Reactome | UniProt:P51580 TPMT

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UniProt:P51580 TPMT Show undefined attributes

chain	chain:1-245
checksum	190E781155B97BB9
comment	FUNCTION 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.CATALYTIC ACTIVITY S-adenosyl-L-methionine + a thiopurine = S-adenosyl-L-homocysteine + a thiopurine S-methylether.CATALYTIC ACTIVITY mercaptopurine + S-adenosyl-L-methionine = 6-methylthiopurine + H(+) + S-adenosyl-L-homocysteineCATALYTIC ACTIVITY 6-thioguanine + S-adenosyl-L-methionine = 6-methylthioguanine + H(+) + S-adenosyl-L-homocysteineACTIVITY REGULATION Inhibited by S-adenosyl-L-homocysteine (SAH).BIOPHYSICOCHEMICAL PROPERTIES Optimum pH is 7.5.SUBUNIT Monomer.INTERACTION 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 [MIM: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 TPMT2 and TPMT3A. The proteins encoded by TPMT2 and TPMT3A mutant are degraded more rapidly by an ATP-dependent proteasome-mediated pathway (PubMed:9177237, PubMed:8644731).POLYMORPHISM TPMT3A 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. TPMT3C 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 TPMT3C is the oldest mutation, with TPMT3B being acquired later to form the TPMT3A allele in the Caucasian and South West Asian populations. TPMT2 appears to be a more recent allele, which has only been detected in Caucasians to date.SIMILARITY Belongs to the class I-like SAM-binding methyltransferase superfamily. TPMT family.
crossReference	[DatabaseIdentifier:10974001] Pharos - Targets:P51580 [DatabaseIdentifier:11044589] IntEnz:2.1.1.67 [DatabaseIdentifier:11058771] OpenTargets:ENSG00000137364 [DatabaseIdentifier:11592173] RefSeq:NP_000358.1 [DatabaseIdentifier:11592177] RefSeq:NP_001333746.1 [DatabaseIdentifier:11592188] RefSeq:NP_001333747.1 [DatabaseIdentifier:11722418] PDB:2BZG [DatabaseIdentifier:11722424] PDB:2H11 [DatabaseIdentifier:11824564] PRO:P51580 [DatabaseIdentifier:11844979] GeneCards:P51580 [DatabaseIdentifier:11853481] ZINC - Substances:TPMT_HUMAN [DatabaseIdentifier:11857743] ZINC - Metabolites:TPMT_HUMAN [DatabaseIdentifier:11858629] ZINC - Biogenic:TPMT_HUMAN [DatabaseIdentifier:11861561] ZINC - Predictions - Purchasable:TPMT_HUMAN [DatabaseIdentifier:11864720] ZINC target:P51580 [DatabaseIdentifier:11882862] Orphanet:15650 [DatabaseIdentifier:11888533] HMDB Protein:HMDBP00428 [DatabaseIdentifier:11897525] HPA:ENSG00000137364-TPMT [DatabaseIdentifier:12022276] Ensembl:ENSG00000137364 [DatabaseIdentifier:12022277] Ensembl:ENSP00000312304 [DatabaseIdentifier:12022278] Ensembl:ENST00000309983
databaseName	UniProt
dbId	66307
description	recommendedName: fullName evidence="20"Thiopurine S-methyltransferase ecNumber evidence="9 10"2.1.1.67 alternativeName: fullName evidence="21"Thiopurine methyltransferase
displayName	UniProt:P51580 TPMT
geneName	TPMT
identifier	P51580
isSequenceChanged	false
keyword	3D-structure Acetylation Cytoplasm Direct protein sequencing Methyltransferase Phosphoprotein Reference proteome S-adenosyl-L-methionine Transferase
modified	[InstanceEdit:12187927] Wright, Adam, 2024-03-12
name	TPMT
otherIdentifier	11727822_a_at 11727823_x_at 11727824_at 11727825_x_at 17015975 203671_PM_at 203671_at 203672_PM_x_at 203672_x_at 2944026 2944027 2944028 2944029 2944030 2944031 2944034 2944035 2944037 2944038 2944040 2944042 2944043 2944044 2944045 2944050 32810_at 3787362 3787364 7172 8124134 A_23_P214108 A_24_P397498 A_33_P3317321 GE62974 GO:0003824 GO:0005515 GO:0005737 GO:0005829 GO:0006139 GO:0006805 GO:0008119 GO:0008168 GO:0008757 GO:0016740 GO:0032259 GO:0042178 GO:1904047 HMNXSV003028526 Hs.296922.0.A4_3p_at ILMN_1740185 PH_hs_0024285 S62904_s_at TC06001301.hg U12387_s_at g805083_3p_a_at
physicalEntity	[EntityWithAccessionedSequence:R-HSA-158628] TPMT [cytosol] - Homo sapiens [EntityWithAccessionedSequence:R-HSA-5603333] TPMT A154T [cytosol] - Homo sapiens [EntityWithAccessionedSequence:R-HSA-5603346] TPMT A80P [cytosol] - Homo sapiens [EntityWithAccessionedSequence:R-HSA-5603357] TPMT A167G [cytosol] - Homo sapiens [EntityWithAccessionedSequence:R-HSA-5603343] TPMT Y240C [cytosol] - Homo sapiens
referenceDatabase	[ReferenceDatabase:2] UniProt
referenceGene	[ReferenceDNASequence:8998058] ENSEMBL:ENSG00000137364 TPMT [ReferenceDNASequence:11025411] KEGG Gene (Homo sapiens):7172 TPMT [ReferenceDNASequence:11244321] NCBI Gene:7172 TPMT [ReferenceDNASequence:11244322] BioGPS Gene:7172 TPMT [ReferenceDNASequence:11244323] CTD Gene:7172 TPMT [ReferenceDNASequence:11244324] dbSNP Gene:7172 TPMT [ReferenceDNASequence:11244325] Monarch:7172 TPMT [ReferenceDNASequence:11347047] ENSEMBL_homo_sapiens_GENE:ENSG00000137364.5 TPMT [ReferenceDNASequence:11512152] UCSC:P51580 TPMT [ReferenceDNASequence:11796391] OMIM:187680 TPMT [ReferenceDNASequence:11872334] HGNC:12014 TPMT [ReferenceDNASequence:12195563] COSMIC (genes):TPMT TPMT
referenceTranscript	[ReferenceRNASequence:11449004] RefSeq:NM_000367.4 TPMT [ReferenceRNASequence:11449007] RefSeq:NM_001346817.1 TPMT [ReferenceRNASequence:11449017] RefSeq:NM_001346818.1 TPMT
schemaClass	ReferenceGeneProduct
secondaryIdentifier	TPMT_HUMAN O14806 O15423 O15424 O15425 O15426 O15515 O15548 O43213 Q5VUK6 Q9UBE6 Q9UBT8 Q9UE62
sequenceLength	245
species	[Species:48887] Homo sapiens
url	https://purl.uniprot.org/uniprot/P51580

Referrals

(referenceEntity)	[EntityWithAccessionedSequence:R-HSA-158628] TPMT [cytosol] [EntityWithAccessionedSequence:R-HSA-5603333] TPMT A154T [cytosol] [EntityWithAccessionedSequence:R-HSA-5603346] TPMT A80P [cytosol] [EntityWithAccessionedSequence:R-HSA-5603357] TPMT A167G [cytosol] [EntityWithAccessionedSequence:R-HSA-5603343] TPMT Y240C [cytosol]
(referenceSequence)	[ReplacedResidue:5603344] L-alanine 154 replaced with L-threonine [ReplacedResidue:5603348] L-alanine 80 replaced with L-proline [ReplacedResidue:5603361] L-alanine 167 replaced with glycine [ReplacedResidue:5603359] L-tyrosine 240 replaced with L-cysteine
(interactor)	[UndirectedInteraction:12315313] UniProt:P51580 <-> UniProt:P61981 (IntAct) [UndirectedInteraction:12315309] UniProt:P51580 <-> UniProt:Q15047-2 (IntAct) [UndirectedInteraction:12315311] UniProt:P51580 <-> UniProt:Q8TAP4-4 (IntAct)