Thiopurine methyltransferase: Difference between revisions

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{{Infobox_gene}}
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'''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.<ref name="entrez">{{cite web | title = Entrez Gene: TPMT thiopurine S-methyltransferase| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=7172| accessdate =2012-07-02 |publisher=[[National Center for Biotechnology Information]] }}</ref><ref name="pmid7628307">{{cite journal |vauthors=Lee D, Szumlanski C, Houtman J, Honchel R, Rojas K, Overhauser J, Wieben ED, Weinshilboum RM | title = Thiopurine methyltransferase pharmacogenetics. Cloning of human liver cDNA and a processed pseudogene on human chromosome 18q21.1 | journal = Drug Metab. Dispos. | volume = 23 | issue = 3 | pages = 398–405 |date=March 1995 | pmid = 7628307 | doi = }}</ref>
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| require_manual_inspection = no
== Function ==
| update_protein_box = yes
{{Infobox enzyme|align=left
| update_summary = yes
| Name = thiopurine S-methyltransferase
| update_citations = yes
| EC_number = 2.1.1.67
| CAS_number = 67339-09-7
| IUBMB_EC_number = 2/1/1/67
| GO_code = 0008119
| image =  
| width =  
| caption =  
}}
}}
Thiopurine methyltransferase [[methylation|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 methionine|S-adenosyl-L-methionine]] as the S-methyl donor and [[S-Adenosyl-L-homocysteine|S-adenosyl-L-homocysteine]] as a byproduct.<ref name="entrez"/><ref name="xl">{{Cite journal |vauthors=Weinshilboum RM, Sladek SL | title = Mercaptopurine pharmacogenetics: Monogenic inheritance of erythrocyte thiopurine methyltransferase activity | journal = American Journal of Human Genetics | volume = 32 | issue = 5 | pages = 651–662 | year = 1980 | pmid = 7191632 | pmc = 1686086 }}</ref>


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== Clinical significance ==
{{GNF_Protein_box
 
| image = PBB_Protein_TPMT_image.jpg
Thiopurine drugs such as [[6-mercaptopurine]] are used as [[Chemotherapy|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. About 1/300 individual is deficient for the enzyme.<ref name="entrez"/>
| image_source = [[Protein_Data_Bank|PDB]] rendering based on 2bzg.
| PDB = {{PDB2|2bzg}}, {{PDB2|2h11}}
| Name = Thiopurine S-methyltransferase
| HGNCid = 12014
| Symbol = TPMT
| AltSymbols =;
| OMIM = 187680
| ECnumber = 
| Homologene = 313
| MGIid = 98812
| GeneAtlas_image1 = PBB_GE_TPMT_203671_at_tn.png
| GeneAtlas_image2 = PBB_GE_TPMT_203672_x_at_tn.png
| Function = {{GNF_GO|id=GO:0008119 |text = thiopurine S-methyltransferase activity}} {{GNF_GO|id=GO:0008168 |text = methyltransferase activity}} {{GNF_GO|id=GO:0016740 |text = transferase activity}}
| Component = {{GNF_GO|id=GO:0005737 |text = cytoplasm}}
| Process = {{GNF_GO|id=GO:0006139 |text = nucleobase, nucleoside, nucleotide and nucleic acid metabolic process}} {{GNF_GO|id=GO:0008152 |text = metabolic process}}
| Orthologs = {{GNF_Ortholog_box
    | Hs_EntrezGene = 7172
    | Hs_Ensembl = ENSG00000137364
    | Hs_RefseqProtein = NP_000358
    | Hs_RefseqmRNA = NM_000367
    | Hs_GenLoc_db = 
    | Hs_GenLoc_chr = 6
    | Hs_GenLoc_start = 18236526
    | Hs_GenLoc_end = 18263353
    | Hs_Uniprot = P51580
    | Mm_EntrezGene = 22017
    | Mm_Ensembl = ENSMUSG00000021376
    | Mm_RefseqmRNA = NM_016785
    | Mm_RefseqProtein = NP_058065
    | Mm_GenLoc_db = 
    | Mm_GenLoc_chr = 13
    | Mm_GenLoc_start = 47036149
    | Mm_GenLoc_end = 47054175
    | Mm_Uniprot = O55060
  }}
}}
[[Image:Thiopurine methyltransferase.png|thumb|Thiopurine methyltransferase, drawn from  {{PDB|2BZG}}.]]
'''Thiopurine methyltransferase''' or '''thiopurine S-methyltransferase''' ('''TPMT''') is an [[enzyme]] ({{EC number|2.1.1.67}}) that [[methylation|methylates]] [[thiopurine]] compounds. The methyl donor is [[S-adenosyl-L-methionine]], which is converted to [[S-adenosyl-L-homocysteine]].


<!-- The PBB_Summary template is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
== Pharmacology ==
{{PBB_Summary
| section_title =  
| summary_text = This gene encodes the enzyme that 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.<ref name="entrez">{{cite web | title = Entrez Gene: TPMT thiopurine S-methyltransferase| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=7172| accessdate = }}</ref>
}}


==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.<ref name="pmid17691917">{{cite journal |vauthors=Fujita K, Sasaki Y | title=Pharmacogenomics in drug-metabolizing enzymes catalyzing anticancer drugs for personalized cancer chemotherapy | journal=Curr. Drug Metab. | volume=8 | issue=6 | pages=554–62 |date=August 2007 | pmid=17691917 | url=http://www.bentham-direct.org/pages/content.php?CDM/2007/00000008/00000006/0002F.SGM | doi=10.2174/138920007781368890 }}</ref><ref name="Oncea I, Duley J. 2008">{{cite journal |vauthors=Oncea I, Duley J |title= Pharmacogenetics of Thiopurines. |journal= Goodman & Gilman's “The Pharmacological Basis of Therapeutics”, published McGraw-Hill's Access Medicine (on-line) |volume= Chapter 38 |year=2008 |edition=11th }}</ref><ref name="pmid15228163">{{cite journal |author= Evans WE. |title= Pharmacogenetics of thiopurine S-methyltransferase and thiopurine therapy. |journal= Ther Drug Monit. |volume= 26 |issue=2 |pages=186–91 |year=2004 |pmid=15228163 |doi=10.1097/00007691-200404000-00018}}</ref>
TPMT is best known for its role in the metabolism of the [[medication|drugs]] [[6-mercaptopurine]], [[azathioprine]] and [[6-thioguanine]].  TPMT catalyzes the S-methylation of thiopurine drugs, including [[6MP]]. Defects in the TPMT gene leads to decreased methylation and decreased inactivation of [[6MP]] leading to enhanced bone marrow toxicity. <ref>Pharmacogenomics in Drug-Metabolizing Enzymes Catalyzing Anticancer Drugs for Personalized Cancer Chemotherapy. Ken-ichi Fujita,; Yasutsuna Sasaki, Current Drug Metabolism, Volume 8, Number 6, August 2007 , pp. 554-562(9)
</ref>


==Diagnostic use==
==Diagnostic use==
Measurement of TPMT activity is encouraged prior to commencing [[azathioprine]] or [[6-mercaptopurine]], as patients with low activity (10% prevalence) or especially absent activity (prevalence 0.3%) are at a heightened risk of drug-induced [[bone marrow suppression|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]]<ref>[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 Human Gene TPMT (uc003ncm.1) Description and Page Index<!-- Bot generated title -->]</ref>.
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 suppression|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]].<ref name="Oncea I, Duley J. 2008"/><ref name="urlHuman Gene TPMT (uc003ncm.1) Description and Page Index">{{cite web | url = 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 | title = Human Gene TPMT (uc003ncm.1) | author = Genome Bioinformatics Group, Center for Biomolecular Science and Engineering | date = | format = | work = UCSC Genome Browser | publisher = University of California Santa Cruz | pages = | language = | archiveurl = | archivedate = | quote = | accessdate = 2008-07-25}}</ref>
 
Genetic variants of TPMT have also been associated with [[cisplatin]]-induced [[ototoxicity]] in children.<ref name="pmid19898482">{{cite journal |vauthors=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 | title = Genetic variants in TPMT and COMT are associated with hearing loss in children receiving cisplatin chemotherapy | journal = Nat. Genet. | volume = 41 | issue = 12 | pages = 1345–9 |date=December 2009 | pmid = 19898482 | doi = 10.1038/ng.478 }}</ref> TPMT is now listed as a pharmacogenomic [[Biomarker (medicine)|biomarker]] for adverse drug reactions to cisplatin by the FDA.<ref name="urlCisplatin">{{cite web | url = http://www.fda.gov/Drugs/ScienceResearch/ResearchAreas/Pharmacogenetics/ucm287714.htm | title = Cisplatin | date = | work = Science & Research (Drugs) | publisher = United States Food and Drug Administration }}</ref>


==References==
==References==
{{reflist|2}}
{{reflist}}
{{Clear}}
 
==Further reading==
==Further reading==
{{refbegin | 2}}
{{refbegin | 2}}
* Reuther LO, Vainer B, Sonne J, Larsen NE. 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'' 2004;59:797-801. PMID 14634700.
*{{cite journal | pmid = 14634700 | doi=10.1007/s00228-003-0698-8 | volume=59 | issue=11 | title=Thiopurine methyltransferase (TPMT) genotype distribution in azathioprine-tolerant and -intolerant patients with various disorders. The impact of TPMT genotyping in predicting toxicity |date=January 2004 | journal=Eur. J. Clin. Pharmacol. | pages=797–801 |vauthors=Reuther LO, Vainer B, Sonne J, Larsen NE }}.
{{PBB_Further_reading
*{{cite journal  |vauthors=Krynetski EY, Tai HL, Yates CR, etal |title=Genetic polymorphism of thiopurine S-methyltransferase: clinical importance and molecular mechanisms. |journal=Pharmacogenetics |volume=6 |issue= 4 |pages= 279–90 |year= 1997 |pmid= 8873214 |doi=10.1097/00008571-199608000-00001  }}
| citations =  
*{{cite journal  |vauthors=Krynetski E, Evans WE |title=Drug methylation in cancer therapy: lessons from the TPMT polymorphism. |journal=Oncogene |volume=22 |issue= 47 |pages= 7403–13 |year= 2003 |pmid= 14576848 |doi= 10.1038/sj.onc.1206944 }}
*{{cite journal  | author=Krynetski EY, Tai HL, Yates CR, ''et al.'' |title=Genetic polymorphism of thiopurine S-methyltransferase: clinical importance and molecular mechanisms. |journal=Pharmacogenetics |volume=6 |issue= 4 |pages= 279-90 |year= 1997 |pmid= 8873214 |doi= }}
*{{cite journal  |vauthors=Corominas H, Baiget M |title=Clinical utility of thiopurine S-methyltransferase genotyping. |journal=American Journal of Pharmacogenomics |volume=4 |issue= 1 |pages= 1–8 |year= 2004 |pmid= 14987117 |doi=  10.2165/00129785-200404010-00001}}
*{{cite journal  | author=Krynetski E, Evans WE |title=Drug methylation in cancer therapy: lessons from the TPMT polymorphism. |journal=Oncogene |volume=22 |issue= 47 |pages= 7403-13 |year= 2003 |pmid= 14576848 |doi= 10.1038/sj.onc.1206944 }}
*{{cite journal  |vauthors=Krynetskiy EY, Evans WE |title=Closing the gap between science and clinical practice: the thiopurine S-methyltransferase polymorphism moves forward. |journal=Pharmacogenetics |volume=14 |issue= 7 |pages= 395–6 |year= 2005 |pmid= 15226671 |doi=  10.1097/01.fpc.0000114753.08559.e9}}
*{{cite journal  | author=Corominas H, Baiget M |title=Clinical utility of thiopurine S-methyltransferase genotyping. |journal=American journal of pharmacogenomics : genomics-related research in drug development and clinical practice |volume=4 |issue= 1 |pages= 1-8 |year= 2004 |pmid= 14987117 |doi=  }}
*{{cite journal  |vauthors=Coulthard SA, Matheson EC, Hall AG, Hogarth LA |title=The clinical impact of thiopurine methyltransferase polymorphisms on thiopurine treatment. |journal=Nucleosides Nucleotides Nucleic Acids |volume=23 |issue= 8–9 |pages= 1385–91 |year= 2005 |pmid= 15571264 |doi=10.1081/NCN-200027637 }}
*{{cite journal  | author=Krynetskiy EY, Evans WE |title=Closing the gap between science and clinical practice: the thiopurine S-methyltransferase polymorphism moves forward. |journal=Pharmacogenetics |volume=14 |issue= 7 |pages= 395-6 |year= 2005 |pmid= 15226671 |doi=  }}
*{{cite journal  |vauthors=Lee W, Lockhart AC, Kim RB, Rothenberg ML |title=Cancer pharmacogenomics: powerful tools in cancer chemotherapy and drug development. |journal=Oncologist |volume=10 |issue= 2 |pages= 104–11 |year= 2005 |pmid= 15709212 |doi= 10.1634/theoncologist.10-2-104 }}
*{{cite journal  | author=Coulthard SA, Matheson EC, Hall AG, Hogarth LA |title=The clinical impact of thiopurine methyltransferase polymorphisms on thiopurine treatment. |journal=Nucleosides Nucleotides Nucleic Acids |volume=23 |issue= 8-9 |pages= 1385-91 |year= 2005 |pmid= 15571264 |doi=  }}
*{{cite journal  |vauthors=Pierik M, Rutgeerts P, Vlietinck R, Vermeire S |title=Pharmacogenetics in inflammatory bowel disease. |journal=World J. Gastroenterol. |volume=12 |issue= 23 |pages= 3657–67 |year= 2006 |pmid= 16773681 |doi=  }}
*{{cite journal  | author=Lee W, Lockhart AC, Kim RB, Rothenberg ML |title=Cancer pharmacogenomics: powerful tools in cancer chemotherapy and drug development. |journal=Oncologist |volume=10 |issue= 2 |pages= 104-11 |year= 2005 |pmid= 15709212 |doi= 10.1634/theoncologist.10-2-104 }}
*{{cite journal   |vauthors=Krynetski EY, Schuetz JD, Galpin AJ, etal |title=A single point mutation leading to loss of catalytic activity in human thiopurine S-methyltransferase. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=92 |issue= 4 |pages= 949–53 |year= 1995 |pmid= 7862671 |doi=10.1073/pnas.92.4.949  | pmc=42614  }}
*{{cite journal  | author=Pierik M, Rutgeerts P, Vlietinck R, Vermeire S |title=Pharmacogenetics in inflammatory bowel disease. |journal=World J. Gastroenterol. |volume=12 |issue= 23 |pages= 3657-67 |year= 2006 |pmid= 16773681 |doi=  }}
*{{cite journal   |vauthors=Honchel R, Aksoy IA, Szumlanski C, etal |title=Human thiopurine methyltransferase: molecular cloning and expression of T84 colon carcinoma cell cDNA. |journal=Mol. Pharmacol. |volume=43 |issue= 6 |pages= 878–87 |year= 1993 |pmid= 8316220 |doi=  }}
*{{cite journal | author=Lee D, Szumlanski C, Houtman J, ''et al.'' |title=Thiopurine methyltransferase pharmacogenetics. Cloning of human liver cDNA and a processed pseudogene on human chromosome 18q21.1. |journal=Drug Metab. Dispos. |volume=23 |issue= 3 |pages= 398-405 |year= 1995 |pmid= 7628307 |doi= }}
*{{cite journal   |vauthors=Glauser TA, Nelson AN, Zembower DE, etal |title=Diethyldithiocarbamate S-methylation: evidence for catalysis by human liver thiol methyltransferase and thiopurine methyltransferase. |journal=J. Pharmacol. Exp. Ther. |volume=266 |issue= 1 |pages= 23–32 |year= 1993 |pmid= 8392551 |doi=  }}
*{{cite journal | author=Krynetski EY, Schuetz JD, Galpin AJ, ''et al.'' |title=A single point mutation leading to loss of catalytic activity in human thiopurine S-methyltransferase. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=92 |issue= 4 |pages= 949-53 |year= 1995 |pmid= 7862671 |doi=  }}
*{{cite journal   |vauthors=Szumlanski C, Otterness D, Her C, etal |title=Thiopurine methyltransferase pharmacogenetics: human gene cloning and characterization of a common polymorphism. |journal=DNA Cell Biol. |volume=15 |issue= 1 |pages= 17–30 |year= 1996 |pmid= 8561894 |doi=10.1089/dna.1996.15.17  }}
*{{cite journal | author=Honchel R, Aksoy IA, Szumlanski C, ''et al.'' |title=Human thiopurine methyltransferase: molecular cloning and expression of T84 colon carcinoma cell cDNA. |journal=Mol. Pharmacol. |volume=43 |issue= 6 |pages= 878-87 |year= 1993 |pmid= 8316220 |doi=  }}
*{{cite journal   |vauthors=Tai HL, Krynetski EY, Yates CR, etal |title=Thiopurine S-methyltransferase deficiency: two nucleotide transitions define the most prevalent mutant allele associated with loss of catalytic activity in Caucasians. |journal=Am. J. Hum. Genet. |volume=58 |issue= 4 |pages= 694–702 |year= 1996 |pmid= 8644731 |doi= | pmc=1914689 }}
*{{cite journal | author=Glauser TA, Nelson AN, Zembower DE, ''et al.'' |title=Diethyldithiocarbamate S-methylation: evidence for catalysis by human liver thiol methyltransferase and thiopurine methyltransferase. |journal=J. Pharmacol. Exp. Ther. |volume=266 |issue= 1 |pages= 23-32 |year= 1993 |pmid= 8392551 |doi= }}
*{{cite journal   |vauthors=Yates CR, Krynetski EY, Loennechen T, etal |title=Molecular diagnosis of thiopurine S-methyltransferase deficiency: genetic basis for azathioprine and mercaptopurine intolerance. |journal=Ann. Intern. Med. |volume=126 |issue= 8 |pages= 608–14 |year= 1997 |pmid= 9103127 |doi=  10.7326/0003-4819-126-8-199704150-00003}}
*{{cite journal | author=Szumlanski C, Otterness D, Her C, ''et al.'' |title=Thiopurine methyltransferase pharmacogenetics: human gene cloning and characterization of a common polymorphism. |journal=DNA Cell Biol. |volume=15 |issue= 1 |pages= 17-30 |year= 1996 |pmid= 8561894 |doi=  }}
*{{cite journal   |vauthors=Tai HL, Krynetski EY, Schuetz EG, etal |title=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. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=94 |issue= 12 |pages= 6444–9 |year= 1997 |pmid= 9177237 |doi=10.1073/pnas.94.12.6444  | pmc=21069  }}
*{{cite journal | author=Tai HL, Krynetski EY, Yates CR, ''et al.'' |title=Thiopurine S-methyltransferase deficiency: two nucleotide transitions define the most prevalent mutant allele associated with loss of catalytic activity in Caucasians. |journal=Am. J. Hum. Genet. |volume=58 |issue= 4 |pages= 694-702 |year= 1996 |pmid= 8644731 |doi=  }}
*{{cite journal   |vauthors=Otterness D, Szumlanski C, Lennard L, etal |title=Human thiopurine methyltransferase pharmacogenetics: gene sequence polymorphisms. |journal=Clin. Pharmacol. Ther. |volume=62 |issue= 1 |pages= 60–73 |year= 1997 |pmid= 9246020 |doi= 10.1016/S0009-9236(97)90152-1 }}
*{{cite journal | author=Yates CR, Krynetski EY, Loennechen T, ''et al.'' |title=Molecular diagnosis of thiopurine S-methyltransferase deficiency: genetic basis for azathioprine and mercaptopurine intolerance. |journal=Ann. Intern. Med. |volume=126 |issue= 8 |pages= 608-14 |year= 1997 |pmid= 9103127 |doi= }}
*{{cite journal  |vauthors=Leipold G, Schütz E, Haas JP, Oellerich M |title=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. |journal=Arthritis Rheum. |volume=40 |issue= 10 |pages= 1896–8 |year= 1997 |pmid= 9336428 |doi= 10.1002/1529-0131(199710)40:10<1896::AID-ART26>3.0.CO;2-A }}
*{{cite journal | author=Tai HL, Krynetski EY, Schuetz EG, ''et al.'' |title=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. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=94 |issue= 12 |pages= 6444-9 |year= 1997 |pmid= 9177237 |doi= }}
*{{cite journal   |vauthors=Krynetski EY, Fessing MY, Yates CR, etal |title=Promoter and intronic sequences of the human thiopurine S-methyltransferase (TPMT) gene isolated from a human PAC1 genomic library. |journal=Pharm. Res. |volume=14 |issue= 12 |pages= 1672–8 |year= 1998 |pmid= 9453052 |doi=10.1023/A:1012111325397 }}
*{{cite journal  | author=Otterness D, Szumlanski C, Lennard L, ''et al.'' |title=Human thiopurine methyltransferase pharmacogenetics: gene sequence polymorphisms. |journal=Clin. Pharmacol. Ther. |volume=62 |issue= 1 |pages= 60-73 |year= 1997 |pmid= 9246020 |doi= 10.1016/S0009-9236(97)90152-1 }}
*{{cite journal   |vauthors=Spire-Vayron de la Moureyre C, Debuysère H, Sabbagh N, etal |title=Detection of known and new mutations in the thiopurine S-methyltransferase gene by single-strand conformation polymorphism analysis. |journal=Hum. Mutat. |volume=12 |issue= 3 |pages= 177–85 |year= 1998 |pmid= 9711875 |doi= 10.1002/(SICI)1098-1004(1998)12:3<177::AID-HUMU5>3.0.CO;2-E }}
*{{cite journal | author=Leipold G, Schütz E, Haas JP, Oellerich M |title=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. |journal=Arthritis Rheum. |volume=40 |issue= 10 |pages= 1896-8 |year= 1997 |pmid= 9336428 |doi= 10.1002/1529-0131(199710)40:10&lt;1896::AID-ART26&gt;3.0.CO;2-A }}
*{{cite journal  | author=Krynetski EY, Fessing MY, Yates CR, ''et al.'' |title=Promoter and intronic sequences of the human thiopurine S-methyltransferase (TPMT) gene isolated from a human PAC1 genomic library. |journal=Pharm. Res. |volume=14 |issue= 12 |pages= 1672-8 |year= 1998 |pmid= 9453052 |doi= }}
*{{cite journal | author=Spire-Vayron de la Moureyre C, Debuysère H, Sabbagh N, ''et al.'' |title=Detection of known and new mutations in the thiopurine S-methyltransferase gene by single-strand conformation polymorphism analysis. |journal=Hum. Mutat. |volume=12 |issue= 3 |pages= 177-85 |year= 1998 |pmid= 9711875 |doi= 10.1002/(SICI)1098-1004(1998)12:3<177::AID-HUMU5>3.0.CO;2-E }}
}}
{{refend}}
{{refend}}


==External links==
==External links==
* [http://www.cityassays.org.uk/tpmt.html City Assays] page on the TPMT assay
* [http://www.cityassays.org.uk/tpmt.html City Assays] page on the TPMT assay
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[[Category:EC 2.1.1]]
[[Category:EC 2.1.1]]
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Latest revision as of 02:16, 27 October 2017

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Identifiers
Aliases
External IDsGeneCards: [1]
Orthologs
SpeciesHumanMouse
Entrez

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Ensembl

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UniProt

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RefSeq (mRNA)

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RefSeq (protein)

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Location (UCSC)n/an/a
PubMed searchn/an/a
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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
Identifiers
EC number2.1.1.67
CAS number67339-09-7
Databases
IntEnzIntEnz view
BRENDABRENDA entry
ExPASyNiceZyme view
KEGGKEGG entry
MetaCycmetabolic pathway
PRIAMprofile
PDB structuresRCSB PDB PDBe PDBsum
Gene OntologyAmiGO / QuickGO

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 enzymatic activity are correlated with variations in sensitivity and toxicity to such drugs within individuals. 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]

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][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

  1. ↑ 1.0 1.1 1.2 "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. ↑ 5.0 5.1 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

External links

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