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Protein

Thiopurine S-methyltransferase

Gene

TPMT

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

Catalyzes the S-methylation of thiopurine drugs such as 6-mercaptopurine (also called mercaptopurine, 6-MP or its brand name Purinethol) and 6-thioguanine (also called tioguanine or 6-TG) using S-adenosyl-L-methionine as the methyl donor (PubMed:657528, PubMed:18484748). TPMT activity modulates the cytotoxic effects of thiopurine prodrugs. A natural substrate for this enzyme has yet to be identified.Curated2 Publications

Catalytic activityi

S-adenosyl-L-methionine + a thiopurine = S-adenosyl-L-homocysteine + a thiopurine S-methylether.2 Publications
Mercaptopurine + S-adenosyl-L-methionine = 6-methylthiopurine + S-adenosyl-L-homocysteine.2 Publications
6-thioguanine + S-adenosyl-L-methionine = 6-methylthioguanine + S-adenosyl-L-homocysteine.1 Publication

Enzyme regulationi

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

Kineticsi

  1. KM=18.5 µM for S-adenosyl-L-methionine (at pH 6.5 and 37 degrees Celsius)1 Publication
  2. KM=0.68 mM for 6-mercaptopurine (at pH 6.5 and 37 degrees Celsius)1 Publication
  3. KM=1.7 µM for S-adenosyl-L-methionine (at pH 7.5 and 37 degrees Celsius)1 Publication
  4. KM=0.32 mM for 6-mercaptopurine (at pH 7.5 and 37 degrees Celsius)1 Publication
  5. KM=0.20 mM for 6-thioguanine (at pH 7.5 and 37 degrees Celsius)1 Publication
  1. Vmax=1.23 nmol/sec/mg enzyme toward 6-mercaptopurine (at pH 6.5 and 37 degrees Celsius)1 Publication

pH dependencei

Optimum pH is 7.5.1 Publication

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Binding sitei40SubstrateBy similarity1
Binding sitei69S-adenosyl-L-methionine; via carbonyl oxygen1
Binding sitei90S-adenosyl-L-methionine1
Binding sitei152S-adenosyl-L-methionine1

GO - Molecular functioni

  • S-adenosyl-L-methionine binding Source: UniProtKB
  • thiopurine S-methyltransferase activity Source: UniProtKB

GO - Biological processi

  • drug metabolic process Source: UniProtKB
  • methylation Source: Reactome
  • nucleobase-containing compound metabolic process Source: ProtInc

Keywordsi

Molecular functionMethyltransferase, Transferase
LigandS-adenosyl-L-methionine

Enzyme and pathway databases

BioCyciMetaCyc:HS06327-MONOMER
BRENDAi2.1.1.67 2681
ReactomeiR-HSA-156581 Methylation
R-HSA-5578995 Defective TPMT causes Thiopurine S-methyltransferase deficiency (TPMT deficiency)

Names & Taxonomyi

Protein namesi
Recommended name:
Thiopurine S-methyltransferase1 Publication (EC:2.1.1.672 Publications)
Alternative name(s):
Thiopurine methyltransferase1 Publication
Gene namesi
Name:TPMT
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 6

Organism-specific databases

EuPathDBiHostDB:ENSG00000137364.4
HGNCiHGNC:12014 TPMT
MIMi187680 gene
neXtProtiNX_P51580

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Keywords - Cellular componenti

Cytoplasm

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi152R → E: Decreases affinity for 6-mercaptopurine. Slightly decreases catalytic activity. 1 Publication1

Organism-specific databases

DisGeNETi7172
MalaCardsiTPMT
MIMi610460 phenotype
OpenTargetsiENSG00000137364
Orphaneti413687 Azathioprine or 6-mercatopurine toxicity or dose selection
240863 Cisplatin toxicity
3315 Thiopurine S-methyltransferase deficiency
PharmGKBiPA356

Chemistry databases

ChEMBLiCHEMBL2500
DrugBankiDB00993 Azathioprine
DB00436 Bendroflumethiazide
DB01327 Cefazolin
DB01033 Mercaptopurine
DB01250 Olsalazine
DB01021 Trichlormethiazide

Polymorphism and mutation databases

BioMutaiTPMT
DMDMi1730006

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00002201021 – 245Thiopurine S-methyltransferaseAdd BLAST245

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei14PhosphoserineCombined sources1
Modified residuei58N6-acetyllysineCombined sources1

Keywords - PTMi

Acetylation, Phosphoprotein

Proteomic databases

EPDiP51580
MaxQBiP51580
PaxDbiP51580
PeptideAtlasiP51580
PRIDEiP51580
ProteomicsDBi56338

PTM databases

iPTMnetiP51580
PhosphoSitePlusiP51580

Expressioni

Gene expression databases

BgeeiENSG00000137364
ExpressionAtlasiP51580 baseline and differential
GenevisibleiP51580 HS

Organism-specific databases

HPAiHPA019851

Interactioni

Subunit structurei

Monomer.1 Publication

Protein-protein interaction databases

BioGridi113025, 1 interactor
STRINGi9606.ENSP00000312304

Chemistry databases

BindingDBiP51580

Structurei

Secondary structure

1245
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Turni18 – 21Combined sources4
Helixi26 – 35Combined sources10
Helixi47 – 57Combined sources11
Beta strandi64 – 67Combined sources4
Helixi75 – 81Combined sources7
Beta strandi85 – 89Combined sources5
Helixi93 – 102Combined sources10
Beta strandi107 – 111Combined sources5
Beta strandi119 – 123Combined sources5
Beta strandi126 – 133Combined sources8
Helixi135 – 140Combined sources6
Beta strandi146 – 154Combined sources9
Turni155 – 157Combined sources3
Helixi160 – 162Combined sources3
Helixi163 – 172Combined sources10
Beta strandi174 – 186Combined sources13
Turni189 – 191Combined sources3
Helixi201 – 208Combined sources8
Turni209 – 211Combined sources3
Beta strandi212 – 221Combined sources10
Helixi225 – 230Combined sources6
Beta strandi236 – 244Combined sources9

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
2BZGX-ray1.58A16-245[»]
2H11X-ray1.89A/B17-245[»]
ProteinModelPortaliP51580
SMRiP51580
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiP51580

Family & Domainsi

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni29 – 40S-adenosyl-L-methionine bindingAdd BLAST12
Regioni134 – 135S-adenosyl-L-methionine binding2

Sequence similaritiesi

Phylogenomic databases

eggNOGiENOG410IGTR Eukaryota
ENOG4111GNF LUCA
GeneTreeiENSGT00390000016823
HOVERGENiHBG003037
InParanoidiP51580
KOiK00569
OMAiMKWFADR
OrthoDBiEOG091G0VS2
PhylomeDBiP51580
TreeFamiTF328951

Family and domain databases

HAMAPiMF_00812 Thiopur_methtran, 1 hit
InterProiView protein in InterPro
IPR029063 SAM-dependent_MTases
IPR025835 Thiopurine_S-MeTrfase
IPR008854 TPMT
PANTHERiPTHR10259 PTHR10259, 1 hit
PfamiView protein in Pfam
PF05724 TPMT, 1 hit
PIRSFiPIRSF023956 Thiopurine_S-methyltransferase, 1 hit
SUPFAMiSSF53335 SSF53335, 1 hit
PROSITEiView protein in PROSITE
PS51585 SAM_MT_TPMT, 1 hit

Sequencei

Sequence statusi: Complete.

P51580-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MDGTRTSLDI EEYSDTEVQK NQVLTLEEWQ DKWVNGKTAF HQEQGHQLLK
60 70 80 90 100
KHLDTFLKGK SGLRVFFPLC GKAVEMKWFA DRGHSVVGVE ISELGIQEFF
110 120 130 140 150
TEQNLSYSEE PITEIPGTKV FKSSSGNISL YCCSIFDLPR TNIGKFDMIW
160 170 180 190 200
DRGALVAINP GDRKCYADTM FSLLGKKFQY LLCVLSYDPT KHPGPPFYVP
210 220 230 240
HAEIERLFGK ICNIRCLEKV DAFEERHKSW GIDCLFEKLY LLTEK
Length:245
Mass (Da):28,180
Last modified:October 1, 1996 - v1
Checksum:i190E781155B97BB9
GO

Sequence cautioni

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

Polymorphismi

Polymorphic variations define TPMT activity levels that are variable among ethnic groups. 90% of Caucasians have high TPMT activity, 10% have intermediate activity, and 1 in 300 individuals has low activity (PubMed:10208641). These differences influence the clinical use and therapeutic efficacy of thiopurine drugs, generally used as immunosuppressants or cytotoxic drugs in conditions including leukemia, autoimmune disease and organ transplantation. Intermediate or low TPMT activity is associated with thiopurine intolerance and patients are at risk of toxicity after receiving standard doses of thiopurine drugs [MIMi:610460] (PubMed:10751626, PubMed:15819814, PubMed:16220112, PubMed:16476125, PubMed:16789994, PubMed:7862671, PubMed:8561894, PubMed:8644731, PubMed:9246020, PubMed:9336428, PubMed:9711875, PubMed:9931345, PubMed:9931346). The most prevalent TPMT alleles associated with TPMT deficiency are TPMT*2 and TPMT*3A. The proteins encoded by TPMT*2 and TPMT*3A mutant are degraded more rapidly by an ATP-dependent proteasome-mediated pathway (PubMed:9177237, PubMed:8644731).15 Publications
TPMT*3A is the most common allele in the Caucasians and American Caucasians; it is the only mutant allele found in the South West Asians; it is not found in the Chinese. TPMT*3C is common in African-Americans and is the only allele in Chinese, Japanese and Taiwanese individuals. 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.3 Publications

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_00563649L → S Polymorphism; allele TPMT*5; has very low activity when expressed in a heterologous system. 2 PublicationsCorresponds to variant dbSNP:rs72552740Ensembl.1
Natural variantiVAR_00563780A → P Polymorphism; allele TPMT*2; TPMT*2 allele frequency is 0.5%; seems to be restricted to the Caucasian population; 100-fold reduction in activity; protein shows enhanced degradation. 8 PublicationsCorresponds to variant dbSNP:rs1800462EnsemblClinVar.1
Natural variantiVAR_005638154A → T Polymorphism; allele TPMT*3A and allele TPMT*3B; very low activity; protein shows enhanced degradation leading to strongly reduced protein levels. 13 PublicationsCorresponds to variant dbSNP:rs1800460EnsemblClinVar.1
Natural variantiVAR_052368179Q → H. Corresponds to variant dbSNP:rs6921269Ensembl.1
Natural variantiVAR_005639180Y → F Polymorphism; allele TPMT*6; reduced activity. 2 PublicationsCorresponds to variant dbSNP:rs75543815Ensembl.1
Natural variantiVAR_008715215R → H Polymorphism; allele TPMT*8; intermediate activity. 2 PublicationsCorresponds to variant dbSNP:rs56161402EnsemblClinVar.1
Natural variantiVAR_005640227H → Q Polymorphism; allele TPMT*7; reduced activity. 2 PublicationsCorresponds to variant dbSNP:rs72552736Ensembl.1
Natural variantiVAR_005641240Y → C Polymorphism; allele TPMT*3B and allele TPMT*3C; reduced activity; protein shows enhanced degradation. 12 PublicationsCorresponds to variant dbSNP:rs1142345EnsemblClinVar.1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
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 No translation available.
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_000367.4
NP_001333746.1, NM_001346817.1
NP_001333747.1, NM_001346818.1
UniGeneiHs.444319

Genome annotation databases

EnsembliENST00000309983; ENSP00000312304; ENSG00000137364
GeneIDi7172
KEGGihsa:7172
UCSCiuc003ncm.4 human

Keywords - Coding sequence diversityi

Polymorphism

Similar proteinsi

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 historyiIntegrated into UniProtKB/Swiss-Prot: October 1, 1996
Last sequence update: October 1, 1996
Last modified: June 20, 2018
This is version 181 of the entry and version 1 of the sequence. See 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

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

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