Biology:Thiopurine methyltransferase
 Generic protein structure example |
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
| thiopurine S-methyltransferase | |||||||||
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| 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 / QuickGO | ||||||||
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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
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.[1]
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.[4][5][6] Allopurinol inhibits thiopurine S-methyltransferase, which can increase the utility of 6-MP.[7]
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.[5][8]
Genetic variants of TPMT have also been associated with cisplatin-induced ototoxicity in children.[9] TPMT is now listed as a pharmacogenomic biomarker for adverse drug reactions to cisplatin by the FDA.[10]
See also
References
- ↑ 1.0 1.1 1.2 "Entrez Gene: TPMT thiopurine S-methyltransferase". National Center for Biotechnology Information. https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=7172.
- ↑ "Thiopurine methyltransferase pharmacogenetics. Cloning of human liver cDNA and a processed pseudogene on human chromosome 18q21.1". Drug Metab. Dispos. 23 (3): 398–405. March 1995. PMID 7628307.
- ↑ "Mercaptopurine pharmacogenetics: Monogenic inheritance of erythrocyte thiopurine methyltransferase activity". American Journal of Human Genetics 32 (5): 651–662. 1980. PMID 7191632.
- ↑ "Pharmacogenomics in drug-metabolizing enzymes catalyzing anticancer drugs for personalized cancer chemotherapy". Curr. Drug Metab. 8 (6): 554–62. August 2007. doi:10.2174/138920007781368890. PMID 17691917. http://www.bentham-direct.org/pages/content.php?CDM%2F2007%2F00000008%2F00000006%2F0002F.SGM. Retrieved 2008-07-25.
- ↑ 5.0 5.1 "Chapter 38: Pharmacogenetics of Thiopurines". Goodman & Gilman's The Pharmacological Basis of Therapeutics (11th ed.). McGraw-Hill's Access Medicine. 2008.
- ↑ 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.
- ↑ "The Mechanism and Drug Interaction - Allopurinol and Azathioprine and Risk of Bone Marrow Suppression". https://www.ebmconsult.com/articles/allopurinol-azathioprine-interaction-mechanism-wbc.
- ↑ Genome Bioinformatics Group, Center for Biomolecular Science and Engineering. "Human Gene TPMT (uc003ncm.1)". UCSC Genome Browser. University of California Santa Cruz. 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.
- ↑ "Genetic variants in TPMT and COMT are associated with hearing loss in children receiving cisplatin chemotherapy". Nat. Genet. 41 (12): 1345–9. December 2009. doi:10.1038/ng.478. PMID 19898482.
- ↑ "Cisplatin". Science & Research (Drugs). United States Food and Drug Administration. https://www.fda.gov/Drugs/ScienceResearch/ResearchAreas/Pharmacogenetics/ucm287714.htm.
Further reading
- "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. January 2004. doi:10.1007/s00228-003-0698-8. PMID 14634700..
- "Genetic polymorphism of thiopurine S-methyltransferase: clinical importance and molecular mechanisms.". Pharmacogenetics 6 (4): 279–90. 1997. doi:10.1097/00008571-199608000-00001. PMID 8873214.
- "Drug methylation in cancer therapy: lessons from the TPMT polymorphism.". Oncogene 22 (47): 7403–13. 2003. doi:10.1038/sj.onc.1206944. PMID 14576848.
- "Clinical utility of thiopurine S-methyltransferase genotyping.". American Journal of Pharmacogenomics 4 (1): 1–8. 2004. doi:10.2165/00129785-200404010-00001. PMID 14987117.
- "Closing the gap between science and clinical practice: the thiopurine S-methyltransferase polymorphism moves forward.". Pharmacogenetics 14 (7): 395–6. 2005. doi:10.1097/01.fpc.0000114753.08559.e9. PMID 15226671.
- "The clinical impact of thiopurine methyltransferase polymorphisms on thiopurine treatment.". Nucleosides Nucleotides Nucleic Acids 23 (8–9): 1385–91. 2005. doi:10.1081/NCN-200027637. PMID 15571264.
- "Cancer pharmacogenomics: powerful tools in cancer chemotherapy and drug development.". Oncologist 10 (2): 104–11. 2005. doi:10.1634/theoncologist.10-2-104. PMID 15709212.
- "Pharmacogenetics in inflammatory bowel disease.". World J. Gastroenterol. 12 (23): 3657–67. 2006. doi:10.3748/wjg.v12.i23.3657. PMID 16773681.
- "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. 1995. doi:10.1073/pnas.92.4.949. PMID 7862671. Bibcode: 1995PNAS...92..949K.
- "Human thiopurine methyltransferase: molecular cloning and expression of T84 colon carcinoma cell cDNA.". Mol. Pharmacol. 43 (6): 878–87. 1993. PMID 8316220.
- "Diethyldithiocarbamate S-methylation: evidence for catalysis by human liver thiol methyltransferase and thiopurine methyltransferase.". J. Pharmacol. Exp. Ther. 266 (1): 23–32. 1993. PMID 8392551.
- "Thiopurine methyltransferase pharmacogenetics: human gene cloning and characterization of a common polymorphism.". DNA Cell Biol. 15 (1): 17–30. 1996. doi:10.1089/dna.1996.15.17. PMID 8561894.
- "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. 1996. PMID 8644731.
- "Molecular diagnosis of thiopurine S-methyltransferase deficiency: genetic basis for azathioprine and mercaptopurine intolerance.". Ann. Intern. Med. 126 (8): 608–14. 1997. doi:10.7326/0003-4819-126-8-199704150-00003. PMID 9103127.
- "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. 1997. doi:10.1073/pnas.94.12.6444. PMID 9177237.
- "Human thiopurine methyltransferase pharmacogenetics: gene sequence polymorphisms.". Clin. Pharmacol. Ther. 62 (1): 60–73. 1997. doi:10.1016/S0009-9236(97)90152-1. PMID 9246020.
- "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. 1997. doi:10.1002/art.1780401026. PMID 9336428.
- "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. 1998. doi:10.1023/A:1012111325397. PMID 9453052.
- "Detection of known and new mutations in the thiopurine S-methyltransferase gene by single-strand conformation polymorphism analysis.". Hum. Mutat. 12 (3): 177–85. 1998. doi:10.1002/(SICI)1098-1004(1998)12:3<177::AID-HUMU5>3.0.CO;2-E. PMID 9711875.
External links
- 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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