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 PDB Ortholog search: PDBe RCSB List of PDB id codes 2BZG, 2H11
Identifiers
Aliases	TPMT, entrez:7172, TPMTD, thiopurine S-methyltransferase
External IDs	OMIM: 187680; MGI: 98812; HomoloGene: 313; GeneCards: TPMT; OMA:TPMT - orthologs
Gene location (Human) Chr. Chromosome 6 (human)[1] Band 6p22.3 Start 18,128,311 bp[1] End 18,155,077 bp[1]
Gene location (Mouse) Chr. Chromosome 13 (mouse)[2] Band 13 A5|13 24.5 cM Start 47,175,958 bp[2] End 47,198,213 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in buccal mucosa cell tendon of biceps brachii rectum left lobe of thyroid gland right lobe of thyroid gland internal globus pallidus mucosa of transverse colon right lobe of liver mucosa of ileum human kidney Top expressed in right kidney proximal tubule human kidney left lobe of liver zygote primary oocyte secondary oocyte transitional epithelium of urinary bladder tail of embryo otic vesicle More reference expression data BioGPS More reference expression data
Gene ontology Molecular function S-adenosylmethionine-dependent methyltransferase activity transferase activity methyltransferase activity thiopurine S-methyltransferase activity S-adenosyl-L-methionine binding Cellular component cytosol cytoplasm Biological process nucleobase-containing compound metabolic process methylation Sources:Amigo / QuickGO
Orthologs Species Human Mouse 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 Mb Chr 13: 47.18 – 47.2 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Function

thiopurine S-methyltransferase
Identifiers
EC no.	2.1.1.67
CAS no.	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
Search PMC articles PubMed articles NCBI proteins

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

• Cancer pharmacogenomics

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.{{cite journal}}: CS1 maint: unfit URL (link)
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

• 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. S2CID 530045..
• 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. S2CID 22198609.
• Corominas H, Baiget M (2004). "Clinical utility of thiopurine S-methyltransferase genotyping". American Journal of Pharmacogenomics. 4 (1): 1–8. doi:10.2165/00129785-200404010-00001. PMID 14987117. S2CID 1954995.
• 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. doi:10.1097/01.fpc.0000114753.08559.e9. 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. S2CID 627569.
• 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. doi:10.3748/wjg.v12.i23.3657. PMC 4087457. PMID 16773681.
• 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. Bibcode:1995PNAS...92..949K. doi:10.1073/pnas.92.4.949. PMC 42614. 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. 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.
• 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. doi:10.7326/0003-4819-126-8-199704150-00003. PMID 9103127. S2CID 23831294.
• 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.
• 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. S2CID 22016760.
• 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/art.1780401026. 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. S2CID 22214838.
• 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. S2CID 11311096.

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.