E-01	5.00E-02	5.46E-01
Sjogren's syndrome	4A43.2	Salivary gland tissue	8.61E-01	-1.44E-01	-1.58E+00
Skin cancer	2C30-2C3Z	Skin	2.46E-51	1.14E+00	1.64E+00
Thrombocythemia	3B63	Whole blood	4.44E-01	1.05E-01	5.97E-01
Thrombocytopenia	3B64	Whole blood	4.59E-01	2.90E-02	4.09E-02
Thyroid cancer	2D10	Thyroid	1.82E-05	2.43E-01	4.79E-01
Tibial muscular dystrophy	8C75	Muscle tissue	1.29E-03	8.10E-01	1.49E+00
Tuberous sclerosis complex	LD2D.2	Perituberal tissue	4.25E-01	3.14E-01	3.21E+00
Type 2 diabetes	5A11	Liver tissue	4.11E-01	2.06E-01	7.56E-01
Ureter cancer	2C92	Urothelium	1.69E-01	1.38E-01	6.22E-01
Uterine cancer	2C78	Endometrium tissue	6.99E-09	7.88E-01	7.71E-01
Vitiligo	ED63.0	Skin	6.38E-01	-1.50E-01	-4.42E-01

The Drug Therapeutic Target (DTT) Role of This DME

• DME DTT Name: Dihydrofolate reductase (DHFR) DTT Info
• DME DTT Type: Successful

4 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Aminosalicylic acid	DMENSL5	Inflammatory bowel disease	DD72	Approved	[1]
Leucovorin Calcium	DMNWZJG	Solid tumour/cancer	2A00-2F9Z	Approved	[2]
Methotrexate Sodium	DM5XH2C	Solid tumour/cancer	2A00-2F9Z	Approved	[1]
Trimethoprim	DMM7CHK	Urinary tract infection	GC08	Approved	[1]

6 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Iclaprim	DM7YNV9	Bacterial infection	1A00-1C4Z	Phase 3	[3]
CH-4051	DMLQRYH	Rheumatoid arthritis	FA20	Phase 2	[4]
Piritrexim	DM276N1	Bladder cancer	2C94	Phase 2	[5]
L-MDAM	DMU901D	Solid tumour/cancer	2A00-2F9Z	Phase 1	[6]
MDAM (y-methylene-10-deazaaminopterin)	DM1DISM	Solid tumour/cancer	2A00-2F9Z	Phase 1	[7]
VYR 006	DMC9N7D	Toxoplasmosis	1F57	Phase 1	[8]

1 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
TNP-351	DMW05DS	Solid tumour/cancer	2A00-2F9Z	Discontinued in Phase 2	[9]

1 Preclinical Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
1954U89	DM503DN	Solid tumour/cancer	2A00-2F9Z	Preclinical	[10]

References

• [1] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
• [2] Biochemical factors in the selectivity of leucovorin rescue: selective inhibition of leucovorin reactivation of dihydrofolate reductase and leucovorin utilization in purine and pyrimidine biosynthesis by methotrexate and dihydrofolate polyglutamates.NCI Monogr.1987;(5):17-26.
• [3] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [4] CH-1504, a metabolically inert antifolate for the potential treatment of rheumatoid arthritis. IDrugs. 2010 Aug;13(8):559-67.
• [5] Structural variations of piritrexim, a lipophilic inhibitor of human dihydrofolate reductase: synthesis, antitumor activity and molecular modeling ... Eur J Med Chem. 2004 Dec;39(12):1079-88.
• [6] Polyglutamylation of the dihydrofolate reductase inhibitor gamma-methylene-10-deazaaminopterin is not essential for antitumor activity. Clin Cancer Res. 1996 Apr;2(4):707-12.
• [7] Evaluation of the importance of hydrophobic interactions in drug binding to dihydrofolate reductase. J Med Chem. 1988 Jan;31(1):129-37.
• [8] Clinical pipeline report, company report or official report of Vyera Pharmaceuticals.
• [9] A Ring-Transformation/Ring-Annulation Strategy for the Synthesis of the DHFR Inhibitor, TNP-351: A Correction. J Org Chem. 1996 Nov 1;61(22):7973-7974.
• [10] The pharmacokinetics of 1954U89, 1,3-diamino-7-(1-ethylpropyl)-8-methyl-7H-pyrrolo-(3,2-f)quinazoline, in dogs and rats after intravenous and oral administration. Biopharm Drug Dispos. 1997 Jul;18(5):433-42.
• [11] The dihydrofolate reductase 19 bp polymorphism is not associated with biomarkers of folate status in healthy young adults, irrespective of folic acid intake. J Nutr. 2015 Oct;145(10):2207-11.
• [12] The pharmacogenetics of methotrexate. Rheumatology (Oxford). 2007 Oct;46(10):1520-4.