Details of Drug-Metabolizing Enzyme (DME)

General Information of Drug-Metabolizing Enzyme (DME) (ID: DESOEW1)

• DME Name: Dihydrothymine dehydrogenase (DPYD)
• Synonyms: Dihydropyrimidine dehydrogenase [NADP(+)]; Dihydrouracil dehydrogenase; DHPDHase; DPD; DPYD
• Gene Name: DPYD
• UniProt ID: DPYD_HUMAN
• INTEDE ID: DME0053
• Gene ID: 1806
• EC Number:
  EC: 1.3.1.2
  Oxidoreductase
  CH-CH donor oxidoreductase
  NAD/NADP acceptor oxidoreductase
  EC: 1.3.1.2
• Lineage:
  Species: Homo sapiens
  Kingdom: Metazoa
  Phylum: Chordata
  Class: Mammalia
  Order: Primates
  Family: Hominidae
  Genus: Homo
  Species: Homo sapiens
• Sequence:
  MAPVLSKDSADIESILALNPRTQTHATLCSTSAKKLDKKHWKRNPDKNCFNCEKLENNFD
  DIKHTTLGERGALREAMRCLKCADAPCQKSCPTNLDIKSFITSIANKNYYGAAKMIFSDN
  PLGLTCGMVCPTSDLCVGGCNLYATEEGPINIGGLQQFATEVFKAMSIPQIRNPSLPPPE
  KMSEAYSAKIALFGAGPASISCASFLARLGYSDITIFEKQEYVGGLSTSEIPQFRLPYDV
  VNFEIELMKDLGVKIICGKSLSVNEMTLSTLKEKGYKAAFIGIGLPEPNKDAIFQGLTQD
  QGFYTSKDFLPLVAKGSKAGMCACHSPLPSIRGVVIVLGAGDTAFDCATSALRCGARRVF
  IVFRKGFVNIRAVPEEMELAKEEKCEFLPFLSPRKVIVKGGRIVAMQFVRTEQDETGKWN
  EDEDQMVHLKADVVISAFGSVLSDPKVKEALSPIKFNRWGLPEVDPETMQTSEAWVFAGG
  DVVGLANTTVESVNDGKQASWYIHKYVQSQYGASVSAKPELPLFYTPIDLVDISVEMAGL
  KFINPFGLASATPATSTSMIRRAFEAGWGFALTKTFSLDKDIVTNVSPRIIRGTTSGPMY
  GPGQSSFLNIELISEKTAAYWCQSVTELKADFPDNIVIASIMCSYNKNDWTELAKKSEDS
  GADALELNLSCPHGMGERGMGLACGQDPELVRNICRWVRQAVQIPFFAKLTPNVTDIVSI
  ARAAKEGGANGVTATNTVSGLMGLKSDGTPWPAVGIAKRTTYGGVSGTAIRPIALRAVTS
  IARALPGFPILATGGIDSAESGLQFLHSGASVLQVCSAIQNQDFTVIEDYCTGLKALLYL
  KSIEELQDWDGQSPATVSHQKGKPVPRIAELMDKKLPSFGPYLEQRKKIIAENKIRLKEQ
  NVAFSPLKRNCFIPKRPIPTIKDVIGKALQYLGTFGELSNVEQVVAMIDEEMCINCGKCY
  MTCNDSGYQAIQFDPETHLPTITDTCTGCTLCLSVCPIVDCIKMVSRTTPYEPKRGVPLS
  VNPVC
• Function: This enzyme is involved in pyrimidine base degradation. It catalyzes the reduction of uracil and thymine and also involved the degradation of the chemotherapeutic drug 5-fluorouracil.
• KEGG Pathway:
  Drug metabolism - other enzymes (hsa00983)
  Metabolic pathways (hsa01100)
  Pantothenate and CoA biosynthesis (hsa00770)
  Pyrimidine metabolism (hsa00240)
  beta-Alanine metabolism (hsa00410)
• Reactome Pathway: Pyrimidine catabolism (R-HSA-73621)

Molecular Interaction Atlas (MIA) of This DME

1 Approved Drug(s) Metabolized by This DME

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Fluorouracil	DMUM7HZ	Adenocarcinoma	2D40	Approved	[7]

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	2.95E-10	-1.85E-01	-7.83E-01
Alopecia	ED70	Skin from scalp	9.09E-04	2.17E-01	8.20E-01
Alzheimer's disease	8A20	Entorhinal cortex	3.34E-01	-5.33E-02	-2.33E-01
Ankylosing spondylitis	FA92.0	Pheripheral blood	3.89E-01	3.82E-04	2.35E-03
Aortic stenosis	BB70	Calcified aortic valve	7.34E-01	2.11E-01	2.34E-01
Apnea	7A40	Hyperplastic tonsil	9.91E-01	4.47E-03	1.03E-02
Arthropathy	FA00-FA5Z	Peripheral blood	2.10E-02	1.83E-01	1.11E+00
Asthma	CA23	Nasal and bronchial airway	6.12E-04	-2.84E-01	-4.60E-01
Atopic dermatitis	EA80	Skin	3.60E-01	-1.36E-02	-8.06E-02
Autism	6A02	Whole blood	9.95E-01	-6.57E-02	-2.55E-01
Autoimmune uveitis	9A96	Peripheral monocyte	4.16E-01	-4.23E-02	-9.01E-02
Autosomal dominant monocytopenia	4B04	Whole blood	1.45E-01	-3.50E-01	-8.92E-01
Bacterial infection of gingival	1C1H	Gingival tissue	5.44E-01	-8.95E-03	-2.52E-02
Batten disease	5C56.1	Whole blood	5.55E-01	6.29E-02	6.03E-01
Behcet's disease	4A62	Peripheral blood	9.51E-01	-1.84E-02	-9.26E-02
Bipolar disorder	6A60-6A6Z	Prefrontal cortex	2.12E-01	-1.18E-01	-6.76E-01
Bladder cancer	2C94	Bladder tissue	3.60E-03	5.20E-01	1.98E+00
Breast cancer	2C60-2C6Z	Breast tissue	2.74E-08	-8.41E-02	-2.05E-01
Cardioembolic stroke	8B11.20	Whole blood	1.76E-05	2.69E-01	7.23E-01
Cervical cancer	2C77	Cervical tissue	2.02E-02	-1.17E-01	-4.90E-01
Childhood onset rheumatic disease	FA20.Z	Peripheral blood	4.36E-01	-1.17E-01	-1.77E-01
Chronic hepatitis C	1E51.1	Whole blood	5.43E-01	-1.64E-02	-8.01E-02
Chronic obstructive pulmonary disease	CA22	Lung tissue	2.22E-02	2.70E-01	8.27E-01
Chronic obstructive pulmonary disease	CA22	Small airway epithelium	2.50E-02	-6.57E-02	-2.88E-01
Chronic rhinosinusitis	CA0A	Sinus mucosa tissue	6.49E-01	-2.76E-03	-2.58E-02
Colon cancer	2B90	Colon tissue	1.29E-04	-8.60E-02	-3.50E-01
Coronary artery disease	BA80-BA8Z	Peripheral blood	1.81E-01	1.04E-01	7.26E-01
Diffuse large B-cell lymphoma	2A81	Tonsil tissue	4.64E-01	-7.44E-02	-1.54E-01
Endometriosis	GA10	Endometrium tissue	4.42E-01	-1.47E-02	-6.33E-02
Familial hypercholesterolemia	5C80.00	Peripheral blood	4.64E-02	-2.44E-01	-1.30E+00
Familial hypercholesterolemia	5C80.00	Whole blood	3.18E-02	-2.16E-01	-9.45E-01
Gastric cancer	2B72	Gastric tissue	7.66E-01	3.35E-02	2.61E-01
Glioblastopma	2A00.00	Nervous tissue	3.09E-07	7.26E-02	2.11E-01
Glioma	2A00.0Y-2A00.0Z	Brain stem tissue	3.81E-01	1.64E-01	8.25E-01
Glioma	2A00.0Y-2A00.0Z	White matter tissue	8.33E-01	-2.30E-04	-2.53E-04
Head and neck cancer	2D42	Head and neck tissue	9.99E-01	2.67E-03	1.12E-02
HIV-associated neurocognitive impairment	8A2Y-8A2Z	White matter tissue	2.77E-01	1.22E-01	5.87E-01
Huntington's disease	8A01.10	Whole blood	4.94E-01	6.43E-02	4.98E-01
Idiopathic pulmonary fibrosis	CB03.4	Lung tissue	7.15E-02	-2.75E-01	-7.76E-01
Immunodeficiency	4A00-4A20	Peripheral blood	1.94E-01	-7.92E-02	-6.50E-01
Influenza	1E30	Whole blood	1.19E-01	-2.52E-01	-3.40E+00
Interstitial cystitis	GC00.3	Bladder tissue	2.18E-01	-6.01E-02	-1.09E+00
Intracranial aneurysm	8B01.0	Intracranial artery	3.86E-01	7.81E-02	2.51E-01
Irritable bowel syndrome	DD91.0	Rectal colon tissue	2.38E-01	6.43E-02	2.27E-01
Ischemic stroke	8B11	Peripheral blood	3.36E-01	-4.81E-02	-1.97E-01
Juvenile idiopathic arthritis	FA24	Peripheral blood	3.05E-09	2.76E-01	7.03E-01
Lateral sclerosis	8B60.4	Skin	1.30E-01	1.93E-01	8.46E-01
Lateral sclerosis	8B60.4	Cervical spinal cord	5.45E-01	-1.56E-01	-8.80E-01
Liver cancer	2C12.0	Liver tissue	1.64E-03	-2.72E-01	-6.50E-01
Liver failure	DB99.7-DB99.8	Liver tissue	2.20E-02	-2.01E-01	-6.83E-01
Lung cancer	2C25	Lung tissue	5.42E-01	-7.54E-02	-2.16E-01
Lupus erythematosus	4A40	Whole blood	8.92E-06	1.90E-01	3.62E-01
Major depressive disorder	6A70-6A7Z	Hippocampus	7.23E-01	-1.83E-02	-9.83E-02
Major depressive disorder	6A70-6A7Z	Whole blood	3.90E-01	-1.30E-01	-2.58E-01
Melanoma	2C30	Skin	4.61E-01	7.33E-01	7.14E-01
Multiple myeloma	2A83.1	Peripheral blood	1.82E-01	2.87E-02	7.44E-02
Multiple myeloma	2A83.1	Bone marrow	7.55E-03	-2.22E-01	-1.20E+00
Multiple sclerosis	8A40	Plasmacytoid dendritic cells	2.30E-01	3.51E-01	5.74E-01
Myelodysplastic syndrome	2A36-2A3Z	Bone marrow	2.61E-01	-1.15E-01	-3.55E-01
Myelofibrosis	2A20.2	Whole blood	6.37E-01	5.36E-03	4.64E-02
Myocardial infarction	BA41-BA50	Peripheral blood	1.20E-01	2.49E-01	2.98E-01
Myopathy	8C70.6	Muscle tissue	1.83E-01	1.79E-01	6.06E-01
Neonatal sepsis	KA60	Whole blood	2.11E-08	2.09E-01	8.07E-01
Neuroectodermal tumour	2A00.11	Brain stem tissue	4.53E-04	-5.93E-01	-1.90E+00
Non-alcoholic fatty liver disease	DB92	Liver tissue	2.01E-01	2.26E-01	9.19E-01
Obesity related type 2 diabetes	5A11	Omental adipose tissue	6.86E-01	-2.60E-02	-1.13E-01
Olive pollen allergy	CA08.00	Peripheral blood	2.96E-01	1.35E-01	1.02E+00
Oral cancer	2B6E	Oral tissue	8.39E-01	2.09E-02	5.76E-02
Osteoarthritis	FA00-FA0Z	Synovial tissue	2.42E-01	9.37E-03	3.38E-02
Osteoporosis	FB83.1	Bone marrow	2.85E-01	8.38E-02	4.22E-01
Ovarian cancer	2C73	Ovarian tissue	3.33E-01	-2.27E-01	-6.51E-01
Pancreatic cancer	2C10	Pancreas	8.69E-01	6.37E-02	1.82E-01
Parkinson's disease	8A00.0	Substantia nigra tissue	5.69E-01	-9.43E-02	-5.45E-01
Pediatric respiratory syncytial virus infection	CA40.11	Peripheral blood	6.33E-03	2.59E-01	1.05E+00
Pituitary cancer	2D12	Pituitary tissue	1.92E-01	2.12E-01	4.18E-01
Pituitary gonadotrope tumour	2D12	Pituitary tissue	6.30E-04	6.94E-01	2.24E+00
Polycystic ovary syndrome	5A80.1	Vastus lateralis muscle	3.43E-01	8.70E-02	6.27E-01
Polycythemia vera	2A20.4	Whole blood	2.62E-01	-1.46E-02	-1.15E-01
Pompe disease	5C51.3	Biceps muscle	5.58E-01	-4.04E-02	-2.68E-01
Preterm birth	KA21.4Z	Myometrium	8.30E-01	1.79E-02	2.48E-01
Prostate cancer	2C82	Prostate	3.25E-05	-1.08E+00	-1.60E+00
Psoriasis	EA90	Skin	1.95E-05	-2.33E-01	-5.49E-01
Rectal cancer	2B92	Rectal colon tissue	2.67E-01	-1.08E-01	-4.85E-01
Renal cancer	2C90-2C91	Kidney	8.62E-01	-4.15E-02	-1.82E-01
Retinoblastoma	2D02.2	Uvea	1.96E-01	1.04E-01	5.78E-01
Rheumatoid arthritis	FA20	Synovial tissue	4.79E-02	2.20E-01	8.05E-01
Rhinovirus infection	CA42.1	Nasal epithelium tissue	2.24E-01	3.90E-02	2.93E-01
Schizophrenia	6A20	Prefrontal cortex	4.35E-03	1.21E-01	2.85E-01
Schizophrenia	6A20	Superior temporal cortex	3.29E-01	1.08E-01	5.04E-01
Scleroderma	4A42.Z	Whole blood	1.85E-05	4.21E-01	2.70E+00
Seizure	8A60-8A6Z	Whole blood	9.83E-01	-1.55E-01	-5.97E-01
Sensitive skin	EK0Z	Skin	6.30E-01	2.37E-02	1.11E-01
Sepsis with septic shock	1G41	Whole blood	7.14E-14	1.95E-01	7.75E-01
Shwachman-Diamond syndrome	3A70.0	Bone marrow	5.96E-02	7.60E-01	1.47E+00
Sickle cell disease	3A51.0-3A51.3	Peripheral blood	2.43E-02	3.25E-01	1.40E+00
Simpson golabi behmel syndrome	LD2C	Adipose tissue	4.35E-01	8.57E-02	4.76E-01
Sjogren's syndrome	4A43.2	Salivary gland tissue	8.30E-01	8.70E-02	5.13E-01
Skin cancer	2C30-2C3Z	Skin	1.48E-02	1.24E-01	2.31E-01
Thrombocythemia	3B63	Whole blood	4.02E-01	-6.80E-02	-6.00E-01
Thrombocytopenia	3B64	Whole blood	2.07E-01	7.67E-02	5.75E-01
Thyroid cancer	2D10	Thyroid	4.34E-03	1.29E-01	4.82E-01
Tibial muscular dystrophy	8C75	Muscle tissue	4.80E-01	1.30E-02	8.58E-02
Tuberous sclerosis complex	LD2D.2	Perituberal tissue	6.45E-01	1.00E-01	4.28E-01
Type 2 diabetes	5A11	Liver tissue	4.57E-01	-6.94E-02	-2.74E-01
Ureter cancer	2C92	Urothelium	5.08E-01	-1.05E-01	-2.41E-01
Uterine cancer	2C78	Endometrium tissue	6.47E-06	-2.46E-01	-6.47E-01
Vitiligo	ED63.0	Skin	8.48E-01	-5.91E-03	-1.41E-02

The Drug Therapeutic Target (DTT) Role of This DME

• DME DTT Name: Dihydrothymine dehydrogenase (DPYD) DTT Info
• DME DTT Type: Successful

1 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Fluorouracil	DMUM7HZ	Adenocarcinoma	2D40	Approved	[1]

2 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Eniluracil	DM96NCR	Hyperlipidaemia	5C80	Phase 2	[2]
RO-09-4889	DMQ65YW	Solid tumour/cancer	2A00-2F9Z	Phase 1	[3]

1 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
FL-386	DMUQN83	Hyperlipidaemia	5C80	Discontinued in Phase 2	[4]

5 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
(5s)-5-Iododihydro-2,4(1h,3h)-Pyrimidinedione	DMA5DO2	Discovery agent	N.A.	Investigative	[5]
5-Iodouracil	DM4O6I5	Discovery agent	N.A.	Investigative	[5]
6-Carboxymethyluracil	DM9MPDK	Discovery agent	N.A.	Investigative	[5]
Flavin-Adenine Dinucleotide	DM5S4GK	Discovery agent	N.A.	Investigative	[5]
Uracil	DMNPO9Q	Discovery agent	N.A.	Investigative	[6]

References

• [1] Enhancement of the antitumour activity of 5-fluorouracil (5-FU) by inhibiting dihydropyrimidine dehydrogenase activity (DPD) using 5-chloro-2,4-dihydroxypyridine (CDHP) in human tumour cells. Eur J Cancer. 2002 Jun;38(9):1271-7.
• [2] Eniluracil: an irreversible inhibitor of dihydropyrimidine dehydrogenase. Expert Opin Investig Drugs. 2000 Jul;9(7):1635-49.
• [3] Single ascending dose tolerability, pharmacokinetic-pharmacodynamic study of dihydropyrimidine dehydrogenase inhibitor Ro 09-4889. Clin Cancer Res. 2004 Apr 1;10(7):2327-35.
• [4] Effects of FL-386 on faecal lipid excretion in humans. J Int Med Res. 1993 Sep-Oct;21(5):225-33.
• [5] How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6.
• [6] The ChEMBL database in 2017. Nucleic Acids Res. 2017 Jan 4;45(D1):D945-D954.
• [7] 5-Fluorouracil toxicity-attributable IVS14 + 1G > A mutation of the dihydropyrimidine dehydrogenase gene in Polish colorectal cancer patients. Pharmacol Rep. 2008 Mar-Apr;60(2):238-42.