Thiopurine methyltransferase

Thiopurine methyltransferase or thiopurine S-methyltransferase (TPMT) is an enzyme (EC number|2.1.1.67) that methylates thiopurine compounds. The methyl donor is S-adenosyl-L-methionine, which is converted to S-adenosyl-L-homocysteine.

This gene encodes the enzyme that metabolizes thiopurine drugs via S-adenosyl-L-methionine as the S-methyl donor and S-adenosyl-L-homocysteine as a byproduct. Thiopurine drugs such as 6-mercaptopurine are used as chemotherapeutic agents. Genetic polymorphisms that affect this enzymatic activity are correlated with variations in sensitivity and toxicity to such drugs within individuals. A pseudogene for this locus is located on chromosome 18q.cite web | title = Entrez Gene: TPMT thiopurine S-methyltransferase| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=7172| accessdate = ]

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, including 6MP. 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.cite journal | author = Fujita K, Sasaki Y | title = Pharmacogenomics in drug-metabolizing enzymes catalyzing anticancer drugs for personalized cancer chemotherapy | journal = Curr. Drug Metab. | volume = 8 | issue = 6 | pages = 554–62 | year = 2007 | month = August | pmid = 17691917 | url = http://www.bentham-direct.org/pages/content.php?CDM/2007/00000008/00000006/0002F.SGM | issn = ]

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.; as 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.cite web | url = http://genome.ucsc.edu/cgi-bin/hgGene?hgg_gene=uc003ncm.1&hgg_prot=P51580&hgg_chrom=chr6&hgg_start=18236523&hgg_end=18263353&hgg_type=knownGene&db=hg18&hgsid=97455887 | title = Human Gene TPMT (uc003ncm.1) | author = Genome Bioinformatics Group, Center for Biomolecular Science and Engineering | authorlink = | coauthors = | date = | format = | work = UCSC Genome Browser | publisher = University of California Santa Cruz | pages = | language = | archiveurl = | archivedate = | quote = | accessdate = 2008-07-25]

References

Further reading

* Reuther LO, Vainer B, Sonne J, Larsen NE. 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" 2004;59:797-801. PMID 14634700.PBB_Further_reading
citations =
*cite journal | author=Krynetski EY, Tai HL, Yates CR, "et al." |title=Genetic polymorphism of thiopurine S-methyltransferase: clinical importance and molecular mechanisms. |journal=Pharmacogenetics |volume=6 |issue= 4 |pages= 279–90 |year= 1997 |pmid= 8873214 |doi=
*cite journal | author=Krynetski E, Evans WE |title=Drug methylation in cancer therapy: lessons from the TPMT polymorphism. |journal=Oncogene |volume=22 |issue= 47 |pages= 7403–13 |year= 2003 |pmid= 14576848 |doi= 10.1038/sj.onc.1206944
*cite journal | author=Corominas H, Baiget M |title=Clinical utility of thiopurine S-methyltransferase genotyping. |journal=American journal of pharmacogenomics : genomics-related research in drug development and clinical practice |volume=4 |issue= 1 |pages= 1–8 |year= 2004 |pmid= 14987117 |doi=
*cite journal | author=Krynetskiy EY, Evans WE |title=Closing the gap between science and clinical practice: the thiopurine S-methyltransferase polymorphism moves forward. |journal=Pharmacogenetics |volume=14 |issue= 7 |pages= 395–6 |year= 2005 |pmid= 15226671 |doi=
*cite journal | author=Coulthard SA, Matheson EC, Hall AG, Hogarth LA |title=The clinical impact of thiopurine methyltransferase polymorphisms on thiopurine treatment. |journal=Nucleosides Nucleotides Nucleic Acids |volume=23 |issue= 8-9 |pages= 1385–91 |year= 2005 |pmid= 15571264 |doi=
*cite journal | author=Lee W, Lockhart AC, Kim RB, Rothenberg ML |title=Cancer pharmacogenomics: powerful tools in cancer chemotherapy and drug development. |journal=Oncologist |volume=10 |issue= 2 |pages= 104–11 |year= 2005 |pmid= 15709212 |doi= 10.1634/theoncologist.10-2-104
*cite journal | author=Pierik M, Rutgeerts P, Vlietinck R, Vermeire S |title=Pharmacogenetics in inflammatory bowel disease. |journal=World J. Gastroenterol. |volume=12 |issue= 23 |pages= 3657–67 |year= 2006 |pmid= 16773681 |doi=
*cite journal | author=Lee D, Szumlanski C, Houtman J, "et al." |title=Thiopurine methyltransferase pharmacogenetics. Cloning of human liver cDNA and a processed pseudogene on human chromosome 18q21.1. |journal=Drug Metab. Dispos. |volume=23 |issue= 3 |pages= 398–405 |year= 1995 |pmid= 7628307 |doi=
*cite journal | author=Krynetski EY, Schuetz JD, Galpin AJ, "et al." |title=A single point mutation leading to loss of catalytic activity in human thiopurine S-methyltransferase. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=92 |issue= 4 |pages= 949–53 |year= 1995 |pmid= 7862671 |doi=
*cite journal | author=Honchel R, Aksoy IA, Szumlanski C, "et al." |title=Human thiopurine methyltransferase: molecular cloning and expression of T84 colon carcinoma cell cDNA. |journal=Mol. Pharmacol. |volume=43 |issue= 6 |pages= 878–87 |year= 1993 |pmid= 8316220 |doi=
*cite journal | author=Glauser TA, Nelson AN, Zembower DE, "et al." |title=Diethyldithiocarbamate S-methylation: evidence for catalysis by human liver thiol methyltransferase and thiopurine methyltransferase. |journal=J. Pharmacol. Exp. Ther. |volume=266 |issue= 1 |pages= 23–32 |year= 1993 |pmid= 8392551 |doi=
*cite journal | author=Szumlanski C, Otterness D, Her C, "et al." |title=Thiopurine methyltransferase pharmacogenetics: human gene cloning and characterization of a common polymorphism. |journal=DNA Cell Biol. |volume=15 |issue= 1 |pages= 17–30 |year= 1996 |pmid= 8561894 |doi=
*cite journal | author=Tai HL, Krynetski EY, Yates CR, "et al." |title=Thiopurine S-methyltransferase deficiency: two nucleotide transitions define the most prevalent mutant allele associated with loss of catalytic activity in Caucasians. |journal=Am. J. Hum. Genet. |volume=58 |issue= 4 |pages= 694–702 |year= 1996 |pmid= 8644731 |doi=
*cite journal | author=Yates CR, Krynetski EY, Loennechen T, "et al." |title=Molecular diagnosis of thiopurine S-methyltransferase deficiency: genetic basis for azathioprine and mercaptopurine intolerance. |journal=Ann. Intern. Med. |volume=126 |issue= 8 |pages= 608–14 |year= 1997 |pmid= 9103127 |doi=
*cite journal | author=Tai HL, Krynetski EY, Schuetz EG, "et al." |title=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. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=94 |issue= 12 |pages= 6444–9 |year= 1997 |pmid= 9177237 |doi=
*cite journal | author=Otterness D, Szumlanski C, Lennard L, "et al." |title=Human thiopurine methyltransferase pharmacogenetics: gene sequence polymorphisms. |journal=Clin. Pharmacol. Ther. |volume=62 |issue= 1 |pages= 60–73 |year= 1997 |pmid= 9246020 |doi= 10.1016/S0009-9236(97)90152-1
*cite journal | author=Leipold G, Schütz E, Haas JP, Oellerich M |title=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. |journal=Arthritis Rheum. |volume=40 |issue= 10 |pages= 1896–8 |year= 1997 |pmid= 9336428 |doi= 10.1002/1529-0131(199710)40:10<1896::AID-ART26>3.0.CO;2-A
*cite journal | author=Krynetski EY, Fessing MY, Yates CR, "et al." |title=Promoter and intronic sequences of the human thiopurine S-methyltransferase (TPMT) gene isolated from a human PAC1 genomic library. |journal=Pharm. Res. |volume=14 |issue= 12 |pages= 1672–8 |year= 1998 |pmid= 9453052 |doi=
*cite journal | author=Spire-Vayron de la Moureyre C, Debuysère H, Sabbagh N, "et al." |title=Detection of known and new mutations in the thiopurine S-methyltransferase gene by single-strand conformation polymorphism analysis. |journal=Hum. Mutat. |volume=12 |issue= 3 |pages= 177–85 |year= 1998 |pmid= 9711875 |doi= 10.1002/(SICI)1098-1004(1998)12:3<177::AID-HUMU5>3.0.CO;2-E |doilabel=10.1002/(SICI)1098-1004(1998)12:3177::AID-HUMU53.0.CO;2-E

External links

* [http://www.cityassays.org.uk/tpmt.html City Assays] page on the TPMT assay

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