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thiopurine S-methyltransferase
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
PMC
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PMC	articles
PubMed	articles
NCBI	proteins

TPMT
Available structures
PDB	Ortholog search: PDBe RCSB
List of PDB id codes
	2BZG, 2H11
Identifiers
Aliases	TPMT, entrez:7172, TPMTD, thiopurine S-methyltransferase
External IDs	OMIM: 187680; MGI: 98812; HomoloGene: 313; GeneCards: TPMT; OMA:TPMT - orthologs
Gene location (Human)
Chr.	Chromosome 6 (human)
End	18,155,077 bp
Gene location (Mouse)
Chr.	Chromosome 13 (mouse)
End	47,198,213 bp
RNA expression pattern
	Top expressed in
	buccal mucosa cell; ; tendon of biceps brachii; ; rectum; ; left lobe of thyroid gland; ; right lobe of thyroid gland; ; internal globus pallidus; ; mucosa of transverse colon; ; right lobe of liver; ; mucosa of ileum; ; human kidney;
	Top expressed in
	right kidney; ; proximal tubule; ; human kidney; ; left lobe of liver; ; zygote; ; primary oocyte; ; secondary oocyte; ; transitional epithelium of urinary bladder; ; tail of embryo; ; otic vesicle;
	More reference expression data
	; ;
	More reference expression data
Gene ontology
Molecular function	S-adenosylmethionine-dependent methyltransferase activity; transferase activity; methyltransferase activity; thiopurine S-methyltransferase activity; S-adenosyl-L-methionine binding;
Cellular component	cytosol; cytoplasm;
Biological process	nucleobase-containing compound metabolic process; methylation;
	Sources:Amigo / QuickGO
Orthologs
	7172
	22017
	ENSG00000137364
	ENSMUSG00000021376
	P51580
	O55060
	NM_000367; NM_001346817; NM_001346818
	NM_016785
	NP_000358; NP_001333746; NP_001333747
	NP_058065
	Wikidata
View/Edit Human	View/Edit Mouse

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.^[5]^[6]

Function

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.^[5]^[7]

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.^[5]

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.^[8]^[9]^[10] Allopurinol inhibits thiopurine S-methyltransferase, which can increase the utility of 6-MP.^[11]

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.^[9]^[12]

Genetic variants of TPMT have also been associated with cisplatin-induced ototoxicity in children.^[13] TPMT is now listed as a pharmacogenomic biomarker for adverse drug reactions to cisplatin by the FDA.^[14]

References

^ ^a ^b ^c GRCh38: Ensembl release 89: ENSG00000137364 – Ensembl, May 2017
^ ^a ^b ^c GRCm38: Ensembl release 89: ENSMUSG00000021376 – Ensembl, May 2017
^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ ^a ^b ^c "Entrez Gene: TPMT thiopurine S-methyltransferase". National Center for Biotechnology Information. Retrieved 2012-07-02.
^ Lee D, Szumlanski C, Houtman J, Honchel R, Rojas K, Overhauser J, Wieben ED, Weinshilboum RM (March 1995). "Thiopurine methyltransferase pharmacogenetics. Cloning of human liver cDNA and a processed pseudogene on human chromosome 18q21.1". Drug Metab. Dispos. 23 (3): 398–405. PMID 7628307.
^ Weinshilboum RM, Sladek SL (1980). "Mercaptopurine pharmacogenetics: Monogenic inheritance of erythrocyte thiopurine methyltransferase activity". American Journal of Human Genetics. 32 (5): 651–662. PMC 1686086. PMID 7191632.
^ Fujita K, Sasaki Y (August 2007). "Pharmacogenomics in drug-metabolizing enzymes catalyzing anticancer drugs for personalized cancer chemotherapy". Curr. Drug Metab. 8 (6): 554–62. doi:10.2174/138920007781368890. PMID 17691917. Archived from the original on 2013-01-12. Retrieved 2008-07-25.
^ ^a ^b Oncea I, Duley J (2008). "Chapter 38: Pharmacogenetics of Thiopurines". Goodman & Gilman's The Pharmacological Basis of Therapeutics (11th ed.). McGraw-Hill's Access Medicine.
^ Evans WE. (2004). "Pharmacogenetics of thiopurine S-methyltransferase and thiopurine therapy". Ther Drug Monit. 26 (2): 186–91. doi:10.1097/00007691-200404000-00018. PMID 15228163. S2CID 34015182.
^ "The Mechanism and Drug Interaction - Allopurinol and Azathioprine and Risk of Bone Marrow Suppression". www.ebmconsult.com. Retrieved 2019-03-24.
^ Genome Bioinformatics Group, Center for Biomolecular Science and Engineering. "Human Gene TPMT (uc003ncm.1)". UCSC Genome Browser. University of California Santa Cruz. Retrieved 2008-07-25.
^ Ross CJ, Katzov-Eckert H, Dubé MP, Brooks B, Rassekh SR, Barhdadi A, Feroz-Zada Y, Visscher H, Brown AM, Rieder MJ, Rogers PC, Phillips MS, Carleton BC, Hayden MR (December 2009). "Genetic variants in TPMT and COMT are associated with hearing loss in children receiving cisplatin chemotherapy". Nat. Genet. 41 (12): 1345–9. doi:10.1038/ng.478. PMID 19898482. S2CID 21293339.
^ "Cisplatin". Science & Research (Drugs). United States Food and Drug Administration.

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.