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Protein

Thiopurine S-methyltransferase

Gene

TPMT

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

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

GO - Biological processi

  • methylation Source: Reactome
  • nucleobase-containing compound metabolic process Source: ProtInc
Complete GO annotation...

Keywords - Molecular functioni

Methyltransferase, Transferase

Keywords - Ligandi

S-adenosyl-L-methionine

Enzyme and pathway databases

BioCyciZFISH:HS06327-MONOMER.
BRENDAi2.1.1.67. 2681.
ReactomeiR-HSA-156581. 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
Proteomesi
  • UP000005640 Componenti: Chromosome 6

Organism-specific databases

HGNCiHGNC:12014. TPMT.

Subcellular locationi

GO - Cellular componenti

  • cytosol Source: Reactome
  • extracellular exosome Source: UniProtKB
Complete GO annotation...

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.

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.
OMAiKWVNGKT.
OrthoDBiEOG091G0VS2.
PhylomeDBiP51580.
TreeFamiTF328951.

Family and domain databases

Gene3Di3.40.50.150. 1 hit.
HAMAPiMF_00812. Thiopur_methtran. 1 hit.
InterProiIPR029063. SAM-dependent_MTases.
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

        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 rs72552740dbSNPEnsembl.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 rs1800462dbSNPEnsembl.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 rs1800460dbSNPEnsembl.1
Natural variantiVAR_052368179Q → H.Corresponds to variant rs6921269dbSNPEnsembl.1
Natural variantiVAR_005639180Y → F Polymorphism; allele TPMT*6; reduced activity. 2 PublicationsCorresponds to variant rs75543815dbSNPEnsembl.1
Natural variantiVAR_008715215R → H Polymorphism; allele TPMT*8; intermediate activity. 2 PublicationsCorresponds to variant rs56161402dbSNPEnsembl.1
Natural variantiVAR_005640227H → Q Polymorphism; allele TPMT*7; reduced activity. 2 PublicationsCorresponds to variant rs72552736dbSNPEnsembl.1
Natural variantiVAR_005641240Y → C Polymorphism; allele TPMT*3B and allele TPMT*3C; reduced activity; protein shows enhanced degradation. 12 PublicationsCorresponds to variant rs1142345dbSNPEnsembl.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. 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_000367.3.
XP_016866730.1. XM_017011241.1.
UniGeneiHs.444319.

Genome annotation databases

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

Keywords - Coding sequence diversityi

Polymorphism

Cross-referencesi

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. 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_000367.3.
XP_016866730.1. XM_017011241.1.
UniGeneiHs.444319.

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...

Protein-protein interaction databases

BioGridi113025. 1 interactor.
STRINGi9606.ENSP00000312304.

Chemistry databases

BindingDBiP51580.
ChEMBLiCHEMBL2500.
DrugBankiDB00993. Azathioprine.
DB00436. Bendroflumethiazide.
DB01327. Cefazolin.
DB01033. Mercaptopurine.
DB01250. Olsalazine.
DB01021. Trichlormethiazide.

PTM databases

iPTMnetiP51580.
PhosphoSitePlusiP51580.

Polymorphism and mutation databases

BioMutaiTPMT.
DMDMi1730006.

Proteomic databases

EPDiP51580.
MaxQBiP51580.
PaxDbiP51580.
PeptideAtlasiP51580.
PRIDEiP51580.

Protocols and materials databases

DNASUi7172.
Structural Biology KnowledgebaseSearch...

Genome annotation databases

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

Organism-specific databases

CTDi7172.
DisGeNETi7172.
GeneCardsiTPMT.
HGNCiHGNC:12014. TPMT.
HPAiHPA019851.
MalaCardsiTPMT.
MIMi187680. gene.
610460. phenotype.
neXtProtiNX_P51580.
OpenTargetsiENSG00000137364.
Orphaneti413687. Azathioprine or 6-mercatopurine toxicity or dose selection.
240863. Cisplatin toxicity.
3315. Thiopurine S-methyltransferase deficiency.
PharmGKBiPA356.
GenAtlasiSearch...

Phylogenomic databases

eggNOGiENOG410IGTR. Eukaryota.
ENOG4111GNF. LUCA.
GeneTreeiENSGT00390000016823.
HOVERGENiHBG003037.
InParanoidiP51580.
KOiK00569.
OMAiKWVNGKT.
OrthoDBiEOG091G0VS2.
PhylomeDBiP51580.
TreeFamiTF328951.

Enzyme and pathway databases

BioCyciZFISH:HS06327-MONOMER.
BRENDAi2.1.1.67. 2681.
ReactomeiR-HSA-156581. Methylation.

Miscellaneous databases

ChiTaRSiTPMT. human.
EvolutionaryTraceiP51580.
GeneWikiiThiopurine_methyltransferase.
GenomeRNAii7172.
PROiP51580.
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000137364.
ExpressionAtlasiP51580. baseline and differential.
GenevisibleiP51580. HS.

Family and domain databases

Gene3Di3.40.50.150. 1 hit.
HAMAPiMF_00812. Thiopur_methtran. 1 hit.
InterProiIPR029063. SAM-dependent_MTases.
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]
ProtoNetiSearch...

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: November 30, 2016
This is version 171 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

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

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.