Thiopurine methyltransferase
Encyclopedia
Thiopurine methyltransferase or thiopurine S-methyltransferase (TPMT) is an enzyme
that 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. Thiopurine drugs such as 6-mercaptopurine are used as chemotherapeutic
agents. Genetic polymorphisms that affect this enzymatic activity are correlated with variations in sensitivity and toxicity to such drugs within individuals. A pseudogene for this locus is located on chromosome 18q.
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.
drugs such as azathioprine
, 6-mercaptopurine and 6-thioguanine.; as 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.
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
that methylates
Methylation
In the chemical sciences, methylation denotes the addition of a methyl group to a substrate or the substitution of an atom or group by a methyl group. Methylation is a form of alkylation with, to be specific, a methyl group, rather than a larger carbon chain, replacing a hydrogen atom...
thiopurine
Thiopurine
The thiopurine drugs are purine antimetabolites widely used in the treatment of acute lymphoblastic leukemia, autoimmune disorders , and organ transplant recipients.Metabolism is catalyzed by S-methyltransferase....
compounds. The methyl donor is S-adenosyl-L-methionine, which is converted to S-adenosyl-L-homocysteine
S-adenosyl-L-homocysteine
S-Adenosyl-L-homocysteine is an amino acid derivative used in several metabolic pathways in most organisms. It is an intermediate in the synthesis of cysteine and adenosine....
.
This enzyme metabolizes thiopurine
Thiopurine
The thiopurine drugs are purine antimetabolites widely used in the treatment of acute lymphoblastic leukemia, autoimmune disorders , and organ transplant recipients.Metabolism is catalyzed by S-methyltransferase....
drugs via S-adenosyl-L-methionine
S-Adenosyl methionine
S-Adenosyl methionine is a common cosubstrate involved in methyl group transfers. SAM was first discovered in Italy by G. L. Cantoni in 1952. It is made from adenosine triphosphate and methionine by methionine adenosyltransferase . Transmethylation, transsulfuration, and aminopropylation are the...
as the S-methyl donor and S-adenosyl-L-homocysteine
S-adenosyl-L-homocysteine
S-Adenosyl-L-homocysteine is an amino acid derivative used in several metabolic pathways in most organisms. It is an intermediate in the synthesis of cysteine and adenosine....
as a byproduct. Thiopurine drugs such as 6-mercaptopurine are used as chemotherapeutic
Chemotherapy
Chemotherapy is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen....
agents. Genetic polymorphisms that affect this enzymatic activity are correlated with variations in sensitivity and toxicity to such drugs within individuals. A pseudogene for this locus is located on chromosome 18q.
Pharmacology
TPMT is best known for its role in the metabolism of the thiopurineThiopurine
The thiopurine drugs are purine antimetabolites widely used in the treatment of acute lymphoblastic leukemia, autoimmune disorders , and organ transplant recipients.Metabolism is catalyzed by S-methyltransferase....
drugs such as azathioprine
Azathioprine
Azathioprine is a purine analogue immunosuppressive drug. It is used to prevent organ rejection following organ transplantation and to treat a vast array of autoimmune diseases, including rheumatoid arthritis, pemphigus, inflammatory bowel disease , multiple sclerosis, autoimmune hepatitis, atopic...
, 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 thiopurineThiopurine
The thiopurine drugs are purine antimetabolites widely used in the treatment of acute lymphoblastic leukemia, autoimmune disorders , and organ transplant recipients.Metabolism is catalyzed by S-methyltransferase....
drugs such as azathioprine
Azathioprine
Azathioprine is a purine analogue immunosuppressive drug. It is used to prevent organ rejection following organ transplantation and to treat a vast array of autoimmune diseases, including rheumatoid arthritis, pemphigus, inflammatory bowel disease , multiple sclerosis, autoimmune hepatitis, atopic...
, 6-mercaptopurine and 6-thioguanine.; as patients with low activity (10% prevalence) or especially absent activity (prevalence 0.3%) are at a heightened risk of drug-induced bone marrow toxicity
Bone marrow suppression
Bone marrow suppression or myelotoxicity or myelosuppression, is the decrease in cells responsible for providing immunity, carrying oxygen, and those responsible for normal blood clotting is a serious side effect of chemotherapy and certain drugs affecting the immune system such as azathioprine...
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.
Further reading
.External links
- City Assays page on the TPMT assay