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P51580

- TPMT_HUMAN

UniProt

P51580 - TPMT_HUMAN

Protein

Thiopurine S-methyltransferase

Gene

TPMT

Organism
Homo sapiens (Human)
Status
Reviewed - Annotation score: 5 out of 5- Experimental evidence at protein leveli
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    • History
      Entry version 148 (01 Oct 2014)
      Sequence version 1 (01 Oct 1996)
      Previous versions | rss
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    Functioni

    Catalyzes the S-methylation of thiopurine drugs such as 6-mercaptopurine.1 Publication

    Catalytic activityi

    S-adenosyl-L-methionine + a thiopurine = S-adenosyl-L-homocysteine + a thiopurine S-methylether.1 Publication

    Enzyme regulationi

    Inhibited by S-adenosyl-L-homocysteine (SAH).

    Kineticsi

    1. KM=5.6 mM for S-adenosyl-L-methionine1 Publication
    2. KM=0.35 mM for 6-mercaptopurine1 Publication

    Vmax=0.6 nmol/sec/mg enzyme toward 6-mercaptopurine (at 37 degrees Celsius)1 Publication

    Sites

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Binding sitei40 – 401SubstrateBy similarity
    Binding sitei69 – 691S-adenosyl-L-methionine; via carbonyl oxygen
    Binding sitei90 – 901S-adenosyl-L-methionine
    Binding sitei152 – 1521S-adenosyl-L-methionine

    GO - Molecular functioni

    1. thiopurine S-methyltransferase activity Source: ProtInc

    GO - Biological processi

    1. methylation Source: Reactome
    2. nucleobase-containing compound metabolic process Source: ProtInc
    3. response to testosterone Source: Ensembl
    4. small molecule metabolic process Source: Reactome
    5. xenobiotic metabolic process Source: Reactome

    Keywords - Molecular functioni

    Methyltransferase, Transferase

    Keywords - Ligandi

    S-adenosyl-L-methionine

    Enzyme and pathway databases

    ReactomeiREACT_6946. Methylation.

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    Thiopurine S-methyltransferase (EC:2.1.1.67)
    Alternative name(s):
    Thiopurine methyltransferase
    Gene namesi
    Name:TPMT
    OrganismiHomo sapiens (Human)
    Taxonomic identifieri9606 [NCBI]
    Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
    ProteomesiUP000005640: Chromosome 6

    Organism-specific databases

    HGNCiHGNC:12014. TPMT.

    Subcellular locationi

    GO - Cellular componenti

    1. cytosol Source: Reactome
    2. extracellular vesicular exosome Source: UniProt

    Keywords - Cellular componenti

    Cytoplasm

    Pathology & Biotechi

    Involvement in diseasei

    Thiopurine S-methyltransferase deficiency (TPMT deficiency) [MIM:610460]: Enzyme involved in the normal metabolic inactivation of thiopurine drugs. These drugs are generally used as immunosuppressants or cytotoxic drugs and are prescribed for a variety of clinical conditions including leukemia, autoimmune disease and organ transplantation. Patients with intermediate or no TPMT activity are at risk of toxicity after receiving standard doses of thiopurine drugs and it is shown that inter-individual differences in response to these drugs are largely determined by genetic variation at the TPMT locus.14 Publications
    Note: The disease is caused by mutations affecting the gene represented in this entry.
    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Natural varianti80 – 801A → P in TPMT deficiency; allele TPMT*2; 100-fold reduction in activity; protein shows enhanced degradation; TPMT*2 allele frequency is 0.5%; seems to be restricted to the Caucasian population. 7 Publications
    Corresponds to variant rs1800462 [ dbSNP | Ensembl ].
    VAR_005637
    Natural varianti154 – 1541A → T in TPMT deficiency; allele TPMT*3A and allele TPMT*3B; very low activity; protein shows enhanced degradation leading to strongly reduced protein levels; TPMT*3A is most common mutant in American Caucasians; TPMT*3A allele frequencies are 4.5% in the Caucasian; 0.8% in the African Americans and 3.2% in the Caucasian Americans population. 11 Publications
    Corresponds to variant rs1800460 [ dbSNP | Ensembl ].
    VAR_005638
    Natural varianti215 – 2151R → H in TPMT deficiency; allele TPMT*8; intermediate activity. 2 Publications
    Corresponds to variant rs56161402 [ dbSNP | Ensembl ].
    VAR_008715
    Natural varianti227 – 2271H → Q in TPMT deficiency; allele TPMT*7; reduced activity. 2 Publications
    Corresponds to variant rs72552736 [ dbSNP | Ensembl ].
    VAR_005640
    Natural varianti240 – 2401Y → C in TPMT deficiency; allele TPMT*3B and allele TPMT*3C; reduced activity; protein shows enhanced degradation; TPMT*3C is the most common mutant in African-Americans and the only allele in the Japanese and Taiwanese individuals; TPMT*3C frequencies are 7.6% in Ghanaian and 0.3% in Caucasian individuals. 11 Publications
    Corresponds to variant rs1142345 [ dbSNP | Ensembl ].
    VAR_005641

    Mutagenesis

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Mutagenesisi152 – 1521R → E: Decreases affinity for 6-mercaptopurine. Slightly decreases catalytic activity. 1 Publication

    Organism-specific databases

    MIMi610460. phenotype.
    Orphaneti240925. Azathioprine dose selection in the treatment of Crohn disease, leukemia and in transplantation.
    240853. Azathioprine toxicity.
    240863. Cisplatin toxicity.
    240927. Mercaptopurine dose selection in the treatment of Crohn disease, leukemia and in transplantation.
    240889. Mercaptopurine toxicity.
    240999. Susceptibility to deafness due to cisplatin treatment.
    241019. Susceptibility to neutropenia due to azathioprine treatment.
    241021. Susceptibility to neutropenia due to mercaptopurine treatment.
    3315. Thiopurine S-methyltransferase deficiency.
    PharmGKBiPA356.

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Chaini1 – 245245Thiopurine S-methyltransferasePRO_0000220102Add
    BLAST

    Amino acid modifications

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Modified residuei14 – 141Phosphoserine2 Publications
    Modified residuei58 – 581N6-acetyllysine1 Publication

    Keywords - PTMi

    Acetylation, Phosphoprotein

    Proteomic databases

    MaxQBiP51580.
    PaxDbiP51580.
    PeptideAtlasiP51580.
    PRIDEiP51580.

    PTM databases

    PhosphoSiteiP51580.

    Expressioni

    Gene expression databases

    BgeeiP51580.
    GenevestigatoriP51580.

    Organism-specific databases

    HPAiHPA019851.

    Interactioni

    Subunit structurei

    Monomer.1 Publication

    Protein-protein interaction databases

    BioGridi113025. 3 interactions.

    Structurei

    Secondary structure

    1
    245
    Legend: HelixTurnBeta strand
    Show more details
    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Turni18 – 214
    Helixi26 – 3510
    Helixi47 – 5711
    Beta strandi64 – 674
    Helixi75 – 817
    Beta strandi85 – 895
    Helixi93 – 10210
    Beta strandi107 – 1115
    Beta strandi119 – 1235
    Beta strandi126 – 1338
    Helixi135 – 1406
    Beta strandi146 – 1549
    Turni155 – 1573
    Helixi160 – 1623
    Helixi163 – 17210
    Beta strandi174 – 18613
    Turni189 – 1913
    Helixi201 – 2088
    Turni209 – 2113
    Beta strandi212 – 22110
    Helixi225 – 2306
    Beta strandi236 – 2449

    3D structure databases

    Select the link destinations:
    PDBe
    RCSB PDB
    PDBj
    Links Updated
    EntryMethodResolution (Å)ChainPositionsPDBsum
    2BZGX-ray1.58A16-245[»]
    2H11X-ray1.89A/B17-245[»]
    ProteinModelPortaliP51580.
    SMRiP51580. Positions 17-245.
    ModBaseiSearch...
    MobiDBiSearch...

    Miscellaneous databases

    EvolutionaryTraceiP51580.

    Family & Domainsi

    Region

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Regioni29 – 4012S-adenosyl-L-methionine bindingAdd
    BLAST
    Regioni134 – 1352S-adenosyl-L-methionine binding

    Sequence similaritiesi

    Phylogenomic databases

    eggNOGiCOG0500.
    HOVERGENiHBG003037.
    InParanoidiP51580.
    KOiK00569.
    OMAiHSVIGVE.
    OrthoDBiEOG7H4DWQ.
    PhylomeDBiP51580.
    TreeFamiTF328951.

    Family and domain databases

    Gene3Di3.40.50.150. 1 hit.
    HAMAPiMF_00812. Thiopur_methtran.
    InterProiIPR029063. SAM-dependent_MTases-like.
    IPR025835. Thiopurine_S-MeTrfase.
    IPR008854. TPMT.
    [Graphical view]
    PfamiPF05724. TPMT. 1 hit.
    [Graphical view]
    PIRSFiPIRSF023956. Thiopurine_S-methyltransferase. 1 hit.
    SUPFAMiSSF53335. SSF53335. 1 hit.
    PROSITEiPS51585. SAM_MT_TPMT. 1 hit.
    [Graphical view]

    Sequencei

    Sequence statusi: Complete.

    P51580-1 [UniParc]FASTAAdd to Basket

    « Hide

    MDGTRTSLDI EEYSDTEVQK NQVLTLEEWQ DKWVNGKTAF HQEQGHQLLK    50
    KHLDTFLKGK SGLRVFFPLC GKAVEMKWFA DRGHSVVGVE ISELGIQEFF 100
    TEQNLSYSEE PITEIPGTKV FKSSSGNISL YCCSIFDLPR TNIGKFDMIW 150
    DRGALVAINP GDRKCYADTM FSLLGKKFQY LLCVLSYDPT KHPGPPFYVP 200
    HAEIERLFGK ICNIRCLEKV DAFEERHKSW GIDCLFEKLY LLTEK 245
    Length:245
    Mass (Da):28,180
    Last modified:October 1, 1996 - v1
    Checksum:i190E781155B97BB9
    GO

    Sequence cautioni

    The sequence AAB71631.1 differs from that shown. Reason: Erroneous initiation.
    The sequence AAB71632.1 differs from that shown. Reason: Erroneous initiation.

    Polymorphismi

    Individual variation in the toxicity and therapeutic efficacy of thiopurine drugs is associated with a common genetic polymorphism that controls levels of TPMT activity. Genetic polymorphism in the TPMT gene is such that about 90% of Caucasians have high TPMT activity, 10% have intermediate activity and 1 in 300 individuals has low activity. TPMT activity varies among ethnic groups.
    TPMT*3A is the only mutant allele found in the South West Asians. This is also the most common mutant allele in the Caucasians but is not found in the Chinese. All mutant alleles identified in the Chinese population were TPMT*3C. This allele is found at a low frequency in the Caucasians. This suggests that TPMT*3C is the oldest mutation, with TPMT*3B being acquired later to form the TPMT*3A allele in the Caucasian and South West Asian populations. TPMT*2 appears to be a more recent allele, which has only been detected in Caucasians to date. These ethnic differences may be important in the clinical use of thiopurine drugs.

    Natural variant

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Natural varianti49 – 491L → S Allele TPMT*5; found in a patient with intermediate enzyme activity; has very low activity when expressed in a heterologous system. 2 Publications
    Corresponds to variant rs72552740 [ dbSNP | Ensembl ].
    VAR_005636
    Natural varianti80 – 801A → P in TPMT deficiency; allele TPMT*2; 100-fold reduction in activity; protein shows enhanced degradation; TPMT*2 allele frequency is 0.5%; seems to be restricted to the Caucasian population. 7 Publications
    Corresponds to variant rs1800462 [ dbSNP | Ensembl ].
    VAR_005637
    Natural varianti154 – 1541A → T in TPMT deficiency; allele TPMT*3A and allele TPMT*3B; very low activity; protein shows enhanced degradation leading to strongly reduced protein levels; TPMT*3A is most common mutant in American Caucasians; TPMT*3A allele frequencies are 4.5% in the Caucasian; 0.8% in the African Americans and 3.2% in the Caucasian Americans population. 11 Publications
    Corresponds to variant rs1800460 [ dbSNP | Ensembl ].
    VAR_005638
    Natural varianti179 – 1791Q → H.
    Corresponds to variant rs6921269 [ dbSNP | Ensembl ].
    VAR_052368
    Natural varianti180 – 1801Y → F Allele TPMT*6; reduced activity. 2 Publications
    Corresponds to variant rs75543815 [ dbSNP | Ensembl ].
    VAR_005639
    Natural varianti215 – 2151R → H in TPMT deficiency; allele TPMT*8; intermediate activity. 2 Publications
    Corresponds to variant rs56161402 [ dbSNP | Ensembl ].
    VAR_008715
    Natural varianti227 – 2271H → Q in TPMT deficiency; allele TPMT*7; reduced activity. 2 Publications
    Corresponds to variant rs72552736 [ dbSNP | Ensembl ].
    VAR_005640
    Natural varianti240 – 2401Y → C in TPMT deficiency; allele TPMT*3B and allele TPMT*3C; reduced activity; protein shows enhanced degradation; TPMT*3C is the most common mutant in African-Americans and the only allele in the Japanese and Taiwanese individuals; TPMT*3C frequencies are 7.6% in Ghanaian and 0.3% in Caucasian individuals. 11 Publications
    Corresponds to variant rs1142345 [ dbSNP | Ensembl ].
    VAR_005641

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    S62904 mRNA. Translation: AAB27277.1.
    U12387 mRNA. Translation: AAC50130.1.
    U30518
    , U30512, U30513, U30514, U30515, U30516, U30517 Genomic DNA. Translation: AAC50368.1.
    AF019369
    , AF019364, AF019365, AF019366, AF019367, AF019368 Genomic DNA. Translation: AAC51865.1.
    U81562 Genomic DNA. Translation: AAB71625.1.
    U81563 Genomic DNA. Translation: AAB71626.1.
    U81564 Genomic DNA. Translation: AAB71627.1.
    U81565 Genomic DNA. Translation: AAB71628.1.
    U81566 Genomic DNA. Translation: AAB71629.1.
    U81567 Genomic DNA. Translation: AAB71630.1.
    U81568 Genomic DNA. Translation: AAB71631.1. Different initiation.
    U81569 Genomic DNA. Translation: AAB71632.1. Different initiation.
    U81570 Genomic DNA. Translation: AAB71633.1.
    U81571 Genomic DNA. Translation: AAB71634.1.
    U81572 Genomic DNA. Translation: AAB71635.1.
    U81573 Genomic DNA. Translation: AAB71636.1.
    AB045146 Genomic DNA. Translation: BAA97037.1.
    AL589723 Genomic DNA. Translation: CAH71233.1.
    BC009596 mRNA. Translation: AAH09596.1.
    AF035426 Genomic DNA. Translation: AAC32289.1.
    AF021876 mRNA. Translation: AAB80746.1.
    AF021877 mRNA. Translation: AAB80747.1.
    CCDSiCCDS4543.1.
    PIRiI57946.
    RefSeqiNP_000358.1. NM_000367.2.
    UniGeneiHs.444319.

    Genome annotation databases

    EnsembliENST00000309983; ENSP00000312304; ENSG00000137364.
    GeneIDi7172.
    KEGGihsa:7172.
    UCSCiuc003ncm.3. human.

    Polymorphism databases

    DMDMi1730006.

    Keywords - Coding sequence diversityi

    Polymorphism

    Cross-referencesi

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    S62904 mRNA. Translation: AAB27277.1 .
    U12387 mRNA. Translation: AAC50130.1 .
    U30518
    , U30512 , U30513 , U30514 , U30515 , U30516 , U30517 Genomic DNA. Translation: AAC50368.1 .
    AF019369
    , AF019364 , AF019365 , AF019366 , AF019367 , AF019368 Genomic DNA. Translation: AAC51865.1 .
    U81562 Genomic DNA. Translation: AAB71625.1 .
    U81563 Genomic DNA. Translation: AAB71626.1 .
    U81564 Genomic DNA. Translation: AAB71627.1 .
    U81565 Genomic DNA. Translation: AAB71628.1 .
    U81566 Genomic DNA. Translation: AAB71629.1 .
    U81567 Genomic DNA. Translation: AAB71630.1 .
    U81568 Genomic DNA. Translation: AAB71631.1 . Different initiation.
    U81569 Genomic DNA. Translation: AAB71632.1 . Different initiation.
    U81570 Genomic DNA. Translation: AAB71633.1 .
    U81571 Genomic DNA. Translation: AAB71634.1 .
    U81572 Genomic DNA. Translation: AAB71635.1 .
    U81573 Genomic DNA. Translation: AAB71636.1 .
    AB045146 Genomic DNA. Translation: BAA97037.1 .
    AL589723 Genomic DNA. Translation: CAH71233.1 .
    BC009596 mRNA. Translation: AAH09596.1 .
    AF035426 Genomic DNA. Translation: AAC32289.1 .
    AF021876 mRNA. Translation: AAB80746.1 .
    AF021877 mRNA. Translation: AAB80747.1 .
    CCDSi CCDS4543.1.
    PIRi I57946.
    RefSeqi NP_000358.1. NM_000367.2.
    UniGenei Hs.444319.

    3D structure databases

    Select the link destinations:
    PDBe
    RCSB PDB
    PDBj
    Links Updated
    Entry Method Resolution (Å) Chain Positions PDBsum
    2BZG X-ray 1.58 A 16-245 [» ]
    2H11 X-ray 1.89 A/B 17-245 [» ]
    ProteinModelPortali P51580.
    SMRi P51580. Positions 17-245.
    ModBasei Search...
    MobiDBi Search...

    Protein-protein interaction databases

    BioGridi 113025. 3 interactions.

    Chemistry

    ChEMBLi CHEMBL2500.
    DrugBanki DB01033. Mercaptopurine.

    PTM databases

    PhosphoSitei P51580.

    Polymorphism databases

    DMDMi 1730006.

    Proteomic databases

    MaxQBi P51580.
    PaxDbi P51580.
    PeptideAtlasi P51580.
    PRIDEi P51580.

    Protocols and materials databases

    DNASUi 7172.
    Structural Biology Knowledgebase Search...

    Genome annotation databases

    Ensembli ENST00000309983 ; ENSP00000312304 ; ENSG00000137364 .
    GeneIDi 7172.
    KEGGi hsa:7172.
    UCSCi uc003ncm.3. human.

    Organism-specific databases

    CTDi 7172.
    GeneCardsi GC06M018072.
    HGNCi HGNC:12014. TPMT.
    HPAi HPA019851.
    MIMi 187680. gene.
    610460. phenotype.
    neXtProti NX_P51580.
    Orphaneti 240925. Azathioprine dose selection in the treatment of Crohn disease, leukemia and in transplantation.
    240853. Azathioprine toxicity.
    240863. Cisplatin toxicity.
    240927. Mercaptopurine dose selection in the treatment of Crohn disease, leukemia and in transplantation.
    240889. Mercaptopurine toxicity.
    240999. Susceptibility to deafness due to cisplatin treatment.
    241019. Susceptibility to neutropenia due to azathioprine treatment.
    241021. Susceptibility to neutropenia due to mercaptopurine treatment.
    3315. Thiopurine S-methyltransferase deficiency.
    PharmGKBi PA356.
    GenAtlasi Search...

    Phylogenomic databases

    eggNOGi COG0500.
    HOVERGENi HBG003037.
    InParanoidi P51580.
    KOi K00569.
    OMAi HSVIGVE.
    OrthoDBi EOG7H4DWQ.
    PhylomeDBi P51580.
    TreeFami TF328951.

    Enzyme and pathway databases

    Reactomei REACT_6946. Methylation.

    Miscellaneous databases

    EvolutionaryTracei P51580.
    GeneWikii Thiopurine_methyltransferase.
    GenomeRNAii 7172.
    NextBioi 28108.
    PROi P51580.
    SOURCEi Search...

    Gene expression databases

    Bgeei P51580.
    Genevestigatori P51580.

    Family and domain databases

    Gene3Di 3.40.50.150. 1 hit.
    HAMAPi MF_00812. Thiopur_methtran.
    InterProi IPR029063. SAM-dependent_MTases-like.
    IPR025835. Thiopurine_S-MeTrfase.
    IPR008854. TPMT.
    [Graphical view ]
    Pfami PF05724. TPMT. 1 hit.
    [Graphical view ]
    PIRSFi PIRSF023956. Thiopurine_S-methyltransferase. 1 hit.
    SUPFAMi SSF53335. SSF53335. 1 hit.
    PROSITEi PS51585. SAM_MT_TPMT. 1 hit.
    [Graphical view ]
    ProtoNeti Search...

    Publicationsi

    1. "Human thiopurine methyltransferase: molecular cloning and expression of T84 colon carcinoma cell cDNA."
      Honchel R., Aksoy I.A., Szumlanski C., Wood T.C., Otterness D.M., Wieben E.D., Weinshilboum R.M.
      Mol. Pharmacol. 43:878-887(1993) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [MRNA], PARTIAL PROTEIN SEQUENCE.
      Tissue: Kidney.
    2. "Thiopurine methyltransferase pharmacogenetics. Cloning of human liver cDNA and a processed pseudogene on human chromosome 18q21.1."
      Lee D., Szumlanski C.L., Houtman J., Honchel R., Rojas K., Overhauser J., Weiben E.D., Weinshilboum R.M.
      Drug Metab. Dispos. 23:398-405(1995) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [MRNA].
    3. "Thiopurine methyltransferase pharmacogenetics: human gene cloning and characterization of a common polymorphism."
      Szumlanski C., Otterness D., Her C., Lee D., Brandriff B., Kelsell D., Spurr N., Lennard L., Wieben E., Weinshilboum R.M.
      DNA Cell Biol. 15:17-30(1996) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANTS TPMT DEFICIENCY THR-154 AND CYS-240.
    4. "Promoter and intronic sequences of the human thiopurine S-methyltransferase (TPMT) gene isolated from a human PAC1 genomic library."
      Krynetski E.Y., Fessing M.Y., Yates C.R., Sun D., Schuetz J.D., Evans W.E.
      Pharm. Res. 14:1672-1678(1997) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
    5. Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANTS SER-49 AND PHE-180, VARIANTS TPMT DEFICIENCY THR-154 AND CYS-240.
    6. "Genomic structure of thiopurine S-methyltransferase gene."
      Nakamura Y.
      Submitted (JUN-2000) to the EMBL/GenBank/DDBJ databases
      Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
    7. "The DNA sequence and analysis of human chromosome 6."
      Mungall A.J., Palmer S.A., Sims S.K., Edwards C.A., Ashurst J.L., Wilming L., Jones M.C., Horton R., Hunt S.E., Scott C.E., Gilbert J.G.R., Clamp M.E., Bethel G., Milne S., Ainscough R., Almeida J.P., Ambrose K.D., Andrews T.D.
      , Ashwell R.I.S., Babbage A.K., Bagguley C.L., Bailey J., Banerjee R., Barker D.J., Barlow K.F., Bates K., Beare D.M., Beasley H., Beasley O., Bird C.P., Blakey S.E., Bray-Allen S., Brook J., Brown A.J., Brown J.Y., Burford D.C., Burrill W., Burton J., Carder C., Carter N.P., Chapman J.C., Clark S.Y., Clark G., Clee C.M., Clegg S., Cobley V., Collier R.E., Collins J.E., Colman L.K., Corby N.R., Coville G.J., Culley K.M., Dhami P., Davies J., Dunn M., Earthrowl M.E., Ellington A.E., Evans K.A., Faulkner L., Francis M.D., Frankish A., Frankland J., French L., Garner P., Garnett J., Ghori M.J., Gilby L.M., Gillson C.J., Glithero R.J., Grafham D.V., Grant M., Gribble S., Griffiths C., Griffiths M.N.D., Hall R., Halls K.S., Hammond S., Harley J.L., Hart E.A., Heath P.D., Heathcott R., Holmes S.J., Howden P.J., Howe K.L., Howell G.R., Huckle E., Humphray S.J., Humphries M.D., Hunt A.R., Johnson C.M., Joy A.A., Kay M., Keenan S.J., Kimberley A.M., King A., Laird G.K., Langford C., Lawlor S., Leongamornlert D.A., Leversha M., Lloyd C.R., Lloyd D.M., Loveland J.E., Lovell J., Martin S., Mashreghi-Mohammadi M., Maslen G.L., Matthews L., McCann O.T., McLaren S.J., McLay K., McMurray A., Moore M.J.F., Mullikin J.C., Niblett D., Nickerson T., Novik K.L., Oliver K., Overton-Larty E.K., Parker A., Patel R., Pearce A.V., Peck A.I., Phillimore B.J.C.T., Phillips S., Plumb R.W., Porter K.M., Ramsey Y., Ranby S.A., Rice C.M., Ross M.T., Searle S.M., Sehra H.K., Sheridan E., Skuce C.D., Smith S., Smith M., Spraggon L., Squares S.L., Steward C.A., Sycamore N., Tamlyn-Hall G., Tester J., Theaker A.J., Thomas D.W., Thorpe A., Tracey A., Tromans A., Tubby B., Wall M., Wallis J.M., West A.P., White S.S., Whitehead S.L., Whittaker H., Wild A., Willey D.J., Wilmer T.E., Wood J.M., Wray P.W., Wyatt J.C., Young L., Younger R.M., Bentley D.R., Coulson A., Durbin R.M., Hubbard T., Sulston J.E., Dunham I., Rogers J., Beck S.
      Nature 425:805-811(2003) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
    8. "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
      The MGC Project Team
      Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
      Tissue: Bone marrow.
    9. "Detection of known and new mutations in the thiopurine S-methyltransferase gene by single-strand conformation polymorphism analysis."
      Spire-Vayron de la Moureyre C., Debuysere H., Sabbagh N., Marez D., Vinner E., Chevalier E.D., Lo-Guidice J.-M., Broly F.
      Hum. Mutat. 12:177-185(1998) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 210-245, VARIANT TPMT DEFICIENCY GLN-227.
    10. "Structural basis of substrate recognition in thiopurine s-methyltransferase."
      Peng Y., Feng Q., Wilk D., Adjei A.A., Salavaggione O.E., Weinshilboum R.M., Yee V.C.
      Biochemistry 47:6216-6225(2008) [PubMed] [Europe PMC] [Abstract]
      Cited for: CATALYTIC ACTIVITY, FUNCTION, BIOPHYSICOCHEMICAL PROPERTIES, MUTAGENESIS OF ARG-152.
    11. Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-14, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
      Tissue: Cervix carcinoma.
    12. "Large-scale phosphoproteome analysis of human liver tissue by enrichment and fractionation of phosphopeptides with strong anion exchange chromatography."
      Han G., Ye M., Zhou H., Jiang X., Feng S., Jiang X., Tian R., Wan D., Zou H., Gu J.
      Proteomics 8:1346-1361(2008) [PubMed] [Europe PMC] [Abstract]
      Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
      Tissue: Liver.
    13. "Quantitative phosphoproteomic analysis of T cell receptor signaling reveals system-wide modulation of protein-protein interactions."
      Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K., Rodionov V., Han D.K.
      Sci. Signal. 2:RA46-RA46(2009) [PubMed] [Europe PMC] [Abstract]
      Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-14, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
      Tissue: Leukemic T-cell.
    14. "Lysine acetylation targets protein complexes and co-regulates major cellular functions."
      Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M., Walther T.C., Olsen J.V., Mann M.
      Science 325:834-840(2009) [PubMed] [Europe PMC] [Abstract]
      Cited for: ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-58, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
    15. Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
    16. "Structural basis of allele variation of human thiopurine-S-methyltransferase."
      Wu H., Horton J.R., Battaile K., Allali-Hassani A., Martin F., Zeng H., Loppnau P., Vedadi M., Bochkarev A., Plotnikov A.N., Cheng X.
      Proteins 67:198-208(2007) [PubMed] [Europe PMC] [Abstract]
      Cited for: X-RAY CRYSTALLOGRAPHY (1.58 ANGSTROMS) OF 16-245 IN COMPLEX WITH S-ADENOSYL-L-HOMOCYSTEINE, SUBUNIT, CHARACTERIZATION OF VARIANTS TPMT DEFICIENCY THR-154 AND CYS-240.
    17. "A single point mutation leading to loss of catalytic activity in human thiopurine S-methyltransferase."
      Krynetski E.Y., Schuetz J.D., Galpin A.J., Pui C.-H., Relling M.V., Evans W.E.
      Proc. Natl. Acad. Sci. U.S.A. 92:949-953(1995) [PubMed] [Europe PMC] [Abstract]
      Cited for: VARIANT TPMT DEFICIENCY PRO-80.
    18. "Thiopurine S-methyltransferase deficiency: two nucleotide transitions define the most prevalent mutant allele associated with loss of catalytic activity in Caucasians."
      Tai H.-L., Krynetski E.Y., Yates C.R., Loennechen T., Fessing M.Y., Krynetskaia N.F., Evans W.E.
      Am. J. Hum. Genet. 58:694-702(1996) [PubMed] [Europe PMC] [Abstract]
      Cited for: VARIANTS TPMT DEFICIENCY THR-154 AND CYS-240.
    19. "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."
      Leipold G., Schuetz E., Haas J.P., Oellerich M.
      Arthritis Rheum. 40:1896-1898(1997) [PubMed] [Europe PMC] [Abstract]
      Cited for: VARIANTS TPMT DEFICIENCY THR-154 AND CYS-240.
    20. "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."
      Tai H.-L., Krynetski E.Y., Schuetz E.G., Yanishevski Y., Evans W.E.
      Proc. Natl. Acad. Sci. U.S.A. 94:6444-6449(1997) [PubMed] [Europe PMC] [Abstract]
      Cited for: CHARACTERIZATION OF VARIANTS TPMT DEFICIENCY PRO-80 AND THR-154, MECHANISM FOR THE GENETIC POLYMORPHISM OF TPMT ACTIVITY.
    21. "Thiopurine methyltransferase alleles in British and Ghanaian populations."
      Ameyaw M.-M., Collie-Duguid E.S.R., Powrie R.H., Ofori-Adjei D., McLeod H.L.
      Hum. Mol. Genet. 8:367-370(1999) [PubMed] [Europe PMC] [Abstract]
      Cited for: VARIANTS TPMT DEFICIENCY PRO-80; THR-154 AND CYS-240.
    22. "Polymorphism of the thiopurine S-methyltransferase gene in African-Americans."
      Hon Y.Y., Fessing M.Y., Pui C.-H., Relling M.V., Krynetski E.Y., Evans W.E.
      Hum. Mol. Genet. 8:371-376(1999) [PubMed] [Europe PMC] [Abstract]
      Cited for: VARIANT TPMT DEFICIENCY HIS-215.
    23. "The frequency and distribution of thiopurine methyltransferase alleles in Caucasian and Asian populations."
      Collie-Duguid E.S.R., Pritchard S.C., Powrie R.H., Sludden J., Collier D.A., Li T., McLeod H.L.
      Pharmacogenetics 9:37-42(1999) [PubMed] [Europe PMC] [Abstract]
      Cited for: VARIANTS TPMT DEFICIENCY PRO-80; THR-154 AND CYS-240, FREQUENCY AND DISTRIBUTION OF ALLELES.
    24. "Genetic analysis of thiopurine methyltransferase polymorphism in a Japanese population."
      Hiratsuka M., Inoue T., Omori F., Agatsuma Y., Mizugaki M.
      Mutat. Res. 448:91-95(2000) [PubMed] [Europe PMC] [Abstract]
      Cited for: VARIANTS TPMT DEFICIENCY PRO-80; THR-154 AND CYS-240, FREQUENCY AND DISTRIBUTION OF ALLELES.
    25. "Thiopurine S-methyltransferase pharmacogenetics: variant allele functional and comparative genomics."
      Salavaggione O.E., Wang L., Wiepert M., Yee V.C., Weinshilboum R.M.
      Pharmacogenet. Genomics 15:801-815(2005) [PubMed] [Europe PMC] [Abstract]
      Cited for: VARIANTS TPMT DEFICIENCY PRO-80; THR-154; HIS-215; GLN-227 AND CYS-240, VARIANTS SER-49 AND PHE-180, CHARACTERIZATION OF VARIANTS TPMT DEFICIENCY PRO-80; THR-154; HIS-215; GLN-227 AND CYS-240, CHARACTERIZATION OF VARIANTS SER-49 AND PHE-180.
    26. "Severe azathioprine-induced myelotoxicity in a kidney transplant patient with thiopurine S-methyltransferase-deficient genotype (TPMT*3A/*3C)."
      Kurzawski M., Dziewanowski K., Ciechanowski K., Drozdzik M.
      Transpl. Int. 18:623-625(2005) [PubMed] [Europe PMC] [Abstract]
      Cited for: VARIANTS TPMT DEFICIENCY THR-154 AND CYS-240.
    27. "Molecular analysis of thiopurine S-methyltransferase alleles in Taiwan aborigines and Taiwanese."
      Lu H.-F., Shih M.-C., Chang Y.-S., Chang J.-Y., Ko Y.-C., Chang S.-J., Chang J.-G.
      J. Clin. Pharm. Ther. 31:93-98(2006) [PubMed] [Europe PMC] [Abstract]
      Cited for: VARIANTS TPMT DEFICIENCY PRO-80; THR-154 AND CYS-240, FREQUENCY AND DISTRIBUTION OF ALLELES.
    28. "Frequency of the thiopurine S-methyltransferase alleles in the ancient genetic population isolate of Sardinia."
      Rossino R., Vincis C., Alves S., Prata M.J., Macis M.D., Nucaro A.L., Schirru E., Congia M.
      J. Clin. Pharm. Ther. 31:283-287(2006) [PubMed] [Europe PMC] [Abstract]
      Cited for: VARIANTS TPMT DEFICIENCY PRO-80; THR-154 AND CYS-240, FREQUENCY AND DISTRIBUTION OF ALLELES.

    Entry informationi

    Entry nameiTPMT_HUMAN
    AccessioniPrimary (citable) accession number: P51580
    Secondary accession number(s): O14806
    , O15423, O15424, O15425, O15426, O15515, O15548, O43213, Q5VUK6, Q9UBE6, Q9UBT8, Q9UE62
    Entry historyi
    Integrated into UniProtKB/Swiss-Prot: October 1, 1996
    Last sequence update: October 1, 1996
    Last modified: October 1, 2014
    This is version 148 of the entry and version 1 of the sequence. [Complete history]
    Entry statusiReviewed (UniProtKB/Swiss-Prot)
    Annotation programChordata Protein Annotation Program
    DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

    Miscellaneousi

    Miscellaneous

    TPMT deficiency inherited by TPMT*2 and TPMT*3A alleles, are the most prevalent mutant TPMT in humans. TPMT deficiency is associated with lower cellular levels of TPMT protein, and the proteins encoded by TPMT*2 and TPMT*3A mutant alleles are degraded more rapidly by an ATP-dependent proteasome-mediated pathway.

    Keywords - Technical termi

    3D-structure, Complete proteome, Direct protein sequencing, Reference proteome

    Documents

    1. Human chromosome 6
      Human chromosome 6: entries, gene names and cross-references to MIM
    2. Human entries with polymorphisms or disease mutations
      List of human entries with polymorphisms or disease mutations
    3. Human polymorphisms and disease mutations
      Index of human polymorphisms and disease mutations
    4. MIM cross-references
      Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
    5. PDB cross-references
      Index of Protein Data Bank (PDB) cross-references
    6. SIMILARITY comments
      Index of protein domains and families

    External Data

    Dasty 3