- 同
- TPMT
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- the 19th letter of the Roman alphabet (同)s
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- sulfurの化学記号 / {略}South[ern]
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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2017/08/22 16:17:21」(JST)
[Wiki en表示]
| TPMT |
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| Available structures |
| PDB |
Ortholog search: PDBe RCSB |
| List of PDB id codes |
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2BZG, 2H11
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| Identifiers |
| Aliases |
TPMT, entrez:7172, TPMTD, thiopurine S-methyltransferase |
| External IDs |
OMIM: 187680 MGI: 98812 HomoloGene: 313 GeneCards: TPMT |
| Gene location (Human) |
|
| Chr. |
Chromosome 6 (human)[1] |
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| Band |
No data available |
Start |
18,128,311 bp[1] |
| End |
18,155,074 bp[1] |
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| Gene location (Mouse) |
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| Chr. |
Chromosome 13 (mouse)[2] |
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| Band |
No data available |
Start |
47,025,170 bp[2] |
| End |
47,044,737 bp[2] |
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| RNA expression pattern |
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| More reference expression data |
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| Gene ontology |
| Molecular function |
• S-adenosylmethionine-dependent methyltransferase activity
• transferase activity
• methyltransferase activity
• thiopurine S-methyltransferase activity
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| Cellular component |
• cytosol
• extracellular exosome
• cytoplasm
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| Biological process |
• nucleobase-containing compound metabolic process
• methylation
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| Sources:Amigo / QuickGO |
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| Orthologs |
| Species |
Human |
Mouse |
| Entrez |
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|
| Ensembl |
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| UniProt |
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| RefSeq (mRNA) |
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NM_000367
NM_001346817
NM_001346818
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| RefSeq (protein) |
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NP_000358
NP_001333746
NP_001333747
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| Location (UCSC) |
Chr 6: 18.13 – 18.16 Mb |
Chr 6: 47.03 – 47.04 Mb |
| PubMed search |
[3] |
[4] |
| Wikidata |
| View/Edit Human |
View/Edit Mouse |
|
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.[5][6]
Contents
- 1 Function
- 2 Clinical significance
- 3 Pharmacology
- 4 Diagnostic use
- 5 References
- 6 Further reading
- 7 External links
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.[5][7]
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. About 1/300 individual is deficient for the enzyme.[5]
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.[8][9][10]
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.[9][11]
Genetic variants of TPMT have also been associated with cisplatin-induced ototoxicity in children.[12] TPMT is now listed as a pharmacogenomic biomarker for adverse drug reactions to cisplatin by the FDA.[13]
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000137364 - Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000021376 - Ensembl, May 2017
- ^ "Human PubMed Reference:".
- ^ "Mouse PubMed Reference:".
- ^ a b c "Entrez Gene: TPMT thiopurine S-methyltransferase". National Center for Biotechnology Information. Retrieved 2012-07-02.
- ^ Lee D, Szumlanski C, Houtman J, Honchel R, Rojas K, Overhauser J, Wieben ED, Weinshilboum RM (March 1995). "Thiopurine methyltransferase pharmacogenetics. Cloning of human liver cDNA and a processed pseudogene on human chromosome 18q21.1". Drug Metab. Dispos. 23 (3): 398–405. PMID 7628307.
- ^ Weinshilboum RM, Sladek SL (1980). "Mercaptopurine pharmacogenetics: Monogenic inheritance of erythrocyte thiopurine methyltransferase activity". American Journal of Human Genetics. 32 (5): 651–662. PMC 1686086 . PMID 7191632.
- ^ Fujita K, Sasaki Y (August 2007). "Pharmacogenomics in drug-metabolizing enzymes catalyzing anticancer drugs for personalized cancer chemotherapy". Curr. Drug Metab. 8 (6): 554–62. PMID 17691917. doi:10.2174/138920007781368890.
- ^ a b Oncea I, Duley J (2008). "Pharmacogenetics of Thiopurines.". Goodman & Gilman's “The Pharmacological Basis of Therapeutics”, published McGraw-Hill's Access Medicine (on-line) (11th ed.). Chapter 38.
- ^ Evans WE. (2004). "Pharmacogenetics of thiopurine S-methyltransferase and thiopurine therapy.". Ther Drug Monit. 26 (2): 186–91. PMID 15228163. doi:10.1097/00007691-200404000-00018.
- ^ Genome Bioinformatics Group, Center for Biomolecular Science and Engineering. "Human Gene TPMT (uc003ncm.1)". UCSC Genome Browser. University of California Santa Cruz. Retrieved 2008-07-25.
- ^ Ross CJ, Katzov-Eckert H, Dubé MP, Brooks B, Rassekh SR, Barhdadi A, Feroz-Zada Y, Visscher H, Brown AM, Rieder MJ, Rogers PC, Phillips MS, Carleton BC, Hayden MR (December 2009). "Genetic variants in TPMT and COMT are associated with hearing loss in children receiving cisplatin chemotherapy". Nat. Genet. 41 (12): 1345–9. PMID 19898482. doi:10.1038/ng.478.
- ^ "Cisplatin". Science & Research (Drugs). United States Food and Drug Administration.
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. PMID 14634700. doi:10.1007/s00228-003-0698-8. .
- 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. PMID 8873214. doi:10.1097/00008571-199608000-00001.
- Krynetski E, Evans WE (2003). "Drug methylation in cancer therapy: lessons from the TPMT polymorphism.". Oncogene. 22 (47): 7403–13. PMID 14576848. doi:10.1038/sj.onc.1206944.
- Corominas H, Baiget M (2004). "Clinical utility of thiopurine S-methyltransferase genotyping.". American Journal of Pharmacogenomics. 4 (1): 1–8. PMID 14987117. doi:10.2165/00129785-200404010-00001.
- 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. PMID 15226671. doi:10.1097/01.fpc.0000114753.08559.e9.
- 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. PMID 15571264. doi:10.1081/NCN-200027637.
- Lee W, Lockhart AC, Kim RB, Rothenberg ML (2005). "Cancer pharmacogenomics: powerful tools in cancer chemotherapy and drug development.". Oncologist. 10 (2): 104–11. PMID 15709212. doi:10.1634/theoncologist.10-2-104.
- 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. PMC 42614 . PMID 7862671. doi:10.1073/pnas.92.4.949.
- 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.
- 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.
- 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. PMID 8561894. doi:10.1089/dna.1996.15.17.
- 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.
- 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. PMID 9103127. doi:10.7326/0003-4819-126-8-199704150-00003.
- 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. PMC 21069 . PMID 9177237. doi:10.1073/pnas.94.12.6444.
- Otterness D, Szumlanski C, Lennard L, et al. (1997). "Human thiopurine methyltransferase pharmacogenetics: gene sequence polymorphisms.". Clin. Pharmacol. Ther. 62 (1): 60–73. PMID 9246020. doi:10.1016/S0009-9236(97)90152-1.
- 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. PMID 9336428. doi:10.1002/1529-0131(199710)40:10<1896::AID-ART26>3.0.CO;2-A.
- 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. PMID 9453052. doi:10.1023/A:1012111325397.
- 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. PMID 9711875. doi:10.1002/(SICI)1098-1004(1998)12:3<177::AID-HUMU5>3.0.CO;2-E.
External links
- City Assays page on the TPMT assay
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PDB gallery
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2bzg: CRYSTAL STRUCTURE OF THIOPURINE S-METHYLTRANSFERASE.
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2h11: Amino-terminal Truncated Thiopurine S-Methyltransferase Complexed with S-Adenosyl-L-Homocysteine
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Transferase: one carbon transferases (EC 2.1)
|
| 2.1.1: Methyl- |
| N- |
- Histamine N-methyltransferase
- Phenylethanolamine N-methyltransferase
- Amine N-methyltransferase
- Phosphatidylethanolamine N-methyltransferase
|
| O- |
- 5-hydroxyindole-O-methyltransferase/Acetylserotonin O-methyltransferase
- Catechol-O-methyl transferase
|
| Homocysteine |
- Betaine-homocysteine methyltransferase
- Homocysteine methyltransferase
- Methionine synthase
|
| Other |
- Phosphatidyl ethanolamine methyltransferase
- DNMT3B
- Histone methyltransferase
- Thymidylate synthase
- DNA methyltransferase
- Thiopurine methyltransferase
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2.1.2: Hydroxymethyl-,
Formyl- and Related |
| Hydroxymethyltransferase |
- Serine hydroxymethyltransferase
- 3-methyl-2-oxobutanoate hydroxymethyltransferase
|
| Formyltransferase |
- Phosphoribosylglycinamide formyltransferase
- Inosine monophosphate synthase
|
| Other |
- Glutamate formimidoyltransferase
- Aminomethyltransferase
|
|
2.1.3: Carboxy-
and Carbamoyl |
| Carboxy |
- methylmalonyl-CoA carboxytransferase
|
| Carbamoyl |
- Aspartate carbamoyltransferase
- Ornithine carbamoyltransferase
- Oxamate carbamoyltransferase
- Putrescine carbamoyltransferase
- 3-hydroxymethylcephem carbamoyltransferase
- Lysine carbamoyltransferase
- N-acetylornithine carbamoyltransferase
|
|
| 2.1.4: Amidine |
- Arginine:glycine amidinotransferase
|
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Enzymes
|
| Activity |
- Active site
- Binding site
- Catalytic triad
- Oxyanion hole
- Enzyme promiscuity
- Catalytically perfect enzyme
- Coenzyme
- Cofactor
- Enzyme catalysis
|
| Regulation |
- Allosteric regulation
- Cooperativity
- Enzyme inhibitor
|
| Classification |
- EC number
- Enzyme superfamily
- Enzyme family
- List of enzymes
|
| Kinetics |
- Enzyme kinetics
- Eadie–Hofstee diagram
- Hanes–Woolf plot
- Lineweaver–Burk plot
- Michaelis–Menten kinetics
|
| Types |
- EC1 Oxidoreductases (list)
- EC2 Transferases (list)
- EC3 Hydrolases (list)
- EC4 Lyases (list)
- EC5 Isomerases (list)
- EC6 Ligases (list)
|
UpToDate Contents
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English Journal
- Pharmacology and Optimization of Thiopurines and Methotrexate in Inflammatory Bowel Disease.
- Coskun M1, Steenholdt C, de Boer NK, Nielsen OH.
- Clinical pharmacokinetics.Clin Pharmacokinet.2015 Aug 9. [Epub ahead of print]
- Improving the efficacy and reducing the toxicity of thiopurines and methotrexate (MTX) have been areas of intense basic and clinical research. An increased knowledge on pharmacodynamics and pharmacokinetics of these immunomodulators has optimized treatment strategies in inflammatory bowel disease (I
- PMID 26255287
- Thiopurine methyltransferase and treatment outcome in the UK acute lymphoblastic leukaemia trial ALL2003.
- Lennard L1, Cartwright CS1, Wade R2, Vora A3.
- British journal of haematology.Br J Haematol.2015 Aug;170(4):550-8. doi: 10.1111/bjh.13469. Epub 2015 May 5.
- The influence of thiopurine methyltransferase (TPMT) genotype on treatment outcome was investigated in the United Kingdom childhood acute lymphoblastic leukaemia trial ALL2003, a trial in which treatment intensity was adjusted based on minimal residual disease (MRD). TPMT genotype was measured in 23
- PMID 25940902
- Increased liver enzyme levels during azathioprine treatment; beware of concomitant use of proton pump inhibitors.
- van der Schaft J1, van Schaik RH2,3, van den Broek MP4, Bruijnzeel-Koomen CA1, de Bruin-Weller MS1.
- The British journal of dermatology.Br J Dermatol.2015 Jul 3. doi: 10.1111/bjd.14006. [Epub ahead of print]
- Azathioprine (AZA) is a purine antagonist, which is frequently used off label in chronic inflammatory skin diseases. Genetic polymorphisms in thiopurine S-methyltransferase (TPMT) influence the metabolism of AZA. A reduced enzymatic activity of TMPT is associated with increased 6-thioguaninie nucleo
- PMID 26139089
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
- 北村 裕介,井原 敏博
- 分析化学 62(9), 793-810, 2013
- オリゴヌクレオチド（ODN）に金属配位基や金属錯体を導入したDNAコンジュゲートを調製し，これをハイブリダイゼーションプローブとして用いた．標的DNA上で複数のプローブを相互作用させ，そこで得られる特異的なシグナルから遺伝情報を読み取るシステムを構築した．希土類金属イオン捕捉部位としてEDTAを，光増感部位として1,10-フェナントロリン（phen）を別々のODN末端に修飾し，標的DNA上で両構造 …
- NAID 130003382350
- 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
- 井原 敏博,北村 裕介
- 分析化学 = Japan analyst 61(3), 193-206, 2012-03-05
- DNAに金属配位基を共有結合で導入した種々のDNAコンジュゲートを調製した．これらDNAコンジュゲートは，共存する特定の金属イオンと錯生成し，その分子（DNA）認識能，及びその他の様々な性質を可逆的に変化させることができる．コンプレキサン型の配位子であるグルタミン酸，及びハードな配位子であるイミノ二酢酸を有するDNAコンジュゲートは，それぞれ銅イオン，及びハードなルイス酸である希土類金属イオン共存 …
- 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
- … A 62-year-old Chinese patient with recurrent pompholyx submitted his blood sample for pre-treatment thiopurine S-methyltransferase (TPMT) pharmacogenetic profiling, and it was found to harbour a novel single nucleotide polymorphism (SNP). …
- NAID 130004463284
Related Links
- 1. Alves, S., Prata, M.-J., Ferreira, F., Amorim, A. Thiopurine methyltransferase pharmacogenetics: alternative molecular diagnosis and preliminary data from northern Portugal. Pharmacogenetics 9: 257-261, 1999. [PubMed: 10376773, ...
- Proceeds from website advertising help sustain Lab Tests Online. AACC is a not-for-profit organization and does not endorse non-AACC products and services. ... The tests for thiopurine methyltransferase (TPMT) enzyme activity or ...
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- 関
- Thiopurine S-methyltransferase
- 同
- thiopurine S-methyltransferase
- 関
- Thiopurine S-methyltransferase
[★]
メチルトランスフェラーゼ、メチル基転移酵素、メチル化酵素
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