Thiopurine methyltransferase

Thiopurine S-methyltransferase
250px PDB rendering based on 2bzg.
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 2BZG, 2H11
Identifiers
Symbol	TPMT
External IDs	OMIM: 187680 MGI: 98812 HomoloGene: 313 ChEMBL: 2500 GeneCards: TPMT Gene
EC number	2.1.1.67
Gene ontology Molecular function • thiopurine S-methyltransferase activity Cellular component • cytosol • extracellular exosome Biological process • nucleobase-containing compound metabolic process • xenobiotic metabolic process • methylation • small molecule metabolic process Sources: Amigo / QuickGO
RNA expression pattern
File:PBB GE TPMT 203671 at tn.png
File:PBB GE TPMT 203672 x at tn.png
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	7172	22017
Ensembl	ENSG00000137364	ENSMUSG00000021376
UniProt	P51580	O55060
RefSeq (mRNA)	NM_000367	NM_016785
RefSeq (protein)	NP_000358	NP_058065
Location (UCSC)	Chr 6: 18.13 – 18.16 Mb	Chr 13: 47.03 – 47.04 Mb
PubMed search	[1]	[2]

Thiopurine methyltransferase or thiopurine S-methyltransferase (TPMT) is an enzyme that in humans is encoded by the TPMT gene. A pseudogene for this locus is located on chromosome 18q.

Function

thiopurine S-methyltransferase
Identifiers
EC number	2.1.1.67
CAS number	Template:CAS
Databases
IntEnz	IntEnz view
BRENDA	BRENDA entry
ExPASy	NiceZyme view
KEGG	KEGG entry
MetaCyc	metabolic pathway
PRIAM	profile
PDB structures	RCSB PDB PDBe PDBsum
Gene Ontology	AmiGO / EGO
Search PMC articles PubMed articles NCBI proteins

Thiopurine methyltransferase methylates thiopurine compounds. The methyl donor is S-adenosyl-L-methionine, which is converted to S-adenosyl-L-homocysteine. This enzyme metabolizes thiopurine drugs via S-adenosyl-L-methionine as the S-methyl donor and S-adenosyl-L-homocysteine as a byproduct.

Clinical significance

Thiopurine drugs such as 6-mercaptopurine are used as chemotherapeutic agents and immunosuppressive drugs. Genetic polymorphisms that affect this enzymatic activity are correlated with variations in sensitivity and toxicity to such drugs within individuals.

Pharmacology

TPMT is best known for its role in the metabolism of the thiopurine drugs such as azathioprine, 6-mercaptopurine and 6-thioguanine. TPMT catalyzes the S-methylation of thiopurine drugs. Defects in the TPMT gene leads to decreased methylation and decreased inactivation of 6MP leading to enhanced bone marrow toxicity which may cause myelosuppression, anemia, bleeding tendency, leukopenia & infection.

Diagnostic use

Measurement of TPMT activity is encouraged prior to commencing the treatment of patients with thiopurine drugs such as azathioprine, 6-mercaptopurine and 6-thioguanine. Patients with low activity (10% prevalence) or especially absent activity (prevalence 0.3%) are at a heightened risk of drug-induced bone marrow toxicity due to accumulation of the unmetabolised drug. Reuther et al. found that about 5% of all thiopurine therapies will fail due to toxicity. This intolerant group could be anticipated by routine measurement of TPMT activity. There appears to be a great deal of variation in TPMT mutation, with ethnic differences in mutation types accounting for variable responses to 6MP.

Genetic variants of TPMT have also been associated with cisplatin-induced ototoxicity in children. TPMT is now listed as a pharmacogenomic biomarker for adverse drug reactions to cisplatin by the FDA.

Further reading

• .

External links

• City Assays page on the TPMT assay