TPMT

関

Thiopurine S-methyltransferase

同

thiopurine S-methyltransferase

関

Thiopurine S-methyltransferase

Wikipedia preview

出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2015/07/26 20:02:17」(JST)

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Thiopurine S-methyltransferase
PDB rendering based on 2bzg.
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 2BZG, 2H11
Identifiers
Symbol	TPMT
External IDs	OMIM: 187680 MGI: 98812 HomoloGene: 313 ChEMBL: 2500 GeneCards: TPMT Gene
EC number	2.1.1.67
Gene ontology Molecular function • thiopurine S-methyltransferase activity Cellular component • cytosol • extracellular exosome Biological process • nucleobase-containing compound metabolic process • xenobiotic metabolic process • methylation • small molecule metabolic process Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	7172	22017
Ensembl	ENSG00000137364	ENSMUSG00000021376
UniProt	P51580	O55060
RefSeq (mRNA)	NM_000367	NM_016785
RefSeq (protein)	NP_000358	NP_058065
Location (UCSC)	Chr 6: 18.13 – 18.16 Mb	Chr 13: 47.03 – 47.04 Mb
PubMed search	[1]	[2]

Thiopurine methyltransferase or thiopurine S-methyltransferase (TPMT) is an enzyme that in humans is encoded by the TPMT gene. A pseudogene for this locus is located on chromosome 18q.

Function

thiopurine S-methyltransferase
Identifiers
EC number	2.1.1.67
CAS number	67339-09-7
Databases
IntEnz	IntEnz view
BRENDA	BRENDA entry
ExPASy	NiceZyme view
KEGG	KEGG entry
MetaCyc	metabolic pathway
PRIAM	profile
PDB structures	RCSB PDB PDBe PDBsum
Gene Ontology	AmiGO / EGO
Search PMC articles PubMed articles NCBI proteins

Thiopurine methyltransferase methylates thiopurine compounds. The methyl donor is S-adenosyl-L-methionine, which is converted to S-adenosyl-L-homocysteine. This enzyme metabolizes thiopurine drugs via S-adenosyl-L-methionine as the S-methyl donor and S-adenosyl-L-homocysteine as a byproduct.

Clinical significance

Thiopurine drugs such as 6-mercaptopurine are used as chemotherapeutic agents and immunosuppressive drugs. Genetic polymorphisms that affect this enzymatic activity are correlated with variations in sensitivity and toxicity to such drugs within individuals.

Pharmacology

TPMT is best known for its role in the metabolism of the thiopurine drugs such as azathioprine, 6-mercaptopurine and 6-thioguanine. TPMT catalyzes the S-methylation of thiopurine drugs. Defects in the TPMT gene leads to decreased methylation and decreased inactivation of 6MP leading to enhanced bone marrow toxicity which may cause myelosuppression, anemia, bleeding tendency, leukopenia & infection.

Diagnostic use

Measurement of TPMT activity is encouraged prior to commencing the treatment of patients with thiopurine drugs such as azathioprine, 6-mercaptopurine and 6-thioguanine. Patients with low activity (10% prevalence) or especially absent activity (prevalence 0.3%) are at a heightened risk of drug-induced bone marrow toxicity due to accumulation of the unmetabolised drug. Reuther et al. found that about 5% of all thiopurine therapies will fail due to toxicity. This intolerant group could be anticipated by routine measurement of TPMT activity. There appears to be a great deal of variation in TPMT mutation, with ethnic differences in mutation types accounting for variable responses to 6MP.

Genetic variants of TPMT have also been associated with cisplatin-induced ototoxicity in children. TPMT is now listed as a pharmacogenomic biomarker for adverse drug reactions to cisplatin by the FDA.

References

Further reading

• Reuther LO, Vainer B, Sonne J, Larsen NE (January 2004). "Thiopurine methyltransferase (TPMT) genotype distribution in azathioprine-tolerant and -intolerant patients with various disorders. The impact of TPMT genotyping in predicting toxicity". Eur. J. Clin. Pharmacol. 59 (11): 797–801. doi:10.1007/s00228-003-0698-8. PMID 14634700. .
• Krynetski EY, Tai HL, Yates CR et al. (1997). "Genetic polymorphism of thiopurine S-methyltransferase: clinical importance and molecular mechanisms.". Pharmacogenetics 6 (4): 279–90. doi:10.1097/00008571-199608000-00001. PMID 8873214.  CS1 maint: Explicit use of et al. (link)
• Krynetski E, Evans WE (2003). "Drug methylation in cancer therapy: lessons from the TPMT polymorphism.". Oncogene 22 (47): 7403–13. doi:10.1038/sj.onc.1206944. PMID 14576848. 
• Corominas H, Baiget M (2004). "Clinical utility of thiopurine S-methyltransferase genotyping.". American journal of pharmacogenomics : genomics-related research in drug development and clinical practice 4 (1): 1–8. doi:10.2165/00129785-200404010-00001. PMID 14987117. 
• Krynetskiy EY, Evans WE (2005). "Closing the gap between science and clinical practice: the thiopurine S-methyltransferase polymorphism moves forward.". Pharmacogenetics 14 (7): 395–6. doi:10.1097/01.fpc.0000114753.08559.e9. PMID 15226671. 
• Coulthard SA, Matheson EC, Hall AG, Hogarth LA (2005). "The clinical impact of thiopurine methyltransferase polymorphisms on thiopurine treatment.". Nucleosides Nucleotides Nucleic Acids 23 (8–9): 1385–91. doi:10.1081/NCN-200027637. PMID 15571264. 
• Lee W, Lockhart AC, Kim RB, Rothenberg ML (2005). "Cancer pharmacogenomics: powerful tools in cancer chemotherapy and drug development.". Oncologist 10 (2): 104–11. doi:10.1634/theoncologist.10-2-104. PMID 15709212. 
• Pierik M, Rutgeerts P, Vlietinck R, Vermeire S (2006). "Pharmacogenetics in inflammatory bowel disease.". World J. Gastroenterol. 12 (23): 3657–67. PMID 16773681. 
• Krynetski EY, Schuetz JD, Galpin AJ et al. (1995). "A single point mutation leading to loss of catalytic activity in human thiopurine S-methyltransferase.". Proc. Natl. Acad. Sci. U.S.A. 92 (4): 949–53. doi:10.1073/pnas.92.4.949. PMC 42614. PMID 7862671.  CS1 maint: Explicit use of et al. (link)
• Honchel R, Aksoy IA, Szumlanski C et al. (1993). "Human thiopurine methyltransferase: molecular cloning and expression of T84 colon carcinoma cell cDNA.". Mol. Pharmacol. 43 (6): 878–87. PMID 8316220.  CS1 maint: Explicit use of et al. (link)
• Glauser TA, Nelson AN, Zembower DE et al. (1993). "Diethyldithiocarbamate S-methylation: evidence for catalysis by human liver thiol methyltransferase and thiopurine methyltransferase.". J. Pharmacol. Exp. Ther. 266 (1): 23–32. PMID 8392551.  CS1 maint: Explicit use of et al. (link)
• Szumlanski C, Otterness D, Her C et al. (1996). "Thiopurine methyltransferase pharmacogenetics: human gene cloning and characterization of a common polymorphism.". DNA Cell Biol. 15 (1): 17–30. doi:10.1089/dna.1996.15.17. PMID 8561894.  CS1 maint: Explicit use of et al. (link)
• Tai HL, Krynetski EY, Yates CR et al. (1996). "Thiopurine S-methyltransferase deficiency: two nucleotide transitions define the most prevalent mutant allele associated with loss of catalytic activity in Caucasians.". Am. J. Hum. Genet. 58 (4): 694–702. PMC 1914689. PMID 8644731.  CS1 maint: Explicit use of et al. (link)
• Yates CR, Krynetski EY, Loennechen T et al. (1997). "Molecular diagnosis of thiopurine S-methyltransferase deficiency: genetic basis for azathioprine and mercaptopurine intolerance.". Ann. Intern. Med. 126 (8): 608–14. doi:10.7326/0003-4819-126-8-199704150-00003. PMID 9103127.  CS1 maint: Explicit use of et al. (link)
• Tai HL, Krynetski EY, Schuetz EG et al. (1997). "Enhanced proteolysis of thiopurine S-methyltransferase (TPMT) encoded by mutant alleles in humans (TPMT*3A, TPMT*2): mechanisms for the genetic polymorphism of TPMT activity.". Proc. Natl. Acad. Sci. U.S.A. 94 (12): 6444–9. doi:10.1073/pnas.94.12.6444. PMC 21069. PMID 9177237.  CS1 maint: Explicit use of et al. (link)
• Otterness D, Szumlanski C, Lennard L et al. (1997). "Human thiopurine methyltransferase pharmacogenetics: gene sequence polymorphisms.". Clin. Pharmacol. Ther. 62 (1): 60–73. doi:10.1016/S0009-9236(97)90152-1. PMID 9246020.  CS1 maint: Explicit use of et al. (link)
• Leipold G, Schütz E, Haas JP, Oellerich M (1997). "Azathioprine-induced severe pancytopenia due to a homozygous two-point mutation of the thiopurine methyltransferase gene in a patient with juvenile HLA-B27-associated spondylarthritis.". Arthritis Rheum. 40 (10): 1896–8. doi:10.1002/1529-0131(199710)40:10<1896::AID-ART26>3.0.CO;2-A. PMID 9336428. 
• Krynetski EY, Fessing MY, Yates CR et al. (1998). "Promoter and intronic sequences of the human thiopurine S-methyltransferase (TPMT) gene isolated from a human PAC1 genomic library.". Pharm. Res. 14 (12): 1672–8. doi:10.1023/A:1012111325397. PMID 9453052.  CS1 maint: Explicit use of et al. (link)
• Spire-Vayron de la Moureyre C, Debuysère H, Sabbagh N et al. (1998). "Detection of known and new mutations in the thiopurine S-methyltransferase gene by single-strand conformation polymorphism analysis.". Hum. Mutat. 12 (3): 177–85. doi:10.1002/(SICI)1098-1004(1998)12:3<177::AID-HUMU5>3.0.CO;2-E. PMID 9711875.  CS1 maint: Explicit use of et al. (link)

External links

• City Assays page on the TPMT assay

UpToDate Contents

全文を閲覧するには購読必要です。 To read the full text you will need to subscribe.

• 1. 6-メルカプトプリン（6-MP）またはアザチオプリンを用いた炎症性腸疾患治療
  における6-MP代謝産物モニタリングおよびTPMT検査 6 mercaptopurine 6 mp metabolite monitoring and tpmt testing in the treatment of inflammatory bowel disease with 6 mp or azathioprine
• 2. 薬理ゲノム学の概要 overview of pharmacogenomics
• 3. リウマチ性疾患に使用した場合のアザチオプリンの薬理作用および副作用 pharmacology and side effects of azathioprine when used in rheumatic diseases
• 4. 肺移植後の免疫抑制の維持 maintenance immunosuppression following lung transplantation
• 5. 成人における重症または難治性クローン病の内科的マネージメントの概要 overview of the medical management of severe or refractory crohn disease in adults

English Journal

• Validation of a high-performance liquid chromatography method for thiopurine S-methyltransferase activity in whole blood using 6-mercaptopurine as substrate.

• Rieger H1, Schmidt P1, Schaeffeler E1, Abe M1, Schiffhauer M1, Schwab M1, von Ahsen N1, Zurek G1, Kirchherr H1, Shipkova M1, Wieland E1.
• Clinical chemistry and laboratory medicine.Clin Chem Lab Med.2017 Dec 1. pii: /j/cclm.ahead-of-print/cclm-2017-0670/cclm-2017-0670.xml. doi: 10.1515/cclm-2017-0670. [Epub ahead of print]
• PMID 29194039

• Association between TPMT*3C and decreased thiopurine S-methyltransferase activity in patients with neuromyelitis optica spectrum disorders in China.

• Gong X1,2, Mei S3,4, Li X1, Li X3,4, Zhou H1, Liu Y1, Zhou A1, Yang L3,4, Zhao Z3,4, Zhang X1.
• The International journal of neuroscience.Int J Neurosci.2017 Dec 1:1-5. doi: 10.1080/00207454.2017.1401621. [Epub ahead of print]
• PMID 29191122

• Pharmacogenetics of thiopurines for inflammatory bowel disease in East Asia: prospects for clinical application of NUDT15 genotyping.

• Kakuta Y1, Kinouchi Y2, Shimosegawa T3.
• Journal of gastroenterology.J Gastroenterol.2017 Nov 30. doi: 10.1007/s00535-017-1416-0. [Epub ahead of print]
• PMID 29192347

Japanese Journal

• 金属錯体の特異的な形成及び相互作用を利用する新規核酸プローブの開発

• 分析化学 = Japan analyst 62(9), 793-810, 2013-09-05
• NAID 10031186094

• スプリット型プローブの協同的金属錯体形成を利用するDNAの認識及び検出

• 分析化学 = Japan analyst 61(3), 193-206, 2012-03-05
• NAID 10030135293

• Detection of a Novel Single Nucleotide Polymorphism of the Human Thiopurine S-Methyltransferase Gene in a Chinese Individual

• Drug Metabolism and Pharmacokinetics 27(5), 559-561, 2012
• NAID 130004463284

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