Thiopurine methyltransferase

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Thiopurine S-methyltransferase
Protein TPMT PDB 2bzg.png
PDB rendering based on 2bzg.
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbol TPMT
External IDs OMIM187680 MGI98812 HomoloGene313 ChEMBL: 2500 GeneCards: TPMT Gene
EC number 2.1.1.67
RNA expression pattern
PBB GE TPMT 203671 at tn.png
PBB GE TPMT 203672 x at tn.png
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.[1][2]

Function[edit]

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

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.[1][3]

Clinical significance[edit]

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.[1]

Pharmacology[edit]

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.[4][5][6]

Diagnostic use[edit]

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.[5][7]

Genetic variants of TPMT have also been associated with cisplatin-induced ototoxicity in children.[8] TPMT is now listed as a pharmacogenomic biomarker for adverse drug reactions to cisplatin by the FDA.[9]

References[edit]

  1. ^ a b c "Entrez Gene: TPMT thiopurine S-methyltransferase". National Center for Biotechnology Information. Retrieved 2012-07-02. 
  2. ^ 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. 
  3. ^ 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. 
  4. ^ 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. doi:10.2174/138920007781368890. PMID 17691917. 
  5. ^ 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. 
  6. ^ Evans WE. (2004). "Pharmacogenetics of thiopurine S-methyltransferase and thiopurine therapy.". Ther Drug Monit. 26 (2): 186–91. doi:10.1097/00007691-200404000-00018. PMID 15228163. 
  7. ^ 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. 
  8. ^ 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. doi:10.1038/ng.478. PMID 19898482. 
  9. ^ "Cisplatin". Science & Research (Drugs). United States Food and Drug Administration. 


Further reading[edit]

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