Thiopurine methyltransferase

Thiopurine S-methyltransferase
PDB rendering based on 2bzg.
Available structures PDB 2BZG, 2H11
Identifiers
Symbols	TPMT;
External IDs	OMIM: 187680 MGI: 98812 HomoloGene: 313 GeneCards: TPMT Gene
EC number	2.1.1.67
Gene Ontology Molecular function • thiopurine S-methyltransferase activity • transferase activity Cellular component • soluble fraction • cytoplasm • cytosol Biological process • nucleobase, nucleoside, nucleotide and nucleic acid metabolic process • xenobiotic metabolic process • metabolic process • response to organic cyclic compound • methylation • response to testosterone stimulus • S-adenosylhomocysteine metabolic process • S-adenosylmethionine metabolic process Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	7172	22017
Ensembl	ENSG00000137364	ENSMUSG00000021376
UniProt	P51580	O55060
RefSeq (mRNA)	NM_000367.2	NM_016785.2
RefSeq (protein)	NP_000358.1	NP_058065.2
Location (UCSC)	Chr 6: 18.13 – 18.16 Mb	Chr 13: 47.12 – 47.14 Mb
PubMed search	[1]	[2]

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 enzyme 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.

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.

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.

Further reading

• Reuther LO, Vainer B, Sonne J, Larsen NE (January 2004). "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. doi:10.1007/s00228-003-0698-8. 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. doi:10.1097/00008571-199608000-00001. 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. doi:10.1081/NCN-200027637. 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. doi:10.1073/pnas.92.4.949. PMC 42614. PMID 7862671. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=42614. 
• 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. doi:10.1089/dna.1996.15.17. 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. PMC 1914689. PMID 8644731. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1914689. 
• 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. doi:10.1073/pnas.94.12.6444. PMC 21069. PMID 9177237. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=21069. 
• 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<1896::AID-ART26>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. doi:10.1023/A:1012111325397. 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. 

External links

• City Assays page on the TPMT assay