Thiopurine methyltransferase

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]

Thiopurine methyltransferase
TPMT
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesTPMT, entrez:7172, TPMTD, thiopurine S-methyltransferase
External IDsOMIM: 187680 MGI: 98812 HomoloGene: 313 GeneCards: TPMT
Orthologs
SpeciesHumanMouse
Entrez

7172

22017

Ensembl

ENSG00000137364

ENSMUSG00000021376

UniProt

P51580

O55060

RefSeq (mRNA)

NM_000367
NM_001346817
NM_001346818

NM_016785

RefSeq (protein)

NP_000358
NP_001333746
NP_001333747

NP_058065

Location (UCSC)Chr 6: 18.13 – 18.16 MbChr 13: 47.18 – 47.2 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Function

thiopurine S-methyltransferase
Identifiers
EC no.2.1.1.67
CAS no.67339-09-7
Databases
IntEnzIntEnz view
BRENDABRENDA entry
ExPASyNiceZyme view
KEGGKEGG entry
MetaCycmetabolic pathway
PRIAMprofile
PDB structuresRCSB PDB PDBe PDBsum
Gene OntologyAmiGO / QuickGO
Search
PMCarticles
PubMedarticles
NCBIproteins

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 enzyme's activity are correlated with variations in sensitivity and toxicity to such drugs. 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] Allopurinol inhibits thiopurine S-methyltransferase, which can increase the utility of 6-MP.[11]

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][12]

Genetic variants of TPMT have also been associated with cisplatin-induced ototoxicity in children.[13] TPMT is now listed as a pharmacogenomic biomarker for adverse drug reactions to cisplatin by the FDA.[14]

See also

References

  1. GRCh38: Ensembl release 89: ENSG00000137364 - Ensembl, May 2017
  2. GRCm38: Ensembl release 89: ENSMUSG00000021376 - Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. "Entrez Gene: TPMT thiopurine S-methyltransferase". National Center for Biotechnology Information. Retrieved 2012-07-02.
  6. 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.
  7. 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.
  8. 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. Archived from the original on 2013-01-12. Retrieved 2008-07-25.
  9. Oncea I, Duley J (2008). "Chapter 38: Pharmacogenetics of Thiopurines". Goodman & Gilman's The Pharmacological Basis of Therapeutics (11th ed.). McGraw-Hill's Access Medicine.
  10. 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. S2CID 34015182.
  11. "The Mechanism and Drug Interaction - Allopurinol and Azathioprine and Risk of Bone Marrow Suppression". www.ebmconsult.com. Retrieved 2019-03-24.
  12. 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.
  13. 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. S2CID 21293339.
  14. "Cisplatin". Science & Research (Drugs). United States Food and Drug Administration.

Further reading

  • City Assays page on the TPMT assay
  • Overview of all the structural information available in the PDB for UniProt: P51580 (Human Thiopurine S-methyltransferase) at the PDBe-KB.
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