Thiopurine S-methyltransferase

Details

Name
Thiopurine S-methyltransferase
Synonyms
  • 2.1.1.67
  • Thiopurine methyltransferase
Gene Name
TPMT
Organism
Humans
Amino acid sequence
>lcl|BSEQ0001965|Thiopurine S-methyltransferase
MDGTRTSLDIEEYSDTEVQKNQVLTLEEWQDKWVNGKTAFHQEQGHQLLKKHLDTFLKGK
SGLRVFFPLCGKAVEMKWFADRGHSVVGVEISELGIQEFFTEQNLSYSEEPITEIPGTKV
FKSSSGNISLYCCSIFDLPRTNIGKFDMIWDRGALVAINPGDRKCYADTMFSLLGKKFQY
LLCVLSYDPTKHPGPPFYVPHAEIERLFGKICNIRCLEKVDAFEERHKSWGIDCLFEKLY
LLTEK
Number of residues
245
Molecular Weight
28180.09
Theoretical pI
6.16
GO Classification
Functions
thiopurine S-methyltransferase activity
Processes
methylation / nucleobase-containing compound metabolic process / small molecule metabolic process / xenobiotic metabolic process
Components
cytosol / extracellular exosome
General Function
Thiopurine s-methyltransferase activity
Specific Function
Catalyzes the S-methylation of thiopurine drugs such as 6-mercaptopurine.
Pfam Domain Function
Transmembrane Regions
Not Available
Cellular Location
Cytoplasm
Gene sequence
>lcl|BSEQ0010692|Thiopurine S-methyltransferase (TPMT)
ATGGATGGTACAAGAACTTCACTTGACATTGAAGAGTACTCGGATACTGAGGTACAGAAA
AACCAAGTACTAACTCTGGAAGAATGGCAAGACAAGTGGGTGAACGGCAAGACTGCTTTT
CATCAGGAACAAGGACATCAGCTATTAAAGAAGCATTTAGATACTTTCCTTAAAGGCAAG
AGTGGACTGAGGGTATTTTTTCCTCTTTGCGGAAAAGCGGTTGAGATGAAATGGTTTGCA
GACCGGGGACACAGTGTAGTTGGTGTGGAAATCAGTGAACTTGGGATACAAGAATTTTTT
ACAGAGCAGAATCTTTCTTACTCAGAAGAACCAATCACCGAAATTCCTGGAACCAAAGTA
TTTAAGAGTTCTTCGGGGAACATTTCATTGTACTGTTGCAGTATTTTTGATCTTCCCAGG
ACAAATATTGGCAAATTTGACATGATTTGGGATAGAGGAGCATTAGTTGCCATTAATCCA
GGTGATCGCAAATGCTATGCAGATACAATGTTTTCCCTCCTGGGAAAGAAGTTTCAGTAT
CTCCTGTGTGTTCTTTCTTATGATCCAACTAAACATCCAGGTCCACCATTTTATGTTCCA
CATGCTGAAATTGAAAGGTTGTTTGGTAAAATATGCAATATACGTTGTCTTGAGAAGGTT
GATGCTTTTGAAGAACGACATAAAAGTTGGGGAATTGACTGTCTTTTTGAAAAGTTATAT
CTACTTACAGAAAAGTAA
Chromosome Location
6
Locus
6p22.3
External Identifiers
ResourceLink
UniProtKB IDP51580
UniProtKB Entry NameTPMT_HUMAN
GenBank Protein ID386420
GenBank Gene IDS62904
GenAtlas IDTPMT
HGNC IDHGNC:12014
General References
  1. Honchel R, Aksoy IA, Szumlanski C, Wood TC, Otterness DM, Wieben ED, Weinshilboum RM: Human thiopurine methyltransferase: molecular cloning and expression of T84 colon carcinoma cell cDNA. Mol Pharmacol. 1993 Jun;43(6):878-87. [PubMed:8316220]
  2. Lee D, Szumlanski C, Houtman J, Honchel R, Rojas K, Overhauser J, Wieben ED, Weinshilboum RM: Thiopurine methyltransferase pharmacogenetics. Cloning of human liver cDNA and a processed pseudogene on human chromosome 18q21.1. Drug Metab Dispos. 1995 Mar;23(3):398-405. [PubMed:7628307]
  3. Szumlanski C, Otterness D, Her C, Lee D, Brandriff B, Kelsell D, Spurr N, Lennard L, Wieben E, Weinshilboum R: Thiopurine methyltransferase pharmacogenetics: human gene cloning and characterization of a common polymorphism. DNA Cell Biol. 1996 Jan;15(1):17-30. [PubMed:8561894]
  4. Krynetski EY, Fessing MY, Yates CR, Sun D, Schuetz JD, Evans WE: Promoter and intronic sequences of the human thiopurine S-methyltransferase (TPMT) gene isolated from a human PAC1 genomic library. Pharm Res. 1997 Dec;14(12):1672-8. [PubMed:9453052]
  5. Otterness D, Szumlanski C, Lennard L, Klemetsdal B, Aarbakke J, Park-Hah JO, Iven H, Schmiegelow K, Branum E, O'Brien J, Weinshilboum R: Human thiopurine methyltransferase pharmacogenetics: gene sequence polymorphisms. Clin Pharmacol Ther. 1997 Jul;62(1):60-73. [PubMed:9246020]
  6. Mungall AJ, Palmer SA, Sims SK, Edwards CA, Ashurst JL, Wilming L, Jones MC, Horton R, Hunt SE, Scott CE, Gilbert JG, Clamp ME, Bethel G, Milne S, Ainscough R, Almeida JP, Ambrose KD, Andrews TD, Ashwell RI, Babbage AK, Bagguley CL, Bailey J, Banerjee R, Barker DJ, Barlow KF, Bates K, Beare DM, Beasley H, Beasley O, Bird CP, Blakey S, Bray-Allen S, Brook J, Brown AJ, Brown JY, Burford DC, Burrill W, Burton J, Carder C, Carter NP, Chapman JC, Clark SY, Clark G, Clee CM, Clegg S, Cobley V, Collier RE, Collins JE, Colman LK, Corby NR, Coville GJ, Culley KM, Dhami P, Davies J, Dunn M, Earthrowl ME, Ellington AE, Evans KA, Faulkner L, Francis MD, Frankish A, Frankland J, French L, Garner P, Garnett J, Ghori MJ, Gilby LM, Gillson CJ, Glithero RJ, Grafham DV, Grant M, Gribble S, Griffiths C, Griffiths M, Hall R, Halls KS, Hammond S, Harley JL, Hart EA, Heath PD, Heathcott R, Holmes SJ, Howden PJ, Howe KL, Howell GR, Huckle E, Humphray SJ, Humphries MD, Hunt AR, Johnson CM, Joy AA, Kay M, Keenan SJ, Kimberley AM, King A, Laird GK, Langford C, Lawlor S, Leongamornlert DA, Leversha M, Lloyd CR, Lloyd DM, Loveland JE, Lovell J, Martin S, Mashreghi-Mohammadi M, Maslen GL, Matthews L, McCann OT, McLaren SJ, McLay K, McMurray A, Moore MJ, Mullikin JC, Niblett D, Nickerson T, Novik KL, Oliver K, Overton-Larty EK, Parker A, Patel R, Pearce AV, Peck AI, Phillimore B, Phillips S, Plumb RW, Porter KM, Ramsey Y, Ranby SA, Rice CM, Ross MT, Searle SM, Sehra HK, Sheridan E, Skuce CD, Smith S, Smith M, Spraggon L, Squares SL, Steward CA, Sycamore N, Tamlyn-Hall G, Tester J, Theaker AJ, Thomas DW, Thorpe A, Tracey A, Tromans A, Tubby B, Wall M, Wallis JM, West AP, White SS, Whitehead SL, Whittaker H, Wild A, Willey DJ, Wilmer TE, Wood JM, Wray PW, Wyatt JC, Young L, Younger RM, Bentley DR, Coulson A, Durbin R, Hubbard T, Sulston JE, Dunham I, Rogers J, Beck S: The DNA sequence and analysis of human chromosome 6. Nature. 2003 Oct 23;425(6960):805-11. [PubMed:14574404]
  7. Gerhard DS, Wagner L, Feingold EA, Shenmen CM, Grouse LH, Schuler G, Klein SL, Old S, Rasooly R, Good P, Guyer M, Peck AM, Derge JG, Lipman D, Collins FS, Jang W, Sherry S, Feolo M, Misquitta L, Lee E, Rotmistrovsky K, Greenhut SF, Schaefer CF, Buetow K, Bonner TI, Haussler D, Kent J, Kiekhaus M, Furey T, Brent M, Prange C, Schreiber K, Shapiro N, Bhat NK, Hopkins RF, Hsie F, Driscoll T, Soares MB, Casavant TL, Scheetz TE, Brown-stein MJ, Usdin TB, Toshiyuki S, Carninci P, Piao Y, Dudekula DB, Ko MS, Kawakami K, Suzuki Y, Sugano S, Gruber CE, Smith MR, Simmons B, Moore T, Waterman R, Johnson SL, Ruan Y, Wei CL, Mathavan S, Gunaratne PH, Wu J, Garcia AM, Hulyk SW, Fuh E, Yuan Y, Sneed A, Kowis C, Hodgson A, Muzny DM, McPherson J, Gibbs RA, Fahey J, Helton E, Ketteman M, Madan A, Rodrigues S, Sanchez A, Whiting M, Madari A, Young AC, Wetherby KD, Granite SJ, Kwong PN, Brinkley CP, Pearson RL, Bouffard GG, Blakesly RW, Green ED, Dickson MC, Rodriguez AC, Grimwood J, Schmutz J, Myers RM, Butterfield YS, Griffith M, Griffith OL, Krzywinski MI, Liao N, Morin R, Palmquist D, Petrescu AS, Skalska U, Smailus DE, Stott JM, Schnerch A, Schein JE, Jones SJ, Holt RA, Baross A, Marra MA, Clifton S, Makowski KA, Bosak S, Malek J: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome Res. 2004 Oct;14(10B):2121-7. [PubMed:15489334]
  8. Spire-Vayron de la Moureyre C, Debuysere H, Sabbagh N, Marez D, Vinner E, Chevalier ED, Lo Guidice JM, Broly F: Detection of known and new mutations in the thiopurine S-methyltransferase gene by single-strand conformation polymorphism analysis. Hum Mutat. 1998;12(3):177-85. [PubMed:9711875]
  9. Peng Y, Feng Q, Wilk D, Adjei AA, Salavaggione OE, Weinshilboum RM, Yee VC: Structural basis of substrate recognition in thiopurine s-methyltransferase. Biochemistry. 2008 Jun 10;47(23):6216-25. doi: 10.1021/bi800102x. Epub 2008 May 17. [PubMed:18484748]
  10. Dephoure N, Zhou C, Villen J, Beausoleil SA, Bakalarski CE, Elledge SJ, Gygi SP: A quantitative atlas of mitotic phosphorylation. Proc Natl Acad Sci U S A. 2008 Aug 5;105(31):10762-7. doi: 10.1073/pnas.0805139105. Epub 2008 Jul 31. [PubMed:18669648]
  11. Han G, Ye M, Zhou H, Jiang X, Feng S, Jiang X, Tian R, Wan D, Zou H, Gu J: Large-scale phosphoproteome analysis of human liver tissue by enrichment and fractionation of phosphopeptides with strong anion exchange chromatography. Proteomics. 2008 Apr;8(7):1346-61. doi: 10.1002/pmic.200700884. [PubMed:18318008]
  12. Mayya V, Lundgren DH, Hwang SI, Rezaul K, Wu L, Eng JK, Rodionov V, Han DK: Quantitative phosphoproteomic analysis of T cell receptor signaling reveals system-wide modulation of protein-protein interactions. Sci Signal. 2009 Aug 18;2(84):ra46. doi: 10.1126/scisignal.2000007. [PubMed:19690332]
  13. Choudhary C, Kumar C, Gnad F, Nielsen ML, Rehman M, Walther TC, Olsen JV, Mann M: Lysine acetylation targets protein complexes and co-regulates major cellular functions. Science. 2009 Aug 14;325(5942):834-40. doi: 10.1126/science.1175371. Epub 2009 Jul 16. [PubMed:19608861]
  14. Burkard TR, Planyavsky M, Kaupe I, Breitwieser FP, Burckstummer T, Bennett KL, Superti-Furga G, Colinge J: Initial characterization of the human central proteome. BMC Syst Biol. 2011 Jan 26;5:17. doi: 10.1186/1752-0509-5-17. [PubMed:21269460]
  15. Bian Y, Song C, Cheng K, Dong M, Wang F, Huang J, Sun D, Wang L, Ye M, Zou H: An enzyme assisted RP-RPLC approach for in-depth analysis of human liver phosphoproteome. J Proteomics. 2014 Jan 16;96:253-62. doi: 10.1016/j.jprot.2013.11.014. Epub 2013 Nov 22. [PubMed:24275569]
  16. Wu H, Horton JR, Battaile K, Allali-Hassani A, Martin F, Zeng H, Loppnau P, Vedadi M, Bochkarev A, Plotnikov AN, Cheng X: Structural basis of allele variation of human thiopurine-S-methyltransferase. Proteins. 2007 Apr 1;67(1):198-208. [PubMed:17243178]
  17. Krynetski EY, Schuetz JD, Galpin AJ, Pui CH, Relling MV, Evans WE: A single point mutation leading to loss of catalytic activity in human thiopurine S-methyltransferase. Proc Natl Acad Sci U S A. 1995 Feb 14;92(4):949-53. [PubMed:7862671]
  18. Tai HL, Krynetski EY, Yates CR, Loennechen T, Fessing MY, Krynetskaia NF, Evans WE: 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. 1996 Apr;58(4):694-702. [PubMed:8644731]
  19. Leipold G, Schutz E, Haas JP, Oellerich M: 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. 1997 Oct;40(10):1896-8. [PubMed:9336428]
  20. Tai HL, Krynetski EY, Schuetz EG, Yanishevski Y, Evans WE: 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. 1997 Jun 10;94(12):6444-9. [PubMed:9177237]
  21. Ameyaw MM, Collie-Duguid ES, Powrie RH, Ofori-Adjei D, McLeod HL: Thiopurine methyltransferase alleles in British and Ghanaian populations. Hum Mol Genet. 1999 Feb;8(2):367-70. [PubMed:9931345]
  22. Hon YY, Fessing MY, Pui CH, Relling MV, Krynetski EY, Evans WE: Polymorphism of the thiopurine S-methyltransferase gene in African-Americans. Hum Mol Genet. 1999 Feb;8(2):371-6. [PubMed:9931346]
  23. Collie-Duguid ES, Pritchard SC, Powrie RH, Sludden J, Collier DA, Li T, McLeod HL: The frequency and distribution of thiopurine methyltransferase alleles in Caucasian and Asian populations. Pharmacogenetics. 1999 Feb;9(1):37-42. [PubMed:10208641]
  24. Hiratsuka M, Inoue T, Omori F, Agatsuma Y, Mizugaki M: Genetic analysis of thiopurine methyltransferase polymorphism in a Japanese population. Mutat Res. 2000 Mar 14;448(1):91-5. [PubMed:10751626]
  25. Salavaggione OE, Wang L, Wiepert M, Yee VC, Weinshilboum RM: Thiopurine S-methyltransferase pharmacogenetics: variant allele functional and comparative genomics. Pharmacogenet Genomics. 2005 Nov;15(11):801-15. [PubMed:16220112]
  26. Kurzawski M, Dziewanowski K, Ciechanowski K, Drozdzik M: Severe azathioprine-induced myelotoxicity in a kidney transplant patient with thiopurine S-methyltransferase-deficient genotype (TPMT*3A/*3C). Transpl Int. 2005 May;18(5):623-5. [PubMed:15819814]
  27. Lu HF, Shih MC, Chang YS, Chang JY, Ko YC, Chang SJ, Chang JG: Molecular analysis of thiopurine S-methyltransferase alleles in Taiwan aborigines and Taiwanese. J Clin Pharm Ther. 2006 Feb;31(1):93-8. [PubMed:16476125]
  28. Rossino R, Vincis C, Alves S, Prata MJ, Macis MD, Nucaro AL, Schirru E, Congia M: Frequency of the thiopurine S-methyltransferase alleles in the ancient genetic population isolate of Sardinia. J Clin Pharm Ther. 2006 Jun;31(3):283-7. [PubMed:16789994]

Drug Relations

Drug Relations
DrugBank IDNameDrug groupPharmacological action?ActionsDetails
DB00993AzathioprineapprovedunknownsubstrateDetails
DB01033MercaptopurineapprovedunknownsubstrateDetails
DB01250OlsalazineapprovedyesinhibitorDetails
DB00436BendroflumethiazideapprovedunknowninhibitorDetails
DB01327CefazolinapprovedunknownsubstrateDetails
DB01021Trichlormethiazideapproved, vet_approvedunknowninhibitorDetails