ID TPMT_HUMAN Reviewed; 245 AA. AC P51580; O14806; O15423; O15424; O15425; O15426; O15515; O15548; O43213; AC Q5VUK6; Q9UBE6; Q9UBT8; Q9UE62; DT 01-OCT-1996, integrated into UniProtKB/Swiss-Prot. DT 01-OCT-1996, sequence version 1. DT 24-JAN-2024, entry version 210. DE RecName: Full=Thiopurine S-methyltransferase {ECO:0000303|PubMed:18484748}; DE EC=2.1.1.67 {ECO:0000269|PubMed:18484748, ECO:0000269|PubMed:657528}; DE AltName: Full=Thiopurine methyltransferase {ECO:0000303|PubMed:657528}; GN Name=TPMT; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA], AND PARTIAL PROTEIN SEQUENCE. RC TISSUE=Kidney; RX PubMed=8316220; RA Honchel R., Aksoy I.A., Szumlanski C., Wood T.C., Otterness D.M., RA Wieben E.D., Weinshilboum R.M.; RT "Human thiopurine methyltransferase: molecular cloning and expression of RT T84 colon carcinoma cell cDNA."; RL Mol. Pharmacol. 43:878-887(1993). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA]. RX PubMed=7628307; RA Lee D., Szumlanski C.L., Houtman J., Honchel R., Rojas K., Overhauser J., RA Weiben E.D., Weinshilboum R.M.; RT "Thiopurine methyltransferase pharmacogenetics. Cloning of human liver cDNA RT and a processed pseudogene on human chromosome 18q21.1."; RL Drug Metab. Dispos. 23:398-405(1995). RN [3] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS THR-154 AND CYS-240. RX PubMed=8561894; DOI=10.1089/dna.1996.15.17; RA Szumlanski C., Otterness D., Her C., Lee D., Brandriff B., Kelsell D., RA Spurr N., Lennard L., Wieben E., Weinshilboum R.M.; RT "Thiopurine methyltransferase pharmacogenetics: human gene cloning and RT characterization of a common polymorphism."; RL DNA Cell Biol. 15:17-30(1996). RN [4] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RX PubMed=9453052; DOI=10.1023/a:1012111325397; RA Krynetski E.Y., Fessing M.Y., Yates C.R., Sun D., Schuetz J.D., Evans W.E.; RT "Promoter and intronic sequences of the human thiopurine S- RT methyltransferase (TPMT) gene isolated from a human PAC1 genomic library."; RL Pharm. Res. 14:1672-1678(1997). RN [5] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS SER-49; THR-154; PHE-180 RP AND CYS-240. RX PubMed=9246020; DOI=10.1016/s0009-9236(97)90152-1; RA Otterness D., Szumlanski C., Lennard L., Klemetsdal B., Aarbakke J., RA Park-Hah J.O., Iven H., Schmiegelow K., Branum E., O'Brien J., RA Weinshilboum R.M.; RT "Human thiopurine methyltransferase pharmacogenetics: gene sequence RT polymorphisms."; RL Clin. Pharmacol. Ther. 62:60-73(1997). RN [6] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RA Nakamura Y.; RT "Genomic structure of thiopurine S-methyltransferase gene."; RL Submitted (JUN-2000) to the EMBL/GenBank/DDBJ databases. RN [7] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=14574404; DOI=10.1038/nature02055; RA Mungall A.J., Palmer S.A., Sims S.K., Edwards C.A., Ashurst J.L., RA Wilming L., Jones M.C., Horton R., Hunt S.E., Scott C.E., Gilbert J.G.R., RA Clamp M.E., Bethel G., Milne S., Ainscough R., Almeida J.P., Ambrose K.D., RA Andrews T.D., Ashwell R.I.S., Babbage A.K., Bagguley C.L., Bailey J., RA Banerjee R., Barker D.J., Barlow K.F., Bates K., Beare D.M., Beasley H., RA Beasley O., Bird C.P., Blakey S.E., Bray-Allen S., Brook J., Brown A.J., RA Brown J.Y., Burford D.C., Burrill W., Burton J., Carder C., Carter N.P., RA Chapman J.C., Clark S.Y., Clark G., Clee C.M., Clegg S., Cobley V., RA Collier R.E., Collins J.E., Colman L.K., Corby N.R., Coville G.J., RA Culley K.M., Dhami P., Davies J., Dunn M., Earthrowl M.E., Ellington A.E., RA Evans K.A., Faulkner L., Francis M.D., Frankish A., Frankland J., RA French L., Garner P., Garnett J., Ghori M.J., Gilby L.M., Gillson C.J., RA Glithero R.J., Grafham D.V., Grant M., Gribble S., Griffiths C., RA Griffiths M.N.D., Hall R., Halls K.S., Hammond S., Harley J.L., Hart E.A., RA Heath P.D., Heathcott R., Holmes S.J., Howden P.J., Howe K.L., Howell G.R., RA Huckle E., Humphray S.J., Humphries M.D., Hunt A.R., Johnson C.M., RA Joy A.A., Kay M., Keenan S.J., Kimberley A.M., King A., Laird G.K., RA Langford C., Lawlor S., Leongamornlert D.A., Leversha M., Lloyd C.R., RA Lloyd D.M., Loveland J.E., Lovell J., Martin S., Mashreghi-Mohammadi M., RA Maslen G.L., Matthews L., McCann O.T., McLaren S.J., McLay K., McMurray A., RA Moore M.J.F., Mullikin J.C., Niblett D., Nickerson T., Novik K.L., RA Oliver K., Overton-Larty E.K., Parker A., Patel R., Pearce A.V., Peck A.I., RA Phillimore B.J.C.T., Phillips S., Plumb R.W., Porter K.M., Ramsey Y., RA Ranby S.A., Rice C.M., Ross M.T., Searle S.M., Sehra H.K., Sheridan E., RA Skuce C.D., Smith S., Smith M., Spraggon L., Squares S.L., Steward C.A., RA Sycamore N., Tamlyn-Hall G., Tester J., Theaker A.J., Thomas D.W., RA Thorpe A., Tracey A., Tromans A., Tubby B., Wall M., Wallis J.M., RA West A.P., White S.S., Whitehead S.L., Whittaker H., Wild A., Willey D.J., RA Wilmer T.E., Wood J.M., Wray P.W., Wyatt J.C., Young L., Younger R.M., RA Bentley D.R., Coulson A., Durbin R.M., Hubbard T., Sulston J.E., Dunham I., RA Rogers J., Beck S.; RT "The DNA sequence and analysis of human chromosome 6."; RL Nature 425:805-811(2003). RN [8] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Bone marrow; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [9] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 210-245, AND VARIANT GLN-227. RX PubMed=9711875; RX DOI=10.1002/(sici)1098-1004(1998)12:3<177::aid-humu5>3.0.co;2-e; RA Spire-Vayron de la Moureyre C., Debuysere H., Sabbagh N., Marez D., RA Vinner E., Chevalier E.D., Lo-Guidice J.-M., Broly F.; RT "Detection of known and new mutations in the thiopurine S-methyltransferase RT gene by single-strand conformation polymorphism analysis."; RL Hum. Mutat. 12:177-185(1998). RN [10] RP FUNCTION, CATALYTIC ACTIVITY, AND BIOPHYSICOCHEMICAL PROPERTIES. RC TISSUE=Blood, Erythrocyte, and Kidney; RX PubMed=657528; DOI=10.1016/0009-8981(78)90311-x; RA Weinshilboum R.M., Raymond F.A., Pazmino P.A.; RT "Human erythrocyte thiopurine methyltransferase: radiochemical microassay RT and biochemical properties."; RL Clin. Chim. Acta 85:323-333(1978). RN [11] RP CATALYTIC ACTIVITY, FUNCTION, BIOPHYSICOCHEMICAL PROPERTIES, AND RP MUTAGENESIS OF ARG-152. RX PubMed=18484748; DOI=10.1021/bi800102x; RA Peng Y., Feng Q., Wilk D., Adjei A.A., Salavaggione O.E., RA Weinshilboum R.M., Yee V.C.; RT "Structural basis of substrate recognition in thiopurine S- RT methyltransferase."; RL Biochemistry 47:6216-6225(2008). RN [12] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-14, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=18669648; DOI=10.1073/pnas.0805139105; RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., RA Elledge S.J., Gygi S.P.; RT "A quantitative atlas of mitotic phosphorylation."; RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008). RN [13] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Liver; RX PubMed=18318008; DOI=10.1002/pmic.200700884; RA Han G., Ye M., Zhou H., Jiang X., Feng S., Jiang X., Tian R., Wan D., RA Zou H., Gu J.; RT "Large-scale phosphoproteome analysis of human liver tissue by enrichment RT and fractionation of phosphopeptides with strong anion exchange RT chromatography."; RL Proteomics 8:1346-1361(2008). RN [14] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-14, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Leukemic T-cell; RX PubMed=19690332; DOI=10.1126/scisignal.2000007; RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K., RA Rodionov V., Han D.K.; RT "Quantitative phosphoproteomic analysis of T cell receptor signaling RT reveals system-wide modulation of protein-protein interactions."; RL Sci. Signal. 2:RA46-RA46(2009). RN [15] RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-58, AND IDENTIFICATION BY MASS RP SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=19608861; DOI=10.1126/science.1175371; RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M., Walther T.C., RA Olsen J.V., Mann M.; RT "Lysine acetylation targets protein complexes and co-regulates major RT cellular functions."; RL Science 325:834-840(2009). RN [16] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=21269460; DOI=10.1186/1752-0509-5-17; RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., RA Bennett K.L., Superti-Furga G., Colinge J.; RT "Initial characterization of the human central proteome."; RL BMC Syst. Biol. 5:17-17(2011). RN [17] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma, and Erythroleukemia; RX PubMed=23186163; DOI=10.1021/pr300630k; RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J., RA Mohammed S.; RT "Toward a comprehensive characterization of a human cancer cell RT phosphoproteome."; RL J. Proteome Res. 12:260-271(2013). RN [18] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-14, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Liver; RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014; RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L., RA Ye M., Zou H.; RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver RT phosphoproteome."; RL J. Proteomics 96:253-262(2014). RN [19] RP X-RAY CRYSTALLOGRAPHY (1.58 ANGSTROMS) OF 16-245 IN COMPLEX WITH RP S-ADENOSYL-L-HOMOCYSTEINE, SUBUNIT, AND CHARACTERIZATION OF VARIANTS RP THR-154 AND CYS-240. RX PubMed=17243178; DOI=10.1002/prot.21272; RA Wu H., Horton J.R., Battaile K., Allali-Hassani A., Martin F., Zeng H., RA Loppnau P., Vedadi M., Bochkarev A., Plotnikov A.N., Cheng X.; RT "Structural basis of allele variation of human thiopurine-S- RT methyltransferase."; RL Proteins 67:198-208(2007). RN [20] RP VARIANT PRO-80. RX PubMed=7862671; DOI=10.1073/pnas.92.4.949; RA Krynetski E.Y., Schuetz J.D., Galpin A.J., Pui C.-H., Relling M.V., RA Evans W.E.; RT "A single point mutation leading to loss of catalytic activity in human RT thiopurine S-methyltransferase."; RL Proc. Natl. Acad. Sci. U.S.A. 92:949-953(1995). RN [21] RP VARIANTS THR-154 AND CYS-240. RX PubMed=8644731; RA Tai H.-L., Krynetski E.Y., Yates C.R., Loennechen T., Fessing M.Y., RA Krynetskaia N.F., Evans W.E.; RT "Thiopurine S-methyltransferase deficiency: two nucleotide transitions RT define the most prevalent mutant allele associated with loss of catalytic RT activity in Caucasians."; RL Am. J. Hum. Genet. 58:694-702(1996). RN [22] RP VARIANTS THR-154 AND CYS-240. RX PubMed=9336428; DOI=10.1002/art.1780401026; RA Leipold G., Schuetz E., Haas J.P., Oellerich M.; RT "Azathioprine-induced severe pancytopenia due to a homozygous two-point RT mutation of the thiopurine methyltransferase gene in a patient with RT juvenile HLA-B27-associated spondylarthritis."; RL Arthritis Rheum. 40:1896-1898(1997). RN [23] RP CHARACTERIZATION OF VARIANTS PRO-80 AND THR-154, AND MECHANISM FOR THE RP GENETIC POLYMORPHISM OF TPMT ACTIVITY. RX PubMed=9177237; DOI=10.1073/pnas.94.12.6444; RA Tai H.-L., Krynetski E.Y., Schuetz E.G., Yanishevski Y., Evans W.E.; RT "Enhanced proteolysis of thiopurine S-methyltransferase (TPMT) encoded by RT mutant alleles in humans (TPMT*3A, TPMT*2): mechanisms for the genetic RT polymorphism of TPMT activity."; RL Proc. Natl. Acad. Sci. U.S.A. 94:6444-6449(1997). RN [24] RP VARIANTS PRO-80; THR-154 AND CYS-240. RX PubMed=9931345; DOI=10.1093/hmg/8.2.367; RA Ameyaw M.-M., Collie-Duguid E.S.R., Powrie R.H., Ofori-Adjei D., RA McLeod H.L.; RT "Thiopurine methyltransferase alleles in British and Ghanaian RT populations."; RL Hum. Mol. Genet. 8:367-370(1999). RN [25] RP VARIANT HIS-215. RX PubMed=9931346; DOI=10.1093/hmg/8.2.371; RA Hon Y.Y., Fessing M.Y., Pui C.-H., Relling M.V., Krynetski E.Y., RA Evans W.E.; RT "Polymorphism of the thiopurine S-methyltransferase gene in African- RT Americans."; RL Hum. Mol. Genet. 8:371-376(1999). RN [26] RP VARIANTS PRO-80; THR-154 AND CYS-240, AND FREQUENCY AND DISTRIBUTION OF RP ALLELES. RX PubMed=10208641; DOI=10.1097/00008571-199902000-00006; RA Collie-Duguid E.S.R., Pritchard S.C., Powrie R.H., Sludden J., RA Collier D.A., Li T., McLeod H.L.; RT "The frequency and distribution of thiopurine methyltransferase alleles in RT Caucasian and Asian populations."; RL Pharmacogenetics 9:37-42(1999). RN [27] RP VARIANTS PRO-80; THR-154 AND CYS-240, AND FREQUENCY AND DISTRIBUTION OF RP ALLELES. RX PubMed=10751626; DOI=10.1016/s0027-5107(00)00004-x; RA Hiratsuka M., Inoue T., Omori F., Agatsuma Y., Mizugaki M.; RT "Genetic analysis of thiopurine methyltransferase polymorphism in a RT Japanese population."; RL Mutat. Res. 448:91-95(2000). RN [28] RP VARIANTS SER-49; PRO-80; THR-154; PHE-180; HIS-215; GLN-227 AND CYS-240, RP AND CHARACTERIZATION OF VARIANTS SER-49; PRO-80; THR-154; PHE-180; HIS-215; RP GLN-227 AND CYS-240. RX PubMed=16220112; DOI=10.1097/01.fpc.0000174788.69991.6b; RA Salavaggione O.E., Wang L., Wiepert M., Yee V.C., Weinshilboum R.M.; RT "Thiopurine S-methyltransferase pharmacogenetics: variant allele functional RT and comparative genomics."; RL Pharmacogenet. Genomics 15:801-815(2005). RN [29] RP VARIANTS THR-154 AND CYS-240. RX PubMed=15819814; DOI=10.1111/j.1432-2277.2005.00095.x; RA Kurzawski M., Dziewanowski K., Ciechanowski K., Drozdzik M.; RT "Severe azathioprine-induced myelotoxicity in a kidney transplant patient RT with thiopurine S-methyltransferase-deficient genotype (TPMT*3A/*3C)."; RL Transpl. Int. 18:623-625(2005). RN [30] RP VARIANTS PRO-80; THR-154 AND CYS-240, AND FREQUENCY AND DISTRIBUTION OF RP ALLELES. RX PubMed=16476125; DOI=10.1111/j.1365-2710.2006.00707.x; RA Lu H.-F., Shih M.-C., Chang Y.-S., Chang J.-Y., Ko Y.-C., Chang S.-J., RA Chang J.-G.; RT "Molecular analysis of thiopurine S-methyltransferase alleles in Taiwan RT aborigines and Taiwanese."; RL J. Clin. Pharm. Ther. 31:93-98(2006). RN [31] RP VARIANTS PRO-80; THR-154 AND CYS-240, AND FREQUENCY AND DISTRIBUTION OF RP ALLELES. RX PubMed=16789994; DOI=10.1111/j.1365-2710.2006.00736.x; RA Rossino R., Vincis C., Alves S., Prata M.J., Macis M.D., Nucaro A.L., RA Schirru E., Congia M.; RT "Frequency of the thiopurine S-methyltransferase alleles in the ancient RT genetic population isolate of Sardinia."; RL J. Clin. Pharm. Ther. 31:283-287(2006). CC -!- FUNCTION: Catalyzes the S-methylation of thiopurine drugs such as 6- CC mercaptopurine (also called mercaptopurine, 6-MP or its brand name CC Purinethol) and 6-thioguanine (also called tioguanine or 6-TG) using S- CC adenosyl-L-methionine as the methyl donor (PubMed:657528, CC PubMed:18484748). TPMT activity modulates the cytotoxic effects of CC thiopurine prodrugs. A natural substrate for this enzyme has yet to be CC identified. {ECO:0000269|PubMed:18484748, ECO:0000269|PubMed:657528, CC ECO:0000305}. CC -!- CATALYTIC ACTIVITY: CC Reaction=S-adenosyl-L-methionine + a thiopurine = S-adenosyl-L- CC homocysteine + a thiopurine S-methylether.; EC=2.1.1.67; CC Evidence={ECO:0000269|PubMed:18484748, ECO:0000269|PubMed:657528}; CC -!- CATALYTIC ACTIVITY: CC Reaction=mercaptopurine + S-adenosyl-L-methionine = 6-methylthiopurine CC + H(+) + S-adenosyl-L-homocysteine; Xref=Rhea:RHEA:12609, CC ChEBI:CHEBI:15378, ChEBI:CHEBI:28279, ChEBI:CHEBI:50667, CC ChEBI:CHEBI:57856, ChEBI:CHEBI:59789; EC=2.1.1.67; CC Evidence={ECO:0000269|PubMed:18484748, ECO:0000269|PubMed:657528}; CC -!- CATALYTIC ACTIVITY: CC Reaction=6-thioguanine + S-adenosyl-L-methionine = 6-methylthioguanine CC + H(+) + S-adenosyl-L-homocysteine; Xref=Rhea:RHEA:56580, CC ChEBI:CHEBI:9555, ChEBI:CHEBI:15378, ChEBI:CHEBI:57856, CC ChEBI:CHEBI:59789, ChEBI:CHEBI:140528; EC=2.1.1.67; CC Evidence={ECO:0000269|PubMed:657528}; CC -!- ACTIVITY REGULATION: Inhibited by S-adenosyl-L-homocysteine (SAH). CC -!- BIOPHYSICOCHEMICAL PROPERTIES: CC Kinetic parameters: CC KM=18.5 uM for S-adenosyl-L-methionine (at pH 6.5 and 37 degrees CC Celsius) {ECO:0000269|PubMed:18484748}; CC KM=0.68 mM for 6-mercaptopurine (at pH 6.5 and 37 degrees Celsius) CC {ECO:0000269|PubMed:18484748}; CC KM=1.7 uM for S-adenosyl-L-methionine (at pH 7.5 and 37 degrees CC Celsius) {ECO:0000269|PubMed:657528}; CC KM=0.32 mM for 6-mercaptopurine (at pH 7.5 and 37 degrees Celsius) CC {ECO:0000269|PubMed:657528}; CC KM=0.2 mM for 6-thioguanine (at pH 7.5 and 37 degrees Celsius) CC {ECO:0000269|PubMed:657528}; CC Vmax=1.23 nmol/sec/mg enzyme toward 6-mercaptopurine (at pH 6.5 and CC 37 degrees Celsius) {ECO:0000269|PubMed:18484748}; CC pH dependence: CC Optimum pH is 7.5. {ECO:0000269|PubMed:657528}; CC -!- SUBUNIT: Monomer. {ECO:0000269|PubMed:17243178}. CC -!- INTERACTION: CC P51580; Q8TAP4-4: LMO3; NbExp=3; IntAct=EBI-25902017, EBI-11742507; CC P51580; Q15047-2: SETDB1; NbExp=3; IntAct=EBI-25902017, EBI-9090795; CC P51580; P61981: YWHAG; NbExp=3; IntAct=EBI-25902017, EBI-359832; CC -!- SUBCELLULAR LOCATION: Cytoplasm. CC -!- POLYMORPHISM: Polymorphic variations define TPMT activity levels that CC are variable among ethnic groups. 90% of Caucasians have high TPMT CC activity, 10% have intermediate activity, and 1 in 300 individuals has CC low activity (PubMed:10208641). These differences influence the CC clinical use and therapeutic efficacy of thiopurine drugs, generally CC used as immunosuppressants or cytotoxic drugs in conditions including CC leukemia, autoimmune disease and organ transplantation. Intermediate or CC low TPMT activity is associated with thiopurine intolerance and CC patients are at risk of toxicity after receiving standard doses of CC thiopurine drugs [MIM:610460] (PubMed:10751626, PubMed:15819814, CC PubMed:16220112, PubMed:16476125, PubMed:16789994, PubMed:7862671, CC PubMed:8561894, PubMed:8644731, PubMed:9246020, PubMed:9336428, CC PubMed:9711875, PubMed:9931345, PubMed:9931346). The most prevalent CC TPMT alleles associated with TPMT deficiency are TPMT*2 and TPMT*3A. CC The proteins encoded by TPMT*2 and TPMT*3A mutant are degraded more CC rapidly by an ATP-dependent proteasome-mediated pathway CC (PubMed:9177237, PubMed:8644731). {ECO:0000269|PubMed:10208641, CC ECO:0000269|PubMed:10751626, ECO:0000269|PubMed:15819814, CC ECO:0000269|PubMed:16220112, ECO:0000269|PubMed:16476125, CC ECO:0000269|PubMed:16789994, ECO:0000269|PubMed:7862671, CC ECO:0000269|PubMed:8561894, ECO:0000269|PubMed:8644731, CC ECO:0000269|PubMed:9177237, ECO:0000269|PubMed:9246020, CC ECO:0000269|PubMed:9336428, ECO:0000269|PubMed:9711875, CC ECO:0000269|PubMed:9931345, ECO:0000269|PubMed:9931346}. CC -!- POLYMORPHISM: TPMT*3A is the most common allele in the Caucasians and CC American Caucasians; it is the only mutant allele found in the South CC West Asians; it is not found in the Chinese. TPMT*3C is common in CC African-Americans and is the only allele in Chinese, Japanese and CC Taiwanese individuals. This allele is found at a low frequency in the CC Caucasians. This suggests that TPMT*3C is the oldest mutation, with CC TPMT*3B being acquired later to form the TPMT*3A allele in the CC Caucasian and South West Asian populations. TPMT*2 appears to be a more CC recent allele, which has only been detected in Caucasians to date. CC {ECO:0000269|PubMed:10208641, ECO:0000269|PubMed:10751626, CC ECO:0000269|PubMed:16476125}. CC -!- SIMILARITY: Belongs to the class I-like SAM-binding methyltransferase CC superfamily. TPMT family. {ECO:0000305}. CC -!- SEQUENCE CAUTION: CC Sequence=AAB71631.1; Type=Erroneous initiation; Evidence={ECO:0000305}; CC Sequence=AAB71632.1; Type=Erroneous initiation; Evidence={ECO:0000305}; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; S62904; AAB27277.1; -; mRNA. DR EMBL; U12387; AAC50130.1; -; mRNA. DR EMBL; U30518; AAC50368.1; -; Genomic_DNA. DR EMBL; U30512; AAC50368.1; JOINED; Genomic_DNA. DR EMBL; U30513; AAC50368.1; JOINED; Genomic_DNA. DR EMBL; U30514; AAC50368.1; JOINED; Genomic_DNA. DR EMBL; U30515; AAC50368.1; JOINED; Genomic_DNA. DR EMBL; U30516; AAC50368.1; JOINED; Genomic_DNA. DR EMBL; U30517; AAC50368.1; JOINED; Genomic_DNA. DR EMBL; AF019369; AAC51865.1; -; Genomic_DNA. DR EMBL; AF019364; AAC51865.1; JOINED; Genomic_DNA. DR EMBL; AF019365; AAC51865.1; JOINED; Genomic_DNA. DR EMBL; AF019366; AAC51865.1; JOINED; Genomic_DNA. DR EMBL; AF019367; AAC51865.1; JOINED; Genomic_DNA. DR EMBL; AF019368; AAC51865.1; JOINED; Genomic_DNA. DR EMBL; U81562; AAB71625.1; -; Genomic_DNA. DR EMBL; U81563; AAB71626.1; -; Genomic_DNA. DR EMBL; U81564; AAB71627.1; -; Genomic_DNA. DR EMBL; U81565; AAB71628.1; -; Genomic_DNA. DR EMBL; U81566; AAB71629.1; -; Genomic_DNA. DR EMBL; U81567; AAB71630.1; -; Genomic_DNA. DR EMBL; U81568; AAB71631.1; ALT_INIT; Genomic_DNA. DR EMBL; U81569; AAB71632.1; ALT_INIT; Genomic_DNA. DR EMBL; U81570; AAB71633.1; -; Genomic_DNA. DR EMBL; U81571; AAB71634.1; -; Genomic_DNA. DR EMBL; U81572; AAB71635.1; -; Genomic_DNA. DR EMBL; U81573; AAB71636.1; -; Genomic_DNA. DR EMBL; AB045146; BAA97037.1; -; Genomic_DNA. DR EMBL; AL589723; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; BC009596; AAH09596.1; -; mRNA. DR EMBL; AF035426; AAC32289.1; -; Genomic_DNA. DR EMBL; AF021876; AAB80746.1; -; mRNA. DR EMBL; AF021877; AAB80747.1; -; mRNA. DR CCDS; CCDS4543.1; -. DR PIR; I57946; I57946. DR RefSeq; NP_000358.1; NM_000367.4. DR RefSeq; NP_001333746.1; NM_001346817.1. DR RefSeq; NP_001333747.1; NM_001346818.1. DR PDB; 2BZG; X-ray; 1.58 A; A=16-245. DR PDB; 2H11; X-ray; 1.89 A; A/B=17-245. DR PDBsum; 2BZG; -. DR PDBsum; 2H11; -. DR AlphaFoldDB; P51580; -. DR BMRB; P51580; -. DR SMR; P51580; -. DR BioGRID; 113025; 13. DR IntAct; P51580; 3. DR STRING; 9606.ENSP00000312304; -. DR BindingDB; P51580; -. DR ChEMBL; CHEMBL2500; -. DR DrugBank; DB00993; Azathioprine. DR DrugBank; DB00436; Bendroflumethiazide. DR DrugBank; DB01327; Cefazolin. DR DrugBank; DB01033; Mercaptopurine. DR DrugBank; DB01250; Olsalazine. DR DrugBank; DB01021; Trichlormethiazide. DR DrugCentral; P51580; -. DR GlyGen; P51580; 1 site, 1 O-linked glycan (1 site). DR iPTMnet; P51580; -. DR PhosphoSitePlus; P51580; -. DR BioMuta; TPMT; -. DR DMDM; 1730006; -. DR EPD; P51580; -. DR jPOST; P51580; -. DR MassIVE; P51580; -. DR MaxQB; P51580; -. DR PaxDb; 9606-ENSP00000312304; -. DR PeptideAtlas; P51580; -. DR ProteomicsDB; 56338; -. DR Pumba; P51580; -. DR Antibodypedia; 10352; 477 antibodies from 32 providers. DR DNASU; 7172; -. DR Ensembl; ENST00000309983.5; ENSP00000312304.4; ENSG00000137364.5. DR GeneID; 7172; -. DR KEGG; hsa:7172; -. DR MANE-Select; ENST00000309983.5; ENSP00000312304.4; NM_000367.5; NP_000358.1. DR UCSC; uc003ncm.4; human. DR AGR; HGNC:12014; -. DR CTD; 7172; -. DR DisGeNET; 7172; -. DR GeneCards; TPMT; -. DR HGNC; HGNC:12014; TPMT. DR HPA; ENSG00000137364; Tissue enhanced (kidney, liver, thyroid gland). DR MalaCards; TPMT; -. DR MIM; 187680; gene. DR MIM; 610460; phenotype. DR neXtProt; NX_P51580; -. DR OpenTargets; ENSG00000137364; -. DR PharmGKB; PA356; -. DR VEuPathDB; HostDB:ENSG00000137364; -. DR eggNOG; ENOG502QSF5; Eukaryota. DR GeneTree; ENSGT00390000016823; -. DR HOGENOM; CLU_085515_2_0_1; -. DR InParanoid; P51580; -. DR OMA; LWCGDFF; -. DR OrthoDB; 2902171at2759; -. DR PhylomeDB; P51580; -. DR TreeFam; TF328951; -. DR BioCyc; MetaCyc:HS06327-MONOMER; -. DR BRENDA; 2.1.1.67; 2681. DR PathwayCommons; P51580; -. DR Reactome; R-HSA-156581; Methylation. DR Reactome; R-HSA-5578995; Defective TPMT causes TPMT deficiency. DR Reactome; R-HSA-9748787; Azathioprine ADME. DR SABIO-RK; P51580; -. DR SignaLink; P51580; -. DR BioGRID-ORCS; 7172; 9 hits in 1121 CRISPR screens. DR ChiTaRS; TPMT; human. DR EvolutionaryTrace; P51580; -. DR GeneWiki; Thiopurine_methyltransferase; -. DR GenomeRNAi; 7172; -. DR Pharos; P51580; Tchem. DR PRO; PR:P51580; -. DR Proteomes; UP000005640; Chromosome 6. DR RNAct; P51580; Protein. DR Bgee; ENSG00000137364; Expressed in buccal mucosa cell and 204 other cell types or tissues. DR ExpressionAtlas; P51580; baseline and differential. DR GO; GO:0005829; C:cytosol; TAS:Reactome. DR GO; GO:1904047; F:S-adenosyl-L-methionine binding; IDA:UniProtKB. DR GO; GO:0008119; F:thiopurine S-methyltransferase activity; IDA:UniProtKB. DR GO; GO:0032259; P:methylation; TAS:Reactome. DR GO; GO:0006139; P:nucleobase-containing compound metabolic process; TAS:ProtInc. DR GO; GO:0042178; P:xenobiotic catabolic process; TAS:Reactome. DR GO; GO:0006805; P:xenobiotic metabolic process; IDA:UniProtKB. DR Gene3D; 3.40.50.150; Vaccinia Virus protein VP39; 1. DR HAMAP; MF_00812; Thiopur_methtran; 1. DR InterPro; IPR029063; SAM-dependent_MTases_sf. DR InterPro; IPR025835; Thiopurine_S-MeTrfase. DR InterPro; IPR008854; TPMT. DR PANTHER; PTHR10259; THIOPURINE S-METHYLTRANSFERASE; 1. DR PANTHER; PTHR10259:SF11; THIOPURINE S-METHYLTRANSFERASE; 1. DR Pfam; PF05724; TPMT; 1. DR PIRSF; PIRSF023956; Thiopurine_S-methyltransferase; 1. DR SUPFAM; SSF53335; S-adenosyl-L-methionine-dependent methyltransferases; 1. DR PROSITE; PS51585; SAM_MT_TPMT; 1. DR Genevisible; P51580; HS. PE 1: Evidence at protein level; KW 3D-structure; Acetylation; Cytoplasm; Direct protein sequencing; KW Methyltransferase; Phosphoprotein; Reference proteome; KW S-adenosyl-L-methionine; Transferase. FT CHAIN 1..245 FT /note="Thiopurine S-methyltransferase" FT /id="PRO_0000220102" FT BINDING 29..40 FT /ligand="S-adenosyl-L-methionine" FT /ligand_id="ChEBI:CHEBI:59789" FT BINDING 40 FT /ligand="substrate" FT /evidence="ECO:0000250" FT BINDING 69 FT /ligand="S-adenosyl-L-methionine" FT /ligand_id="ChEBI:CHEBI:59789" FT BINDING 90 FT /ligand="S-adenosyl-L-methionine" FT /ligand_id="ChEBI:CHEBI:59789" FT BINDING 134..135 FT /ligand="S-adenosyl-L-methionine" FT /ligand_id="ChEBI:CHEBI:59789" FT BINDING 152 FT /ligand="S-adenosyl-L-methionine" FT /ligand_id="ChEBI:CHEBI:59789" FT MOD_RES 14 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18669648, FT ECO:0007744|PubMed:19690332, ECO:0007744|PubMed:24275569" FT MOD_RES 58 FT /note="N6-acetyllysine" FT /evidence="ECO:0007744|PubMed:19608861" FT VARIANT 49 FT /note="L -> S (allele TPMT*5; has very low activity when FT expressed in a heterologous system; dbSNP:rs72552740)" FT /evidence="ECO:0000269|PubMed:16220112, FT ECO:0000269|PubMed:9246020" FT /id="VAR_005636" FT VARIANT 80 FT /note="A -> P (allele TPMT*2; TPMT*2 allele frequency is FT 0.5%; seems to be restricted to the Caucasian population; FT 100-fold reduction in activity; protein shows enhanced FT degradation; dbSNP:rs1800462)" FT /evidence="ECO:0000269|PubMed:10208641, FT ECO:0000269|PubMed:10751626, ECO:0000269|PubMed:16220112, FT ECO:0000269|PubMed:16476125, ECO:0000269|PubMed:16789994, FT ECO:0000269|PubMed:7862671, ECO:0000269|PubMed:9177237, FT ECO:0000269|PubMed:9931345" FT /id="VAR_005637" FT VARIANT 154 FT /note="A -> T (allele TPMT*3A and allele TPMT*3B; very low FT activity; protein shows enhanced degradation leading to FT strongly reduced protein levels; dbSNP:rs1800460)" FT /evidence="ECO:0000269|PubMed:10208641, FT ECO:0000269|PubMed:10751626, ECO:0000269|PubMed:15819814, FT ECO:0000269|PubMed:16220112, ECO:0000269|PubMed:16476125, FT ECO:0000269|PubMed:16789994, ECO:0000269|PubMed:17243178, FT ECO:0000269|PubMed:8561894, ECO:0000269|PubMed:8644731, FT ECO:0000269|PubMed:9177237, ECO:0000269|PubMed:9246020, FT ECO:0000269|PubMed:9336428, ECO:0000269|PubMed:9931345" FT /id="VAR_005638" FT VARIANT 179 FT /note="Q -> H (in dbSNP:rs6921269)" FT /id="VAR_052368" FT VARIANT 180 FT /note="Y -> F (allele TPMT*6; reduced activity; FT dbSNP:rs75543815)" FT /evidence="ECO:0000269|PubMed:16220112, FT ECO:0000269|PubMed:9246020" FT /id="VAR_005639" FT VARIANT 215 FT /note="R -> H (allele TPMT*8; intermediate activity; FT dbSNP:rs56161402)" FT /evidence="ECO:0000269|PubMed:16220112, FT ECO:0000269|PubMed:9931346" FT /id="VAR_008715" FT VARIANT 227 FT /note="H -> Q (allele TPMT*7; reduced activity; FT dbSNP:rs72552736)" FT /evidence="ECO:0000269|PubMed:16220112, FT ECO:0000269|PubMed:9711875" FT /id="VAR_005640" FT VARIANT 240 FT /note="Y -> C (allele TPMT*3B and allele TPMT*3C; reduced FT activity; protein shows enhanced degradation; FT dbSNP:rs1142345)" FT /evidence="ECO:0000269|PubMed:10208641, FT ECO:0000269|PubMed:10751626, ECO:0000269|PubMed:15819814, FT ECO:0000269|PubMed:16220112, ECO:0000269|PubMed:16476125, FT ECO:0000269|PubMed:16789994, ECO:0000269|PubMed:17243178, FT ECO:0000269|PubMed:8561894, ECO:0000269|PubMed:8644731, FT ECO:0000269|PubMed:9246020, ECO:0000269|PubMed:9336428, FT ECO:0000269|PubMed:9931345" FT /id="VAR_005641" FT MUTAGEN 152 FT /note="R->E: Decreases affinity for 6-mercaptopurine. FT Slightly decreases catalytic activity." FT /evidence="ECO:0000269|PubMed:18484748" FT TURN 18..21 FT /evidence="ECO:0007829|PDB:2BZG" FT HELIX 26..35 FT /evidence="ECO:0007829|PDB:2BZG" FT HELIX 47..57 FT /evidence="ECO:0007829|PDB:2BZG" FT STRAND 64..67 FT /evidence="ECO:0007829|PDB:2BZG" FT HELIX 75..81 FT /evidence="ECO:0007829|PDB:2BZG" FT STRAND 85..89 FT /evidence="ECO:0007829|PDB:2BZG" FT HELIX 93..102 FT /evidence="ECO:0007829|PDB:2BZG" FT STRAND 107..111 FT /evidence="ECO:0007829|PDB:2BZG" FT STRAND 119..123 FT /evidence="ECO:0007829|PDB:2BZG" FT STRAND 126..133 FT /evidence="ECO:0007829|PDB:2BZG" FT HELIX 135..140 FT /evidence="ECO:0007829|PDB:2BZG" FT STRAND 146..154 FT /evidence="ECO:0007829|PDB:2BZG" FT TURN 155..157 FT /evidence="ECO:0007829|PDB:2BZG" FT HELIX 160..162 FT /evidence="ECO:0007829|PDB:2BZG" FT HELIX 163..172 FT /evidence="ECO:0007829|PDB:2BZG" FT STRAND 174..186 FT /evidence="ECO:0007829|PDB:2BZG" FT TURN 189..191 FT /evidence="ECO:0007829|PDB:2BZG" FT HELIX 201..208 FT /evidence="ECO:0007829|PDB:2BZG" FT TURN 209..211 FT /evidence="ECO:0007829|PDB:2BZG" FT STRAND 212..221 FT /evidence="ECO:0007829|PDB:2BZG" FT HELIX 225..230 FT /evidence="ECO:0007829|PDB:2BZG" FT STRAND 236..244 FT /evidence="ECO:0007829|PDB:2BZG" SQ SEQUENCE 245 AA; 28180 MW; 190E781155B97BB9 CRC64; MDGTRTSLDI EEYSDTEVQK NQVLTLEEWQ DKWVNGKTAF HQEQGHQLLK KHLDTFLKGK SGLRVFFPLC GKAVEMKWFA DRGHSVVGVE ISELGIQEFF TEQNLSYSEE PITEIPGTKV FKSSSGNISL YCCSIFDLPR TNIGKFDMIW DRGALVAINP GDRKCYADTM FSLLGKKFQY LLCVLSYDPT KHPGPPFYVP HAEIERLFGK ICNIRCLEKV DAFEERHKSW GIDCLFEKLY LLTEK //