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UniProtKB - P51580 (TPMT_HUMAN)
Protein
Thiopurine S-methyltransferase
Gene
TPMT
Organism
Homo sapiens (Human)
Status
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 PublicationsCatalytic activityi
- mercaptopurine + S-adenosyl-L-methionine = 6-methylthiopurine + H+ + S-adenosyl-L-homocysteine2 PublicationsEC:2.1.1.672 Publications
- 6-thioguanine + S-adenosyl-L-methionine = 6-methylthioguanine + H+ + S-adenosyl-L-homocysteine1 PublicationEC:2.1.1.671 Publication
- S-adenosyl-L-methionine + a thiopurine = S-adenosyl-L-homocysteine + a thiopurine S-methylether.2 Publications EC:2.1.1.67
Activity regulationi
Inhibited by S-adenosyl-L-homocysteine (SAH).
Kineticsi
- KM=18.5 µM for S-adenosyl-L-methionine (at pH 6.5 and 37 degrees Celsius)1 Publication
- KM=0.68 mM for 6-mercaptopurine (at pH 6.5 and 37 degrees Celsius)1 Publication
- KM=1.7 µM for S-adenosyl-L-methionine (at pH 7.5 and 37 degrees Celsius)1 Publication
- KM=0.32 mM for 6-mercaptopurine (at pH 7.5 and 37 degrees Celsius)1 Publication
- KM=0.20 mM for 6-thioguanine (at pH 7.5 and 37 degrees Celsius)1 Publication
- 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 key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Binding sitei | 40 | SubstrateBy similarity | 1 | |
Binding sitei | 69 | S-adenosyl-L-methionine; via carbonyl oxygen | 1 | |
Binding sitei | 90 | S-adenosyl-L-methionine | 1 | |
Binding sitei | 152 | S-adenosyl-L-methionine | 1 |
GO - Molecular functioni
- S-adenosyl-L-methionine binding Source: UniProtKB
- thiopurine S-methyltransferase activity Source: UniProtKB
GO - Biological processi
- methylation Source: Reactome
- nucleobase-containing compound metabolic process Source: ProtInc
- xenobiotic metabolic process Source: UniProtKB
Keywordsi
Molecular function | Methyltransferase, Transferase |
Ligand | S-adenosyl-L-methionine |
Enzyme and pathway databases
BRENDAi | 2.1.1.67, 2681 |
PathwayCommonsi | P51580 |
Reactomei | R-HSA-156581, Methylation R-HSA-5578995, Defective TPMT causes TPMT deficiency |
SignaLinki | P51580 |
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 |
Organismi | Homo sapiens (Human) |
Taxonomic identifieri | 9606 [NCBI] |
Taxonomic lineagei | Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo |
Proteomesi |
|
Organism-specific databases
HGNCi | HGNC:12014, TPMT |
MIMi | 187680, gene |
neXtProti | NX_P51580 |
VEuPathDBi | HostDB:ENSG00000137364 |
Subcellular locationi
Cytoplasm and Cytosol
Cytosol
- cytosol Source: Reactome
Keywords - Cellular componenti
CytoplasmPathology & Biotechi
Mutagenesis
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Mutagenesisi | 152 | R → E: Decreases affinity for 6-mercaptopurine. Slightly decreases catalytic activity. 1 Publication | 1 |
Organism-specific databases
DisGeNETi | 7172 |
MalaCardsi | TPMT |
MIMi | 610460, phenotype |
OpenTargetsi | ENSG00000137364 |
Orphaneti | 413687, Azathioprine or 6-mercatopurine toxicity or dose selection 240863, Cisplatin toxicity 3315, NON RARE IN EUROPE: Thiopurine S-methyltransferase deficiency |
PharmGKBi | PA356 |
Miscellaneous databases
Pharosi | P51580, Tchem |
Chemistry databases
ChEMBLi | CHEMBL2500 |
DrugBanki | DB00993, Azathioprine DB00436, Bendroflumethiazide DB01327, Cefazolin DB01033, Mercaptopurine DB01250, Olsalazine DB01021, Trichlormethiazide |
DrugCentrali | P51580 |
Genetic variation databases
BioMutai | TPMT |
DMDMi | 1730006 |
PTM / Processingi
Molecule processing
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
ChainiPRO_0000220102 | 1 – 245 | Thiopurine S-methyltransferaseAdd BLAST | 245 |
Amino acid modifications
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Modified residuei | 14 | PhosphoserineCombined sources | 1 | |
Modified residuei | 58 | N6-acetyllysineCombined sources | 1 |
Keywords - PTMi
Acetylation, PhosphoproteinProteomic databases
EPDi | P51580 |
jPOSTi | P51580 |
MassIVEi | P51580 |
MaxQBi | P51580 |
PaxDbi | P51580 |
PeptideAtlasi | P51580 |
PRIDEi | P51580 |
ProteomicsDBi | 56338 |
PTM databases
GlyGeni | P51580, 1 site, 1 O-linked glycan (1 site) |
iPTMneti | P51580 |
PhosphoSitePlusi | P51580 |
Expressioni
Gene expression databases
Bgeei | ENSG00000137364, Expressed in buccal mucosa cell and 235 other tissues |
ExpressionAtlasi | P51580, baseline and differential |
Genevisiblei | P51580, HS |
Organism-specific databases
HPAi | ENSG00000137364, Tissue enhanced (kidney, liver, thyroid gland) |
Interactioni
Subunit structurei
Monomer.
1 PublicationBinary interactionsi
P51580
With | #Exp. | IntAct |
---|---|---|
LMO3 - isoform 4 [Q8TAP4-4] | 3 | EBI-25902017,EBI-11742507 |
SETDB1 - isoform 2 [Q15047-2] | 3 | EBI-25902017,EBI-9090795 |
YWHAG [P61981] | 3 | EBI-25902017,EBI-359832 |
Protein-protein interaction databases
BioGRIDi | 113025, 8 interactors |
IntActi | P51580, 3 interactors |
STRINGi | 9606.ENSP00000312304 |
Chemistry databases
BindingDBi | P51580 |
Miscellaneous databases
RNActi | P51580, protein |
Structurei
Secondary structure
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details3D structure databases
AlphaFoldDBi | P51580 |
BMRBi | P51580 |
SMRi | P51580 |
ModBasei | Search... |
PDBe-KBi | Search... |
Miscellaneous databases
EvolutionaryTracei | P51580 |
Family & Domainsi
Region
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Regioni | 29 – 40 | S-adenosyl-L-methionine bindingAdd BLAST | 12 | |
Regioni | 134 – 135 | S-adenosyl-L-methionine binding | 2 |
Sequence similaritiesi
Phylogenomic databases
eggNOGi | ENOG502QSF5, Eukaryota |
GeneTreei | ENSGT00390000016823 |
HOGENOMi | CLU_085515_2_0_1 |
InParanoidi | P51580 |
OMAi | LWCGDFF |
OrthoDBi | 1590477at2759 |
PhylomeDBi | P51580 |
TreeFami | TF328951 |
Family and domain databases
Gene3Di | 3.40.50.150, 1 hit |
HAMAPi | MF_00812, Thiopur_methtran, 1 hit |
InterProi | View protein in InterPro IPR029063, SAM-dependent_MTases IPR025835, Thiopurine_S-MeTrfase IPR008854, TPMT |
Pfami | View protein in Pfam PF05724, TPMT, 1 hit |
PIRSFi | PIRSF023956, Thiopurine_S-methyltransferase, 1 hit |
SUPFAMi | SSF53335, SSF53335, 1 hit |
PROSITEi | View protein in PROSITE PS51585, SAM_MT_TPMT, 1 hit |
i Sequence
Sequence statusi: Complete.
P51580-1 [UniParc]FASTAAdd to basket
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
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 key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Natural variantiVAR_005636 | 49 | L → S Allele TPMT*5; has very low activity when expressed in a heterologous system. 2 PublicationsCorresponds to variant dbSNP:rs72552740Ensembl. | 1 | |
Natural variantiVAR_005637 | 80 | A → P 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_005638 | 154 | A → T 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_052368 | 179 | Q → H. Corresponds to variant dbSNP:rs6921269Ensembl. | 1 | |
Natural variantiVAR_005639 | 180 | Y → F Allele TPMT*6; reduced activity. 2 PublicationsCorresponds to variant dbSNP:rs75543815Ensembl. | 1 | |
Natural variantiVAR_008715 | 215 | R → H Allele TPMT*8; intermediate activity. 2 PublicationsCorresponds to variant dbSNP:rs56161402EnsemblClinVar. | 1 | |
Natural variantiVAR_005640 | 227 | H → Q Allele TPMT*7; reduced activity. 2 PublicationsCorresponds to variant dbSNP:rs72552736Ensembl. | 1 | |
Natural variantiVAR_005641 | 240 | Y → C 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 |
CCDSi | CCDS4543.1 |
PIRi | I57946 |
RefSeqi | NP_000358.1, NM_000367.4 NP_001333746.1, NM_001346817.1 NP_001333747.1, NM_001346818.1 |
Genome annotation databases
Ensembli | ENST00000309983.5; ENSP00000312304.4; ENSG00000137364.5 |
GeneIDi | 7172 |
KEGGi | hsa:7172 |
MANE-Selecti | ENST00000309983.5; ENSP00000312304.4; NM_000367.5; NP_000358.1 |
UCSCi | uc003ncm.4, human |
Similar proteinsi
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 No translation available. 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_000367.4 NP_001333746.1, NM_001346817.1 NP_001333747.1, NM_001346818.1 |
3D structure databases
Select the link destinations: PDBei RCSB PDBi PDBji Links Updated | PDB entry | Method | Resolution (Å) | Chain | Positions | PDBsum |
2BZG | X-ray | 1.58 | A | 16-245 | [»] | |
2H11 | X-ray | 1.89 | A/B | 17-245 | [»] | |
AlphaFoldDBi | P51580 | |||||
BMRBi | P51580 | |||||
SMRi | P51580 | |||||
ModBasei | Search... | |||||
PDBe-KBi | Search... |
Protein-protein interaction databases
BioGRIDi | 113025, 8 interactors |
IntActi | P51580, 3 interactors |
STRINGi | 9606.ENSP00000312304 |
Chemistry databases
BindingDBi | P51580 |
ChEMBLi | CHEMBL2500 |
DrugBanki | DB00993, Azathioprine DB00436, Bendroflumethiazide DB01327, Cefazolin DB01033, Mercaptopurine DB01250, Olsalazine DB01021, Trichlormethiazide |
DrugCentrali | P51580 |
PTM databases
GlyGeni | P51580, 1 site, 1 O-linked glycan (1 site) |
iPTMneti | P51580 |
PhosphoSitePlusi | P51580 |
Genetic variation databases
BioMutai | TPMT |
DMDMi | 1730006 |
Proteomic databases
EPDi | P51580 |
jPOSTi | P51580 |
MassIVEi | P51580 |
MaxQBi | P51580 |
PaxDbi | P51580 |
PeptideAtlasi | P51580 |
PRIDEi | P51580 |
ProteomicsDBi | 56338 |
Protocols and materials databases
Antibodypediai | 10352, 424 antibodies from 32 providers |
DNASUi | 7172 |
Genome annotation databases
Ensembli | ENST00000309983.5; ENSP00000312304.4; ENSG00000137364.5 |
GeneIDi | 7172 |
KEGGi | hsa:7172 |
MANE-Selecti | ENST00000309983.5; ENSP00000312304.4; NM_000367.5; NP_000358.1 |
UCSCi | uc003ncm.4, human |
Organism-specific databases
CTDi | 7172 |
DisGeNETi | 7172 |
GeneCardsi | TPMT |
HGNCi | HGNC:12014, TPMT |
HPAi | ENSG00000137364, Tissue enhanced (kidney, liver, thyroid gland) |
MalaCardsi | TPMT |
MIMi | 187680, gene 610460, phenotype |
neXtProti | NX_P51580 |
OpenTargetsi | ENSG00000137364 |
Orphaneti | 413687, Azathioprine or 6-mercatopurine toxicity or dose selection 240863, Cisplatin toxicity 3315, NON RARE IN EUROPE: Thiopurine S-methyltransferase deficiency |
PharmGKBi | PA356 |
VEuPathDBi | HostDB:ENSG00000137364 |
GenAtlasi | Search... |
Phylogenomic databases
eggNOGi | ENOG502QSF5, Eukaryota |
GeneTreei | ENSGT00390000016823 |
HOGENOMi | CLU_085515_2_0_1 |
InParanoidi | P51580 |
OMAi | LWCGDFF |
OrthoDBi | 1590477at2759 |
PhylomeDBi | P51580 |
TreeFami | TF328951 |
Enzyme and pathway databases
BRENDAi | 2.1.1.67, 2681 |
PathwayCommonsi | P51580 |
Reactomei | R-HSA-156581, Methylation R-HSA-5578995, Defective TPMT causes TPMT deficiency |
SignaLinki | P51580 |
Miscellaneous databases
BioGRID-ORCSi | 7172, 9 hits in 1038 CRISPR screens |
ChiTaRSi | TPMT, human |
EvolutionaryTracei | P51580 |
GeneWikii | Thiopurine_methyltransferase |
GenomeRNAii | 7172 |
Pharosi | P51580, Tchem |
PROi | PR:P51580 |
RNActi | P51580, protein |
SOURCEi | Search... |
Gene expression databases
Bgeei | ENSG00000137364, Expressed in buccal mucosa cell and 235 other tissues |
ExpressionAtlasi | P51580, baseline and differential |
Genevisiblei | P51580, HS |
Family and domain databases
Gene3Di | 3.40.50.150, 1 hit |
HAMAPi | MF_00812, Thiopur_methtran, 1 hit |
InterProi | View protein in InterPro IPR029063, SAM-dependent_MTases IPR025835, Thiopurine_S-MeTrfase IPR008854, TPMT |
Pfami | View protein in Pfam PF05724, TPMT, 1 hit |
PIRSFi | PIRSF023956, Thiopurine_S-methyltransferase, 1 hit |
SUPFAMi | SSF53335, SSF53335, 1 hit |
PROSITEi | View protein in PROSITE PS51585, SAM_MT_TPMT, 1 hit |
MobiDBi | Search... |
Entry informationi
Entry namei | TPMT_HUMAN | |
Accessioni | P51580Primary (citable) accession number: P51580 Secondary accession number(s): O14806 Q9UE62 | |
Entry historyi | Integrated into UniProtKB/Swiss-Prot: | October 1, 1996 |
Last sequence update: | October 1, 1996 | |
Last modified: | May 25, 2022 | |
This is version 201 of the entry and version 1 of the sequence. See complete history. | ||
Entry statusi | Reviewed (UniProtKB/Swiss-Prot) | |
Annotation program | Chordata Protein Annotation Program | |
Disclaimer | Any 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, Direct protein sequencing, Reference proteomeDocuments
- Human chromosome 6
Human chromosome 6: entries, gene names and cross-references to MIM - Human entries with genetic variants
List of human entries with genetic variants - Human variants curated from literature reports
Index of human variants curated from literature reports - MIM cross-references
Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot - PDB cross-references
Index of Protein Data Bank (PDB) cross-references - SIMILARITY comments
Index of protein domains and families