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TPMT_HUMAN
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   03-AUG-2022, entry version 202.
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=0.20 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};
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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; 8.
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; P51580; -.
DR   PeptideAtlas; P51580; -.
DR   PRIDE; P51580; -.
DR   ProteomicsDB; 56338; -.
DR   Antibodypedia; 10352; 431 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   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   Orphanet; 240863; Prediction of cisplatin toxicity.
DR   Orphanet; 413687; Prediction of toxicity or dose selection of azathioprine or 6-mercatopurine.
DR   Orphanet; 3315; Thiopurine S-methyltransferase deficiency.
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; 1590477at2759; -.
DR   PhylomeDB; P51580; -.
DR   TreeFam; TF328951; -.
DR   BioCyc; MetaCyc:HS06327-MON; -.
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   SignaLink; P51580; -.
DR   BioGRID-ORCS; 7172; 9 hits in 1038 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 202 other tissues.
DR   ExpressionAtlas; P51580; baseline and differential.
DR   Genevisible; P51580; HS.
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; -; 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   Pfam; PF05724; TPMT; 1.
DR   PIRSF; PIRSF023956; Thiopurine_S-methyltransferase; 1.
DR   SUPFAM; SSF53335; SSF53335; 1.
DR   PROSITE; PS51585; SAM_MT_TPMT; 1.
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
 
 
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