Thiopurine methyltransferase

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.

File:Thiopurine methyltransferase.png

Thiopurine methyltransferase

Function

thiopurine S-methyltransferase
Identifiers
EC no.	2.1.1.67
CAS no.	67339-09-7
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 / QuickGO
Search PMC articles PubMed articles NCBI proteins

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

A typical reaction is the methylation of mercaptopurine to give 6-methylmercaptopurine.

[[File:|frameless|class=skin-invert-image|alt=2D representation of the chemical structure of Mercaptopurine.]]

Mercaptopurine

+ SAM

 

 

 

 

 

 

 

File:6-Methylmercaptopurine.svg

6-Methylmercaptopurine

+ SAH

 

Clinical significance

Thiopurine drugs such as 6-mercaptopurine are used as chemotherapeutic agents and immunosuppressive drugs. Genetic polymorphisms that affect this enzyme's activity are correlated with variations in sensitivity and toxicity to such drugs. About 1/300 individual is deficient for the enzyme.

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. Allopurinol inhibits thiopurine S-methyltransferase, which can increase the utility of 6-MP.

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.

See also

• Cancer pharmacogenomics

Further reading

• .

External links

• City Assays page on the TPMT assay
• Overview of all the structural information available in the PDB for UniProt: P51580 (Human Thiopurine S-methyltransferase) at the PDBe-KB.