Details of Drug-Metabolizing Enzyme (DME)

General Information of Drug-Metabolizing Enzyme (DME) (ID: DEFQ8VO)

• DME Name: Thiopurine methyltransferase (TPMT)
• Synonyms: Thiopurine S-methyltransferase; Thiopurine-methyl transferase; Thiopurinemethyltransferase; TPMT
• Gene Name: TPMT
• UniProt ID: TPMT_HUMAN
• INTEDE ID: DME0014
• Gene ID: 7172
• EC Number:
  EC: 2.1.1.67
  Transferase
  Methylase
  Methyltransferase
  EC: 2.1.1.67
• Lineage:
  Species: Homo sapiens
  Kingdom: Metazoa
  Phylum: Chordata
  Class: Mammalia
  Order: Primates
  Family: Hominidae
  Genus: Homo
  Species: Homo sapiens
• Sequence:
  MDGTRTSLDIEEYSDTEVQKNQVLTLEEWQDKWVNGKTAFHQEQGHQLLKKHLDTFLKGK
  SGLRVFFPLCGKAVEMKWFADRGHSVVGVEISELGIQEFFTEQNLSYSEEPITEIPGTKV
  FKSSSGNISLYCCSIFDLPRTNIGKFDMIWDRGALVAINPGDRKCYADTMFSLLGKKFQY
  LLCVLSYDPTKHPGPPFYVPHAEIERLFGKICNIRCLEKVDAFEERHKSWGIDCLFEKLY
  LLTEK
• Function: This enzyme catalyzes the S-methylation of thiopurine drugs such as 6- mercaptopurine (also called mercaptopurine, 6-MP or its brand name Purinethol) and 6-thioguanine (also called tioguanine or 6-TG) using S- adenosyl-L-methionine as the methyl donor. TPMT activity modulates the cytotoxic effects of thiopurine prodrugs. A natural substrate for this enzyme has yet to be identified.
• Reactome Pathway:
  Methylation (R-HSA-156581)
  Defective TPMT causes Thiopurine S-methyltransferase deficiency (TPMT deficiency) (R-HSA-5578995)

Molecular Interaction Atlas (MIA) of This DME

15 Approved Drug(s) Metabolized by This DME

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Ademetionine	DMYQDBO	Hepatic fibrosis	DB93.0	Approved	[1]
Azathioprine	DMMZSXQ	Organ transplant rejection	NE84	Approved	[2]
Captopril	DM458UM	Hypertension	BA00-BA04	Approved	[3]
Cefazolin	DMPDYFR	Bacterial infection	1A00-1C4Z	Approved	[4]
Epinephrine	DM3KJBC	Allergy	4A80-4A85	Approved	[5]
Ergotidine	DM78IME	Respiratory allergy	4A80	Approved	[6]
Estradiol	DMUNTE3	Breast cancer	2C60-2C65	Approved	[7]
Isoproterenol	DMK7MEY	Heart block	BC63	Approved	[8]
Levodopa	DMN3E57	Parkinson disease	8A00.0	Approved	[9]
Mercaptopurine	DMTM2IK	Acute lymphoblastic leukaemia	2A85	Approved	[10]
Methotrexate	DM2TEOL	leukaemia	2A60-2B33	Approved	[11]
Methyldopa	DM5I621	Hypertension	BA00-BA04	Approved	[8]
Tamoxifen	DMLB0EZ	Breast cancer	2C60-2C65	Approved	[12]
Thioguanine	DM7NKEV	Acute myeloid leukaemia	2A60	Approved	[13]
Vitamin C	DMXJ7O8	Vitamin C deficiency	5B56	Approved	[14]

Experimental Enzyme Kinetic Data of Drugs

Drug Name	Indication	Highest Status	Kinetic Data	REF
Thioguanine	Acute myeloid leukaemia [2A60]	Approved	Km = 0.0152 microM	[15]

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	1.08E-03	6.02E-02	2.02E-01
Alopecia	ED70	Skin from scalp	8.24E-02	2.09E-01	5.98E-01
Alzheimer's disease	8A20	Entorhinal cortex	1.32E-01	-6.42E-02	-2.31E-01
Ankylosing spondylitis	FA92.0	Pheripheral blood	4.73E-01	3.09E-02	1.29E-01
Aortic stenosis	BB70	Calcified aortic valve	8.52E-01	7.51E-02	1.15E-01
Apnea	7A40	Hyperplastic tonsil	1.69E-01	-4.58E-01	-3.65E+00
Arthropathy	FA00-FA5Z	Peripheral blood	1.48E-01	-8.39E-02	-4.98E-01
Asthma	CA23	Nasal and bronchial airway	8.88E-08	4.84E-01	6.89E-01
Atopic dermatitis	EA80	Skin	7.45E-01	3.17E-02	2.03E-01
Autism	6A02	Whole blood	5.01E-01	4.09E-02	1.52E-01
Autoimmune uveitis	9A96	Peripheral monocyte	1.52E-01	-1.41E-01	-6.81E-01
Autosomal dominant monocytopenia	4B04	Whole blood	2.27E-03	4.19E-01	2.27E+00
Bacterial infection of gingival	1C1H	Gingival tissue	2.63E-09	-2.53E-01	-1.02E+00
Batten disease	5C56.1	Whole blood	9.66E-01	3.25E-02	1.91E-01
Behcet's disease	4A62	Peripheral blood	2.50E-01	8.86E-02	3.64E-01
Bipolar disorder	6A60-6A6Z	Prefrontal cortex	8.67E-01	7.03E-03	2.15E-02
Bladder cancer	2C94	Bladder tissue	6.89E-02	1.07E-01	8.13E-01
Breast cancer	2C60-2C6Z	Breast tissue	7.91E-20	1.86E-01	6.50E-01
Cardioembolic stroke	8B11.20	Whole blood	2.80E-04	2.48E-01	1.11E+00
Cervical cancer	2C77	Cervical tissue	8.17E-03	-3.01E-01	-1.09E+00
Childhood onset rheumatic disease	FA20.Z	Peripheral blood	7.20E-01	5.81E-02	9.55E-02
Chronic hepatitis C	1E51.1	Whole blood	2.90E-02	-1.53E-01	-6.70E-01
Chronic obstructive pulmonary disease	CA22	Lung tissue	8.08E-02	-7.84E-02	-3.53E-01
Chronic obstructive pulmonary disease	CA22	Small airway epithelium	4.19E-01	2.45E-02	8.50E-02
Chronic rhinosinusitis	CA0A	Sinus mucosa tissue	2.77E-01	-1.64E-01	-5.66E-01
Colon cancer	2B90	Colon tissue	5.80E-51	-6.88E-01	-1.84E+00
Coronary artery disease	BA80-BA8Z	Peripheral blood	3.54E-01	4.04E-01	5.17E-01
Diffuse large B-cell lymphoma	2A81	Tonsil tissue	3.95E-01	8.25E-02	1.64E-01
Endometriosis	GA10	Endometrium tissue	3.98E-02	-8.85E-02	-3.36E-01
Familial hypercholesterolemia	5C80.00	Peripheral blood	3.15E-01	1.63E-01	9.75E-01
Familial hypercholesterolemia	5C80.00	Whole blood	1.83E-04	4.86E-01	1.56E+00
Gastric cancer	2B72	Gastric tissue	1.34E-02	7.63E-01	3.55E+00
Glioblastopma	2A00.00	Nervous tissue	1.77E-66	-4.82E-01	-1.14E+00
Glioma	2A00.0Y-2A00.0Z	Brain stem tissue	3.44E-01	3.04E-01	1.09E+00
Glioma	2A00.0Y-2A00.0Z	White matter tissue	6.77E-06	1.07E+00	2.19E+00
Head and neck cancer	2D42	Head and neck tissue	1.27E-13	3.17E-01	1.15E+00
HIV-associated neurocognitive impairment	8A2Y-8A2Z	White matter tissue	9.29E-01	-2.09E-02	-5.23E-02
Huntington's disease	8A01.10	Whole blood	7.94E-01	-8.26E-02	-1.80E-01
Idiopathic pulmonary fibrosis	CB03.4	Lung tissue	6.31E-01	-5.54E-02	-8.54E-01
Immunodeficiency	4A00-4A20	Peripheral blood	2.82E-01	7.33E-02	5.29E-01
Influenza	1E30	Whole blood	1.37E-02	1.89E-01	5.11E+00
Interstitial cystitis	GC00.3	Bladder tissue	1.01E-01	-1.26E-01	-1.05E+00
Intracranial aneurysm	8B01.0	Intracranial artery	5.30E-04	5.68E-01	2.51E+00
Irritable bowel syndrome	DD91.0	Rectal colon tissue	9.44E-01	-1.19E-01	-1.84E-01
Ischemic stroke	8B11	Peripheral blood	6.23E-01	-7.85E-02	-2.28E-01
Juvenile idiopathic arthritis	FA24	Peripheral blood	2.24E-04	-2.83E-01	-6.58E-01
Lateral sclerosis	8B60.4	Skin	1.62E-02	2.72E-01	2.58E+00
Lateral sclerosis	8B60.4	Cervical spinal cord	8.22E-01	-2.95E-01	-7.48E-01
Liver cancer	2C12.0	Liver tissue	1.34E-15	-7.66E-01	-1.74E+00
Liver failure	DB99.7-DB99.8	Liver tissue	4.02E-06	-1.61E+00	-1.01E+01
Lung cancer	2C25	Lung tissue	6.30E-20	2.24E-01	9.09E-01
Lupus erythematosus	4A40	Whole blood	2.29E-01	8.94E-02	2.54E-01
Major depressive disorder	6A70-6A7Z	Hippocampus	7.77E-01	-1.39E-01	-4.43E-01
Major depressive disorder	6A70-6A7Z	Whole blood	4.23E-01	-9.44E-02	-1.56E-01
Melanoma	2C30	Skin	8.64E-01	2.12E-02	3.36E-02
Multiple myeloma	2A83.1	Peripheral blood	2.81E-01	-1.49E-01	-6.38E-01
Multiple myeloma	2A83.1	Bone marrow	2.10E-03	4.35E-01	1.44E+00
Multiple sclerosis	8A40	Plasmacytoid dendritic cells	8.48E-01	-1.76E-01	-5.49E-01
Myelodysplastic syndrome	2A36-2A3Z	Bone marrow	6.32E-06	3.76E-01	1.01E+00
Myelofibrosis	2A20.2	Whole blood	5.08E-02	1.50E-01	9.85E-01
Myocardial infarction	BA41-BA50	Peripheral blood	4.08E-01	2.71E-02	3.99E-02
Myopathy	8C70.6	Muscle tissue	9.81E-01	6.11E-03	4.14E-02
Neonatal sepsis	KA60	Whole blood	3.14E-05	1.43E-01	6.76E-01
Neuroectodermal tumour	2A00.11	Brain stem tissue	3.45E-01	1.78E-01	4.90E-01
Non-alcoholic fatty liver disease	DB92	Liver tissue	1.16E-01	1.90E-01	8.80E-01
Obesity related type 2 diabetes	5A11	Omental adipose tissue	8.87E-02	-8.93E-02	-6.33E-01
Olive pollen allergy	CA08.00	Peripheral blood	9.90E-01	-1.21E-01	-3.24E-01
Oral cancer	2B6E	Oral tissue	2.14E-01	5.04E-03	1.26E-02
Osteoarthritis	FA00-FA0Z	Synovial tissue	3.23E-02	2.10E-01	1.00E+00
Osteoporosis	FB83.1	Bone marrow	1.06E-01	-5.76E-01	-8.98E-01
Ovarian cancer	2C73	Ovarian tissue	1.18E-03	4.98E-01	1.31E+00
Pancreatic cancer	2C10	Pancreas	6.92E-01	-4.99E-02	-9.90E-02
Parkinson's disease	8A00.0	Substantia nigra tissue	7.06E-01	-1.87E-01	-5.89E-01
Pediatric respiratory syncytial virus infection	CA40.11	Peripheral blood	3.74E-04	3.12E-01	1.48E+00
Pituitary cancer	2D12	Pituitary tissue	1.57E-02	5.61E-01	1.54E+00
Pituitary gonadotrope tumour	2D12	Pituitary tissue	6.33E-01	4.41E-02	9.90E-02
Polycystic ovary syndrome	5A80.1	Vastus lateralis muscle	1.02E-01	-5.87E-02	-4.83E-01
Polycythemia vera	2A20.4	Whole blood	2.10E-13	3.48E-01	2.15E+00
Pompe disease	5C51.3	Biceps muscle	6.44E-02	-2.80E-01	-9.05E-01
Preterm birth	KA21.4Z	Myometrium	8.63E-01	4.53E-02	7.53E-02
Prostate cancer	2C82	Prostate	5.59E-01	2.02E-01	3.88E-01
Psoriasis	EA90	Skin	8.68E-04	1.45E-01	4.43E-01
Rectal cancer	2B92	Rectal colon tissue	6.30E-04	-5.56E-01	-2.26E+00
Renal cancer	2C90-2C91	Kidney	9.39E-02	-2.54E-01	-4.53E-01
Retinoblastoma	2D02.2	Uvea	6.65E-04	5.66E-01	1.86E+00
Rheumatoid arthritis	FA20	Synovial tissue	1.02E-02	-4.35E-01	-1.68E+00
Rhinovirus infection	CA42.1	Nasal epithelium tissue	8.44E-01	2.37E-03	2.02E-02
Schizophrenia	6A20	Prefrontal cortex	1.72E-02	-7.07E-02	-2.00E-01
Schizophrenia	6A20	Superior temporal cortex	8.62E-01	-1.86E-02	-8.58E-02
Scleroderma	4A42.Z	Whole blood	3.59E-01	1.01E-01	6.71E-01
Seizure	8A60-8A6Z	Whole blood	6.93E-01	3.61E-02	1.12E-01
Sensitive skin	EK0Z	Skin	4.35E-01	-4.37E-02	-2.40E-01
Sepsis with septic shock	1G41	Whole blood	5.77E-03	-7.06E-02	-3.57E-01
Shwachman-Diamond syndrome	3A70.0	Bone marrow	6.64E-01	-1.50E-01	-7.87E-01
Sickle cell disease	3A51.0-3A51.3	Peripheral blood	5.22E-02	-2.11E-01	-7.47E-01
Simpson golabi behmel syndrome	LD2C	Adipose tissue	1.49E-01	-1.26E-01	-7.07E-01
Sjogren's syndrome	4A43.2	Salivary gland tissue	2.24E-01	2.21E-01	1.09E+00
Skin cancer	2C30-2C3Z	Skin	6.18E-13	2.96E-01	8.76E-01
Thrombocythemia	3B63	Whole blood	4.71E-06	3.32E-01	2.19E+00
Thrombocytopenia	3B64	Whole blood	1.14E-01	-2.93E-01	-7.36E-01
Thyroid cancer	2D10	Thyroid	1.30E-19	-7.34E-01	-1.29E+00
Tibial muscular dystrophy	8C75	Muscle tissue	4.51E-03	-3.40E-01	-1.26E+00
Tuberous sclerosis complex	LD2D.2	Perituberal tissue	1.12E-02	-3.72E-01	-4.19E+00
Type 2 diabetes	5A11	Liver tissue	4.52E-01	1.18E-03	3.75E-03
Ureter cancer	2C92	Urothelium	7.57E-01	1.39E-02	6.22E-02
Uterine cancer	2C78	Endometrium tissue	1.30E-08	2.87E-01	7.16E-01
Vitiligo	ED63.0	Skin	1.58E-01	1.22E-01	1.29E+00

References

• [1] Evolution of putrescine N-methyltransferase from spermidine synthase demanded alterations in substrate binding. FEBS Lett. 2009 Oct 20;583(20):3367-74.
• [2] Nodular regenerative liver hyperplasia as a complication of azathioprine-containing immunosuppressive treatment for Crohn's disease. Immunopharmacol Immunotoxicol. 2011 Jun;33(2):398-402.
• [3] S-methylation of captopril. Demonstration of captopril thiol methyltransferase activity in human erythrocytes and enzyme distribution in rat tissues. Biochem Pharmacol. 1983 May 15;32(10):1557-62.
• [4] Cefazolin administration and 2-methyl-1,3,4-thiadiazole-5-thiol in human tissue: possible relationship to hypoprothrombinemia. Drug Metab Dispos. 2002 Oct;30(10):1123-8.
• [5] Adrenal catecholamines and their metabolism in the vitamin A deficient rat. Ann Nutr Metab. 1983;27(3):220-7.
• [6] Histamine-N-methyl transferase polymorphism and risk for multiple sclerosis. Eur J Neurol. 2010 Feb;17(2):335-8.
• [7] Influence of estradiol-17 beta and progesterone on catechol-O-methyltransferase and monoamine oxidase activities in uterine artery and myometrium of ovariectomized pigs. Arch Vet Pol. 1993;33(1-2):29-37.
• [8] Identification, characterization, and ontogenic study of a catechol O-methyltransferase from zebrafish. Aquat Toxicol. 2011 Mar;102(1-2):18-23.
• [9] Reduced 3-O-methyl-dopa levels in OCD patients and their unaffected parents is associated with the low activity M158 COMT allele. Am J Med Genet B Neuropsychiatr Genet. 2010 Mar 5;153B(2):542-548.
• [10] The degree of myelosuppression during maintenance therapy of adolescents with B-lineage intermediate risk acute lymphoblastic leukemia predicts risk of relapse. Leukemia. 2010 Apr;24(4):715-20.
• [11] Genetics of rheumatoid arthritis. Mayo Clin Proc. 2006 Jan;81(1):94-101.
• [12] Polymorphism of estrogen metabolism genes and cataract. Med Hypotheses. 2004;63(3):494-7.
• [13] Usefulness of thiopurine methyltransferase and thiopurine metabolite analysis in clinical practice in patients with inflammatory bowel diseases. Acta Gastroenterol Belg. 2010 Jul-Sep;73(3):331-5.
• [14] Ascorbic acid inhibits spinal meningeal catechol-o-methyl transferase in vitro, markedly increasing epinephrine bioavailability. Anesthesiology. 1997 Feb;86(2):405-9.
• [15] Identification and functional analysis of two rare allelic variants of the thiopurine S-methyltransferase gene, TPMT*16 and TPMT*19. Biochem Pharmacol. 2005 Feb 1;69(3):525-9.