Reactome | TPMT transfers CH3 from AdoMet to 6MP

TPMT transfers CH3 from AdoMet to 6MP

Stable Identifier

R-HSA-158609

Type

Reaction [transition]

Species

Homo sapiens

Compartment

cytosol

Synonyms

6-mercaptopurine can be S-methylated

ReviewStatus

5/5

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Methylation is the major biotransformation route of thiopurine drugs such as 6-mercaptopurine (6MP), used in the treatment of inflammatory diseases such as rheumatoid arthritis and childhood acute lymphoblastic leukemia. 6MP and its thioguanine nucleotide metabolites are principally inactivated by thiopurine methyltransferase (TPMT)-catalysed S-methylation.

Defects in TPMT can cause thiopurine S methyltransferase deficiency (TPMT deficiency; MIM:610460). Patients with intermediate or no TPMT activity are at risk of toxicity such as myelosuppression after receiving standard doses of thiopurine drugs. Inter individual differences in response to these drugs are largely determined by genetic variation at the TPMT locus. TPMT exhibits an autosomal co dominant phenotype: About one in 300 people in Caucasian, African, African-American, and Asian populations are TPMT deficient. Approximately 6-10% of people in these populations inherit intermediate TPMT activity and are heterozygous at the TPMT locus. The rest are homozygous for the wild type allele and have high levels of TPMT activity. (Remy 1963, Weinshilboum et al. 1999, Couldhard & Hogarth 2005, Al Hadithy et al. 2005, Azimi et al. 2014).

Literature References

PubMed ID	Title	Journal	Year
24734162	Assessment of Thiopurine-based drugs according to Thiopurine S-methyltransferase genotype in patients with Acute Lymphoblastic Leukemia Azimi, F, Azad, M, Mortazavi, Y, Jafariyan, M, Khatami, S	Iran J Ped Hematol Oncol	2014
13981612	Metabolism of thiopyrimidines and thiopurines. S-Methylation with S-adenosylmethionine transmethylase and catabolism in mammalian tissues. Remy, CN	J Biol Chem	1963
16267626	The thiopurines: an update Hogarth, L, Coulthard, S	Invest New Drugs	2005
15788214	Thiopurines in inflammatory bowel disease: pharmacogenetics, therapeutic drug monitoring and clinical recommendations de Boer, NK, Al Hadithy, AF, Derijks, LJ, Mulder, CJ, Escher, JC, Brouwers, JR	Dig Liver Dis	2005
10331075	Methylation pharmacogenetics: catechol O-methyltransferase, thiopurine methyltransferase, and histamine N-methyltransferase Otterness, DM, Szumlanski, CL, Weinshilboum, RM	Annu Rev Pharmacol Toxicol	1999