TPMT Gene: Thiopurine S-Methyltransferase
Pharmacogenomic biomarker for thiopurine drug metabolism and toxicity risk
Gene Information Card
| Symbol | TPMT |
|---|---|
| Full Name | Thiopurine S-methyltransferase |
| Gene Type | Protein coding |
| Chromosomal Location | 6p22.3 |
| NCBI Gene ID | 7172 ncbi.nlm.nih.gov/gene/7172 |
| Ensembl ID | ENSG00000137364 |
| UniProt ID | P51580 |
| OMIM ID | 187680 |
| HGNC ID | 12014 |
| Aliases | TMTT, TPMT |
Description
The TPMT gene encodes thiopurine S-methyltransferase, a cytosolic enzyme that catalyzes the S-methylation of thiopurine drugs such as 6-mercaptopurine, 6-thioguanine, and azathioprine. This enzyme inactivates these drugs, thereby regulating their cytotoxic effects. Genetic polymorphisms in TPMT affect enzyme activity, leading to variable drug response and toxicity risk. TPMT is a classic pharmacogenomic gene with well-established clinical guidelines for dosing thiopurines based on genotype.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Thiopurine-induced toxicity (myelosuppression) | Loss-of-function variants reduce enzyme activity, leading to accumulation of cytotoxic thioguanine nucleotides in hematopoietic cells, causing severe bone marrow suppression. | ClinVar, CPIC guidelines |
| Inflammatory bowel disease (IBD) - thiopurine response | TPMT genotype influences thiopurine efficacy and adverse effects; intermediate or poor metabolizers require dose reduction to avoid toxicity. | Multiple studies, CPIC |
| Acute lymphoblastic leukemia (ALL) - thiopurine toxicity | TPMT deficiency increases risk of 6-mercaptopurine-induced myelosuppression, requiring dose adjustment to maintain treatment safety. | ClinVar, COSMIC |
| Autoimmune diseases (e.g., rheumatoid arthritis, lupus) - azathioprine toxicity | Reduced TPMT activity leads to higher risk of leukopenia and other adverse effects when treated with azathioprine. | ClinVar, literature |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Liver | High | High |
| Kidney | Medium | Medium |
| Blood (leukocytes) | Medium | Medium |
| Intestine | Low | Low |
| Bone Marrow | Low | Low |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| HepG2 (liver) | High | Liver-derived cell line |
| K-562 (leukemia) | Medium | Myelogenous leukemia line |
| A549 (lung) | Low | Lung carcinoma line |
| MCF7 (breast) | Low | Breast adenocarcinoma line |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| TPMT*2 (rs1800462) | Missense (Ala80Pro) | ~0.2-0.5% in Caucasians | Reduced enzyme activity |
| TPMT*3A (rs1800460 + rs1142345) | Missense (Ala154Thr + Tyr240Cys) | ~5-10% in Caucasians | Severely reduced activity |
| TPMT*3B (rs1800460) | Missense (Ala154Thr) | Rare | Reduced activity |
| TPMT*3C (rs1142345) | Missense (Tyr240Cys) | ~1-2% in Asians and Africans | Reduced activity |
| TPMT*4 (rs1800584) | Splice site (IVS4-1G>A) | Rare | Loss of function |
Mutation functional classification
Loss of Function (LOF)
Most TPMT variants (e.g., *2, *3A, *3B, *3C, *4) result in reduced or absent enzyme activity due to protein misfolding, instability, or splicing defects, leading to poor metabolism of thiopurines.
Gain of Function (GOF)
No gain-of-function variants have been clinically characterized; increased TPMT activity is not typically associated with disease.
Dominant Negative (DN)
TPMT is a monomeric enzyme; no dominant-negative effects are reported. Loss of function is recessive, with heterozygotes showing intermediate activity.
View complete mutation data：
Gene Ontology (GO)
| • S-methyltransferase activity (GO:0008171) | • Thiopurine S-methyltransferase activity (GO:0008119) |
| • Methylation (GO:0032259) | • Response to xenobiotic stimulus (GO:0009410) |
| • Cytoplasm (GO:0005737) |
Pathways
• Thiopurine metabolism pathway (azathioprine
• 6-mercaptopurine
• 6-thioguanine)
• Drug metabolism - cytochrome P450 and other enzymes
Protein Summary
Thiopurine S-methyltransferase (TPMT) is a 245-amino acid cytosolic enzyme that catalyzes the S-methylation of aromatic and heterocyclic sulfhydryl compounds, including thiopurine drugs. It uses S-adenosyl-L-methionine as a methyl donor. TPMT activity varies widely among individuals due to genetic polymorphisms, affecting drug efficacy and toxicity. The enzyme is expressed in many tissues, with highest levels in liver and kidney. TPMT is a key determinant of thiopurine drug response and is used clinically to guide dosing to prevent severe myelosuppression.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| TPMT Knockout HEK293 Cell Line | EDJ-KQ5960 | Human | 7172 | Details Get a Quote |
| TPMT Knockout A-549 Cell Line | EDJ-KQ29525 | Human | 7172 | Details Get a Quote |
| TPMT Knockout HCT 116 Cell Line | EDJ-KQ29526 | Human | 7172 | Details Get a Quote |
| TPMT Knockout HeLa Cell Line | EDJ-KQ29527 | Human | 7172 | Details Get a Quote |
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