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MGP003185

UniProt Annotations

Entry Information
Gene Namethiopurine S-methyltransferase
Protein EntryTPMT_HUMAN
UniProt IDP51580
SpeciesHuman
Comments
Comment typeDescription
Biophysicochemical PropertiesKinetic parameters: KM=5.6 mM for S-adenosyl-L-methionine {ECO:0000269|PubMed:18484748}; KM=0.35 mM for 6-mercaptopurine {ECO:0000269|PubMed:18484748}; Vmax=0.6 nmol/sec/mg enzyme toward 6-mercaptopurine (at 37 degrees Celsius) {ECO:0000269|PubMed:18484748};
Catalytic ActivityS-adenosyl-L-methionine + a thiopurine = S- adenosyl-L-homocysteine + a thiopurine S-methylether. {ECO:0000269|PubMed:18484748}.
DiseaseThiopurine 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. {ECO:0000269|PubMed:10208641, ECO:0000269|PubMed:10751626, ECO:0000269|PubMed:15819814, ECO:0000269|PubMed:16220112, ECO:0000269|PubMed:16476125, ECO:0000269|PubMed:16789994, ECO:0000269|PubMed:7862671, ECO:0000269|PubMed:8561894, ECO:0000269|PubMed:8644731, ECO:0000269|PubMed:9246020, ECO:0000269|PubMed:9336428, ECO:0000269|PubMed:9711875, ECO:0000269|PubMed:9931345, ECO:0000269|PubMed:9931346}. Note=The disease is caused by mutations affecting the gene represented in this entry.
Enzyme RegulationInhibited by S-adenosyl-L-homocysteine (SAH).
FunctionCatalyzes the S-methylation of thiopurine drugs such as 6-mercaptopurine. {ECO:0000269|PubMed:18484748}.
MiscellaneousTPMT 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.
PolymorphismIndividual 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.
PolymorphismTPMT*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.
Sequence CautionSequence=AAB71631.1; Type=Erroneous initiation; Evidence={ECO:0000305}; Sequence=AAB71632.1; Type=Erroneous initiation; Evidence={ECO:0000305};
SimilarityBelongs to the class I-like SAM-binding methyltransferase superfamily. TPMT family. {ECO:0000305}.
Subcellular LocationCytoplasm.
SubunitMonomer. {ECO:0000269|PubMed:17243178}.
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