Thiopurine methyltransferase

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Thiopurine S-methyltransferase
File:PBB Protein TPMT image.jpg
PDB rendering based on 2bzg.
Available structures
PDB Ortholog search: Template:Homologene2PDBe PDBe, Template:Homologene2uniprot RCSB
Identifiers
Symbols TPMT ;
External IDs Template:OMIM5 Template:MGI HomoloGene: 313
RNA expression pattern
File:PBB GE TPMT 203671 at tn.png
File:PBB GE TPMT 203672 x at tn.png
More reference expression data
Orthologs
Template:GNF Ortholog box
Species Human Mouse
Entrez n/a n/a
Ensembl n/a n/a
UniProt n/a n/a
RefSeq (mRNA) n/a n/a
RefSeq (protein) n/a n/a
Location (UCSC) n/a n/a
PubMed search n/a n/a
File:Thiopurine methyltransferase.png
Thiopurine methyltransferase, drawn from PDB: 2BZG​.

Thiopurine methyltransferase or thiopurine S-methyltransferase (TPMT) is an enzyme (EC 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.[1]

Pharmacology

TPMT is best known for its role in the metabolism of the drugs 6-mercaptopurine, azathioprine 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. [2]

Diagnostic use

Measurement of TPMT activity is encouraged prior to commencing azathioprine or 6-mercaptopurine, 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[3].

References

  1. ↑ "Entrez Gene: TPMT thiopurine S-methyltransferase".
  2. ↑ Pharmacogenomics in Drug-Metabolizing Enzymes Catalyzing Anticancer Drugs for Personalized Cancer Chemotherapy. Ken-ichi Fujita,; Yasutsuna Sasaki, Current Drug Metabolism, Volume 8, Number 6, August 2007 , pp. 554-562(9)
  3. ↑ Human Gene TPMT (uc003ncm.1) Description and Page Index

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.
  • 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.
  • 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. 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. 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. 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.
  • Lee D, Szumlanski C, Houtman J; et al. (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.
  • 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. PMID 7862671.
  • 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.
  • 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. 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.
  • 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. PMID 9177237.
  • 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.
  • 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&lt;1896::AID-ART26&gt;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. PMID 9453052.
  • 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.


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