TPMT

Summary

TPMT (thiopurine S-methyltransferase, HGNC:12014) is a protein-coding gene on chromosome 6p22.3, encoding Thiopurine S-methyltransferase (P51580). Catalyzes the S-methylation of thiopurine drugs such as 6-mercaptopurine (also called mercaptopurine, 6-MP or its brand name Purinethol) and 6-thioguanine (also called tioguanine or 6-TG) using S-adenosyl-L-methionine as the methyl donor.

This gene encodes the enzyme that 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, causing thiopurine S-methyltransferase deficiency. Related pseudogenes have been identified on chromosomes 3, 18 and X.

Source: NCBI Gene 7172 — RefSeq curated summary.

At a glance

• GWAS associations: 6
• Clinical variants (ClinVar): 49 total
• Phenotypes (HPO): 3
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_000367

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:12014
Approved symbol	TPMT
Name	thiopurine S-methyltransferase
Location	6p22.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000137364
Ensembl biotype	protein_coding
OMIM	187680
Entrez	7172

Gene structure

Transcript identifiers

Ensembl transcripts: 18 — 18 protein_coding

ENST00000309983, ENST00000864360, ENST00000864361, ENST00000864362, ENST00000864363, ENST00000864364, ENST00000864365, ENST00000864366, ENST00000864367, ENST00000864368, ENST00000864369, ENST00000864370, ENST00000864371, ENST00000929330, ENST00000929331, ENST00000963990, ENST00000963991, ENST00000963992

RefSeq mRNA: 3 — MANE Select: NM_000367 NM_000367, NM_001346817, NM_001346818

CCDS: CCDS4543

Canonical transcript exons

ENST00000309983 — 9 exons

Exon	Start	End
ENSE00000928736	18132133	18132177
ENSE00000928737	18133804	18133889
ENSE00000928738	18138963	18139037
ENSE00000928739	18139665	18139717
ENSE00000928740	18143596	18143728
ENSE00000928741	18147823	18147915
ENSE00000928742	18148988	18149171
ENSE00001209706	18128311	18130780
ENSE00001478514	18155033	18155077

Expression profiles

Bgee: expression breadth ubiquitous, 270 present calls, max score 99.58.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 21.1999 / max 1263.1084, expressed in 1795 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
72019	20.4351	1794
72020	0.6236	361
72021	0.1412	51

Top tissues by expression

285 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
buccal mucosa cell	CL:0002336	99.58	gold quality
tendon of biceps brachii	UBERON:0008188	95.97	gold quality
type B pancreatic cell	CL:0000169	93.26	gold quality
rectum	UBERON:0001052	93.21	gold quality
olfactory bulb	UBERON:0002264	93.05	gold quality
left lobe of thyroid gland	UBERON:0001120	92.49	gold quality
thyroid gland	UBERON:0002046	92.37	gold quality
right lobe of thyroid gland	UBERON:0001119	91.90	gold quality
medial globus pallidus	UBERON:0002477	91.38	gold quality
mucosa of transverse colon	UBERON:0004991	91.19	gold quality
oviduct epithelium	UBERON:0004804	90.79	gold quality
right lobe of liver	UBERON:0001114	90.38	gold quality
ileal mucosa	UBERON:0000331	89.78	gold quality
globus pallidus	UBERON:0001875	89.72	gold quality
adult mammalian kidney	UBERON:0000082	89.71	gold quality
liver	UBERON:0002107	89.49	gold quality
diaphragm	UBERON:0001103	89.48	silver quality
tongue squamous epithelium	UBERON:0006919	88.99	silver quality
monocyte	CL:0000576	88.83	gold quality
mononuclear cell	CL:0000842	88.34	gold quality
nephron tubule	UBERON:0001231	88.33	gold quality
leukocyte	CL:0000738	88.10	gold quality
cervix squamous epithelium	UBERON:0006922	87.79	silver quality
kidney	UBERON:0002113	87.70	gold quality
islet of Langerhans	UBERON:0000006	87.61	gold quality
epithelial cell of pancreas	CL:0000083	87.52	silver quality
orbitofrontal cortex	UBERON:0004167	87.36	gold quality
cervix epithelium	UBERON:0004801	86.66	silver quality
duodenum	UBERON:0002114	86.54	gold quality
upper arm skin	UBERON:0004263	86.44	silver quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-HCAD-13	yes	25.43
E-ANND-3	yes	8.92

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): SP1, SP3

miRNA regulators (miRDB)

103 targeting TPMT, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-3120-5P	100.00	65.56	965
HSA-MIR-450A-1-3P	100.00	69.33	1837
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-33A-5P	99.99	68.62	1055
HSA-MIR-33B-5P	99.99	68.58	1062
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-6755-5P	99.95	65.59	464
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488
HSA-MIR-548AM-5P	99.94	71.24	3488
HSA-MIR-548AP-5P	99.94	71.14	3489
HSA-MIR-548AQ-5P	99.94	71.34	3426
HSA-MIR-548AR-5P	99.94	71.28	3515
HSA-MIR-548AS-5P	99.94	71.22	3482
HSA-MIR-548AU-5P	99.94	71.24	3488
HSA-MIR-548AY-5P	99.94	71.23	3502

Literature-anchored findings (GeneRIF, showing 40)

• Defective methylation and subsequent hyperhomocysteinemia leading to impairment of thiopurine methyltransferase activity may serve as a MS susceptibility factor. (PMID:11927101)
• Polymorphisms in TPMT are associated with acute lymphoblastic leukemia in Asians and whites (PMID:12142782)
• Azathioprine toxicity is related to enzyme genotype (and mutation) in renal transplant patients. (PMID:12176518)
• polymorphisms of thiopurine methyltransferase were studied in 306 healthy Brazilians who were classed, on the basis of self-declared colour and ancestry (PMID:12777968)
• This study is the first analysis of TPMT mutant allele frequency in a sample of the Brazilian population. (PMID:12815366)
• Allele frequency of TPMT*3C is low among Jing Chinese (1.0%), and TPMT*3C appears to be the most prevalent deleterious allele in this population. (PMID:12903038)
• The pharmacogenetics of TPMT was studied in relation to drug toxicity and therapeutic efficacy. (PMID:12972954)
• REVIEW: pharmacogenetics of TPMT in cancer therapy (PMID:14576848)
• Thiopurine S-methyltransferase (TPMT) polymorphisms have been linked with severe and potentially fatal myelosuppression in deficient metabolizers and rejection of transplanted organs in high metabolizers. (PMID:14985890)
• Allelic variation at the TPMT (thiopurine S-methyltransferase) locus resulted in large inter-individual differences in the activity of enzyme TPMT, which the gene encodes and which are responsible for differences in toxicity/efficacy of thiopurine drugs. (PMID:14985891)
• Polymorphism affects pharmacogenetics. (review) (PMID:15226671)
• Provides solid basis to predict TPMT phenotype in a Northern European Caucasian population by molecular diagnostics. (PMID:15226673)
• When azathioprine is administered at an initial dose of 1.5 mg/kg per day, both coding and promoter TPMT polymorphisms influence the dose tolerated. (PMID:15349717)
• TPMT genotype was an independent predictor for hemoglobin, hematocrit and red blood cell changes during azathioprine treatment after kidney transplantation. (PMID:15476481)
• thiopurine methyltransferase polymorphisms modify the metabolism of the thiopurine drugs [review] (PMID:15571264)
• TPMT promoter Variable Number Tandem Repeats are unlikely to play a significant role in changes in TPMT activity in response to azathioprine therapy (PMID:15571267)
• Specific genetic polymorphisms in drug metabolizing enzymes such as TPMT, drug transporters (MDR1), and drug target enzymes (TS) are associated with clinical outcomes in patients treated with chemotherapy drugs, such as 5-fluorouracil and irinotecan. (PMID:15709212)
• TPMT genotype has a substantial impact on minimal residual disease after administration of mercaptopurine in the early course of childhood ALL, most likely through modulation of mercaptopurine dose intensity. (PMID:15784872)
• Genotyping for the major TPMT variant alleles may be valuable tool in preventing azathioprine toxicity. (PMID:15946151)
• there is a unique pharmacogenetic mechanism by which common polymorphisms affect TPMT protein function and therapeutic response to thiopurine drugs (PMID:15967990)
• TPMT, ITPA, and MTHFR genotypes do not predict adverse drug reactions, including bone marrow suppression, in liver transplant patients. Possible association between nodular regenerative hyperplasia and heterozygous TPMT genotype. (PMID:15973722)
• Genotyping for the major TPMT variant alleles may be valuable tool in preventing azathioprine toxicity. (PMID:16044099)
• polymorphisma in the 5,10-methylenetetrahydrofolate reductase gene may play an important role in determing the erythrocyte thiopurine methyltransferase phenotype (PMID:16306100)
• Importance of performing surveillance testing for allelic characterization prior to treatment with azathioprine for multiple sclerosis. (PMID:16459728)
• The only discovery translated until now into daily practice is the relation between thiopurine S-methyltransferase (TPMT) gene polymorphisms and hematological toxicity of thiopurine treatment in inflammatory bowel diseases (IBD). (PMID:16773681)
• Three novel single nucleotide polymorphisms (SNPs) of thiopurine S-methyltransferase were identified-106G>A in exon 3 (Gly36Ser, *20 allele), 967A>G in 3’-untranslated region, and -87C>T in intron 8. (PMID:16946561)
• TPMT does not appear to have a role in response to thiopurine treatment in inflammatory bowel disease (PMID:17065060)
• The relationship of TPMT genotype to azathioprine side effects is reported in Japanese patients with autoimmune liver diseases. (PMID:17241387)
• Structure of TPMT shows that naturally occurring amino acid polymorphisms scatter throughout, & amino acids whose alteration have most influence on function are those that form intra-molecular stabilizing interactions (mainly van der Waals contacts). (PMID:17243178)
• study provides the first data on the frequency of common TPMT variants in the Turkish population, based on analysis of pediatric patients with acute lymphoblastic leukemia (PMID:17617792)
• The novel variant allele of TPMT affects enzyme activity, as the individuals carrying it had almost undetectable TPMT activity. (PMID:17885628)
• Thiopurine S-methyltransferase gene (TMPT) polymorphisms in a Mexican population of healthy individuals and leukemic patients. (PMID:18188716)
• A higher prevalence of TPMT deficiency was recorded than in previous studies. Afro-Caribbeans have lower activity than Caucasians and South Asians. TPMT enzyme activity was lower among females, especially in South Asians. (PMID:18303966)
• Trinucleotide repeat variants in the promoter of the thiopurine S-methyltransferase gene of patients exhibiting ultra-high enzyme activity. (PMID:18408566)
• The A80P polymorphism in TPMT*2 disrupts helix alpha3 bordering the active site, which breaks several salt-bridge interactions and opens up a large cleft in the protein. The A154T polymorphism is located within the co-substrate binding site. (PMID:18482735)
• Either Arg152 or Arg226 may participate in the TPMT reaction, with one residue compensating when the other is altered, and Arg152 may interact with substrate more directly than Arg226. (PMID:18484748)
• the frequency of functional gene polymorphisms in 396 patients with inflammatory bowel disease and 300 healthy subjects (PMID:18600549)
• Identification and functional characterisation of four novel TPMT allelic variants. (PMID:18602085)
• detected in an Estonoian population were 3 novel mutations -30T>A exon 3, 10A>G intron 3 & 145A>G intron 10; 4 markers whose frequencies were significantly different in intermediate methylators; 1 haplotype associated with intermediate TPMT activity (PMID:18605963)
• analysis of thiopurine S-methyltransferase allelic variants (PMID:18708949)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	tpmt.2	ENSDARG00000028012
danio_rerio	tpmt.1	ENSDARG00000055974
mus_musculus	Tpmt	ENSMUSG00000021376
rattus_norvegicus	Tpmt	ENSRNOG00000016468

Protein

Protein identifiers

Thiopurine S-methyltransferase — P51580 (reviewed: P51580)

Alternative names: Thiopurine methyltransferase

All UniProt accessions (1): P51580

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the S-methylation of thiopurine drugs such as 6-mercaptopurine (also called mercaptopurine, 6-MP or its brand name Purinethol) and 6-thioguanine (also called tioguanine or 6-TG) using S-adenosyl-L-methionine as the methyl donor. TPMT activity modulates the cytotoxic effects of thiopurine prodrugs. A natural substrate for this enzyme has yet to be identified.

Subunit / interactions. Monomer.

Subcellular location. Cytoplasm.

Activity regulation. Inhibited by S-adenosyl-L-homocysteine (SAH).

Polymorphism. Polymorphic variations define TPMT activity levels that are variable among ethnic groups. 90% of Caucasians have high TPMT activity, 10% have intermediate activity, and 1 in 300 individuals has low activity. These differences influence the clinical use and therapeutic efficacy of thiopurine drugs, generally used as immunosuppressants or cytotoxic drugs in conditions including leukemia, autoimmune disease and organ transplantation. Intermediate or low TPMT activity is associated with thiopurine intolerance and patients are at risk of toxicity after receiving standard doses of thiopurine drugs [MIM:610460]. The most prevalent TPMT alleles associated with TPMT deficiency are TPMT2 and TPMT3A. The proteins encoded by TPMT2 and TPMT3A mutant are degraded more rapidly by an ATP-dependent proteasome-mediated pathway. TPMT3A is the most common allele in the Caucasians and American Caucasians; it is the only mutant allele found in the South West Asians; it is not found in the Chinese. TPMT3C is common in African-Americans and is the only allele in Chinese, Japanese and Taiwanese individuals. This allele is found at a low frequency in the Caucasians. This suggests that TPMT3C is the oldest mutation, with TPMT3B being acquired later to form the TPMT3A allele in the Caucasian and South West Asian populations. TPMT2 appears to be a more recent allele, which has only been detected in Caucasians to date.

Similarity. Belongs to the class I-like SAM-binding methyltransferase superfamily. TPMT family.

RefSeq proteins (3): NP_000358, NP_001333746, NP_001333747 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR008854	TPMT	Family
IPR025835	Thiopurine_S-MeTrfase	Family
IPR029063	SAM-dependent_MTases_sf	Homologous_superfamily

Pfam: PF05724

Enzyme classification (BRENDA):

• EC 2.1.1.67 — thiopurine S-methyltransferase (BRENDA: 9 organisms, 80 substrates, 73 inhibitors, 103 Km, 0 kcat entries)

Substrate kinetics (BRENDA)

28 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
6-THIOGUANINE	0.0137–1.45	36
6-MERCAPTOPURINE	0.0003–0.99	24
S-ADENOSYL-L-METHIONINE	0.0024–0.0463	16
2-THIOURACIL	1.7–2	2
2-MERCAPTOETHANOL	168	1
6-HYDROXY-8-MERCAPTOPURINE	0.138	1
6-MERCAPTOPURINE-RIBOSIDE	1.17	1
6-MERCAPTOPURINE-RIBOSIDE-5’-MONOPHOSPHATE	1.27	1
6-MERCAPTOPURINE-RIBOSIDE-5’-TRIPHOSPHATE	0.89	1
6-SELENOGUANINE-RIBOSIDE	0.139	1
6-SELENOPURINE	0.0291	1
6-SELENOPURINE-RIBOSIDE	0.0518	1
6-THIODEOXYGUANOSINE	0.1314	1
6-THIODEOXYINOSINE	0.0127	1
6-THIOGUANINE-RIBOSIDE	0.761	1

Catalyzed reactions (Rhea), 2 shown:

• mercaptopurine + S-adenosyl-L-methionine = 6-methylthiopurine + S-adenosyl-L-homocysteine + H(+) (RHEA:12609)
• 6-thioguanine + S-adenosyl-L-methionine = 6-methylthioguanine + S-adenosyl-L-homocysteine + H(+) (RHEA:56580)

UniProt features (40 total): helix 9, strand 9, sequence variant 8, binding site 6, turn 4, modified residue 2, chain 1, mutagenesis site 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
2BZG	X-RAY DIFFRACTION	1.58
2H11	X-RAY DIFFRACTION	1.89

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P51580-F1	95.15	0.93

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (6): 29–40; 40; 69; 90; 134–135; 152

Post-translational modifications (2): 14, 58

Mutagenesis-validated functional residues (1):

Position	Phenotype
152	decreases affinity for 6-mercaptopurine. slightly decreases catalytic activity.

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-156581	Methylation
R-HSA-5578995	Defective TPMT causes TPMT deficiency
R-HSA-9748787	Azathioprine ADME

MSigDB gene sets: 150 (showing top): REACTOME_BIOLOGICAL_OXIDATIONS, GCANCTGNY_MYOD_Q6, CAGCTG_AP4_Q5, SHETH_LIVER_CANCER_VS_TXNIP_LOSS_PAM1, HOSHIDA_LIVER_CANCER_SUBCLASS_S3, BLALOCK_ALZHEIMERS_DISEASE_UP, MORF_PML, MORF_PDPK1, MORF_IKBKG, DBP_Q6, GOBP_METHYLATION, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_DN, MASSARWEH_TAMOXIFEN_RESISTANCE_UP, MORF_MYST2, KEGG_DRUG_METABOLISM_OTHER_ENZYMES

GO Biological Process (4): nucleobase-containing compound metabolic process (GO:0006139), xenobiotic metabolic process (GO:0006805), methylation (GO:0032259), xenobiotic catabolic process (GO:0042178)

GO Molecular Function (6): thiopurine S-methyltransferase activity (GO:0008119), S-adenosyl-L-methionine binding (GO:1904047), protein binding (GO:0005515), methyltransferase activity (GO:0008168), S-adenosylmethionine-dependent methyltransferase activity (GO:0008757), transferase activity (GO:0016740)

GO Cellular Component (2): cytosol (GO:0005829), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Phase II - Conjugation of compounds	1
Metabolic disorders of biological oxidation enzymes	1
Drug ADME	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
metabolic process	2
cellular anatomical structure	2
primary metabolic process	1
cellular response to xenobiotic stimulus	1
xenobiotic metabolic process	1
catabolic process	1
S-methyltransferase activity	1
S-adenosylmethionine-dependent methyltransferase activity	1
cation binding	1
sulfur compound binding	1
binding	1
transferase activity, transferring one-carbon groups	1
methyltransferase activity	1
catalytic activity	1
cytoplasm	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

3335 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TPMT	SLC19A1	P41440	924
TPMT	CYP2D6	P10635	902
TPMT	NUDT15	Q9NV35	893
TPMT	GGH	Q92820	871
TPMT	ITPA	Q9BY32	822
TPMT	COMT	P21964	796
TPMT	CD82	P27701	793
TPMT	VKORC1	Q9BQB6	786
TPMT	DPYD	Q12882	782
TPMT	XDH	P47989	756
TPMT	CYP2C19	P33259	732
TPMT	UGT1A1	P22309	731
TPMT	CYP2C9	P11712	724
TPMT	UGT1A6	P19224	723
TPMT	UGT1A4	P22310	723
TPMT	UGT1A7	Q9HAW7	723

IntAct

15 interactions, top by confidence:

A	B	Type	Score
TPMT	YWHAG	psi-mi:“MI:0915”(physical association)	0.560
TPMT	SETDB1	psi-mi:“MI:0915”(physical association)	0.560
LMO3	TPMT	psi-mi:“MI:0915”(physical association)	0.560
TPMT	POTEI	psi-mi:“MI:0915”(physical association)	0.400
USPL1	TPMT	psi-mi:“MI:0915”(physical association)	0.400
SRSF1	CASC3	psi-mi:“MI:0914”(association)	0.350
NOTCH2NLA	IGKC	psi-mi:“MI:0914”(association)	0.350
SERTAD1	IGKC	psi-mi:“MI:0914”(association)	0.350

BioGRID (22): TPMT (Affinity Capture-MS), TPMT (Affinity Capture-MS), TPMT (Affinity Capture-MS), POTEI (Affinity Capture-MS), TPMT (Affinity Capture-MS), TPMT (Affinity Capture-MS), TPMT (Co-fractionation), TPMT (Co-fractionation), PPWD1 (Co-fractionation), TPMT (Affinity Capture-MS), TPMT (Affinity Capture-MS), TPMT (Proximity Label-MS), TPMT (Proximity Label-MS), TPMT (Proximity Label-MS), TPMT (Proximity Label-MS)

ESM2 similar proteins: A0JMU5, A0JPF9, A1A4L5, A5PKL6, C0IN03, E1BVR9, E9PYK3, F1ND48, F4IVI0, O94952, P51580, Q32PJ3, Q32PY6, Q3BCR3, Q3BCR4, Q3BCR8, Q3U3W5, Q3UY23, Q4KLT3, Q4R180, Q4R3W5, Q4R6Y8, Q568P9, Q5DJU3, Q5R5S1, Q5RBJ3, Q5RL51, Q5T8I9, Q5U2Z5, Q5ZIB9, Q6DDT5, Q6NTR1, Q6P2P2, Q6P2S7, Q6PCI6, Q7ZU91, Q80Y20, Q8BGG7, Q8BYH3, Q8CAE2

Diamond homologs: A0KSQ0, A0Q3W9, A1RFQ1, A1S2Z7, A1U560, A3D007, A3QI29, A4XVB5, A4YAM5, A5F1V4, A5II06, A5W759, A6V3Q8, A6WSW9, A7IIX3, A7MVH9, A8G0J1, A8H029, A9I3K3, A9L3X6, B0KUP7, B0TSS5, B1J4W2, B1KHT1, B5FEQ9, B6ENK8, B7VAP9, B7VPF3, B8CUG6, B8ECC0, C1DRL5, C3K732, C3LLS2, C5BIS1, O55060, O86262, P51580, Q02NZ5, Q07XD8, Q0ADU3

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

49 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	19
Likely benign	5
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1792 predictions. Top by Δscore:

Variant	Effect	Δscore
6:18133372:T:TA	donor_gain	1.0000
6:18138957:ACTT:A	donor_loss	1.0000
6:18138958:CTT:C	donor_loss	1.0000
6:18138959:TTA:T	donor_loss	1.0000
6:18138960:T:TG	donor_loss	1.0000
6:18138961:A:AC	donor_gain	1.0000
6:18138961:AC:A	donor_gain	1.0000
6:18138962:C:CA	donor_gain	1.0000
6:18138962:CC:C	donor_gain	1.0000
6:18138962:CCA:C	donor_gain	1.0000
6:18138962:CCAT:C	donor_gain	1.0000
6:18139042:C:CT	acceptor_gain	1.0000
6:18139043:A:T	acceptor_gain	1.0000
6:18148986:A:AC	donor_gain	1.0000
6:18148987:C:CC	donor_gain	1.0000
6:18148990:ATGT:A	donor_gain	1.0000
6:18148993:T:TA	donor_gain	1.0000
6:18149000:T:TA	donor_gain	1.0000
6:18155029:CTACC:C	donor_loss	1.0000
6:18155030:TAC:T	donor_loss	1.0000
6:18155031:ACCTC:A	donor_loss	1.0000
6:18155032:C:CT	donor_loss	1.0000
6:18130777:TTACC:T	acceptor_loss	0.9900
6:18130778:TACC:T	acceptor_loss	0.9900
6:18130779:ACC:A	acceptor_loss	0.9900
6:18130780:CCTGA:C	acceptor_loss	0.9900
6:18130781:CTGA:C	acceptor_loss	0.9900
6:18130782:T:A	acceptor_loss	0.9900
6:18132174:GGACC:G	acceptor_loss	0.9900
6:18132176:ACC:A	acceptor_loss	0.9900

AlphaMissense

1624 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:18149008:A:C	F40L	0.990
6:18149008:A:T	F40L	0.990
6:18149010:A:G	F40L	0.990
6:18143665:A:C	F99L	0.984
6:18143665:A:T	F99L	0.984
6:18143667:A:G	F99L	0.984
6:18132167:A:C	F197L	0.976
6:18132167:A:T	F197L	0.976
6:18132169:A:G	F197L	0.976
6:18139005:T:G	D151A	0.972
6:18139006:C:G	D151H	0.971
6:18139005:T:A	D151V	0.970
6:18139009:A:G	W150R	0.970
6:18139009:A:T	W150R	0.970
6:18149041:C:A	W29C	0.962
6:18149041:C:G	W29C	0.962
6:18143666:A:G	F99S	0.960
6:18147841:T:A	K72I	0.959
6:18149029:C:A	W33C	0.958
6:18149029:C:G	W33C	0.958
6:18147844:C:A	G71V	0.957
6:18149043:A:G	W29R	0.953
6:18149043:A:T	W29R	0.953
6:18139007:C:A	W150C	0.951
6:18139007:C:G	W150C	0.951
6:18147846:G:C	C70W	0.951
6:18147829:A:G	M76T	0.946
6:18133850:A:C	F178L	0.944
6:18133850:A:T	F178L	0.944
6:18133852:A:G	F178L	0.944

dbSNP variants (sampled 300 via entrez): RS1000022479 (6:18138589 T>A), RS1000191827 (6:18151180 CTCTCT>C), RS1000423008 (6:18151663 G>A), RS1000595652 (6:18156067 G>A), RS1000857495 (6:18151117 A>G), RS1000909663 (6:18132699 C>T), RS1000928557 (6:18156253 G>A,T), RS1000968386 (6:18155886 T>C), RS1001270394 (6:18152012 T>A,G), RS1001446107 (6:18136599 G>A), RS1001701878 (6:18151791 T>A), RS1001704891 (6:18149723 G>A), RS1001706582 (6:18145142 G>A), RS1001781713 (6:18144881 C>T), RS1001831488 (6:18134542 C>T)

Disease associations

OMIM: gene MIM:187680 | disease phenotypes: MIM:610460

GenCC curated gene-disease

Mondo (1): thiopurine S-methyltransferase deficiency (MONDO:0012503)

Orphanet (1): (Orphanet:3315)

HPO phenotypes

3 total (3 of 3 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0001871	Abnormality of blood and blood-forming tissues
HP:0001939	Abnormality of metabolism/homeostasis

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST003609_1	Thiopurine methyltransferase activity in acute lymphoblastic leukemia patients treated with mercaptopurines	9.000000e-61
GCST003841_2	Thiopurine S-methyltransferase activity	1.000000e-72
GCST007148_1	Erythrocyte thioguanine concentration in 6-mercaptopurine-treated acute lymphoblastic leukaemia	1.000000e-33
GCST007149_1	Erythrocyte methylated 6-mercaptopurine metabolite concentration in 6-mercaptopurine-treated acute lymphoblastic leukaemia	1.000000e-20
GCST007150_1	DNA-incorporated thioguanine levels in 6-mercaptopurine-treated acute lymphoblastic leukaemia	8.000000e-10
GCST008801_1	Thiopurine-induced myelosuppression in inflammatory bowel disease	5.000000e-09

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0007852	thiopurine methyltransferase activity measurement
EFO:0009693	thiopurine metabolite measurement
EFO:0007053	myelosuppression

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C536512	Thiopurine S methyltranferase deficiency (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2500 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 2,165 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1214186	SINEFUNGIN	2	2,165

PharmGKB: 1 entry (VIP=true, CPIC=true)

PharmGKB clinical annotations

27 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs1142345	Efficacy	3	cisplatin;cyclophosphamide	Ovarian Neoplasms
rs1142345	Dosage,Toxicity	3	mercaptopurine	Acute lymphoblastic leukemia
rs1142345	Toxicity	3	cisplatin	Drug Toxicity;Neoplasms;Ototoxicity
rs12201199	Other	3	mercaptopurine
rs12201199	Toxicity	3	cisplatin	Neoplasms
rs17839843	Other	3	mercaptopurine
rs1800460	Toxicity	3	cisplatin	Neoplasms
rs3931660	Other	3	mercaptopurine
TPMT1, TPMT19, TPMT20, TPMT21, TPMT22, TPMT30, TPMT32, TPMT33, TPMT*34	Metabolism/PK	3	thioguanine
TPMT1, TPMT21, TPMT24, TPMT25, TPMT32, TPMT33, TPMT34, TPMT37	Metabolism/PK	3	mercaptopurine	Acute lymphoblastic leukemia;Systemic lupus erythematosus
TPMT1, TPMT21, TPMT33, TPMT34	Toxicity	3	mercaptopurine	Acute lymphoblastic leukemia;Neutropenia;Thrombocytopenia
TPMT1, TPMT21, TPMT33, TPMT34	Toxicity	3	thioguanine	Acute lymphoblastic leukemia;Neutropenia;Thrombocytopenia
TPMT1, TPMT21, TPMT33, TPMT34	Dosage	3	mercaptopurine	Acute lymphoblastic leukemia
TPMT1, TPMT21, TPMT33, TPMT34	Dosage	3	thioguanine	Acute lymphoblastic leukemia
TPMT1, TPMT2, TPMT3A, TPMT3B, TPMT*3C	Dosage	1A	azathioprine	Dose reduction
TPMT1, TPMT2, TPMT3A, TPMT3B, TPMT3C, TPMT4, TPMT5, TPMT6, TPMT7, TPMT8, TPMT9, TPMT12, TPMT14, TPMT15, TPMT16, TPMT23	Metabolism/PK	1A	mercaptopurine
TPMT1, TPMT2, TPMT3A, TPMT3B, TPMT3C, TPMT4, TPMT6, TPMT9, TPMT*12	Toxicity	1A	mercaptopurine
TPMT1, TPMT2, TPMT3A, TPMT3B, TPMT3C, TPMT6	Toxicity	1A	azathioprine	Leukopenia;Myelosuppression
TPMT1, TPMT2, TPMT3A, TPMT3B, TPMT3C, TPMT7, TPMT9, TPMT10, TPMT12, TPMT13, TPMT16, TPMT17, TPMT18, TPMT23	Metabolism/PK	1A	thioguanine	Crohn Disease
TPMT1, TPMT2, TPMT3A, TPMT3B, TPMT3C, TPMT9	Dosage	1A	mercaptopurine	Dose reduction
TPMT1, TPMT2, TPMT3A, TPMT3C	Toxicity	3	azathioprine	Transplantation
TPMT1, TPMT2, TPMT3A, TPMT3C, TPMT*9	Toxicity	1A	thioguanine	Acute lymphoblastic leukemia;Neoplasms;Neutropenia;Pancytopenia;Thrombocytopenia
TPMT1, TPMT2, TPMT3A, TPMT3C, TPMT*9	Dosage	1A	thioguanine	Acute lymphoblastic leukemia
TPMT1, TPMT3A	Toxicity	3	cisplatin	Ototoxicity
TPMT1, TPMT3A, TPMT*3C	Metabolism/PK	1A	azathioprine
TPMT1, TPMT3A, TPMT*3C	Toxicity	3	olanzapine	Fatigue
TPMT1, TPMT3B, TPMT*3C	Efficacy	3	fluorouracil	Neoplasms

PharmGKB variants

42 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs1142345	TPMT	3	5.75	16	cisplatin;cisplatin;cyclophosphamide;mercaptopurine
rs1800460	TPMT	3	2.25	14	cisplatin
rs1800462	TPMT		0.00	9
rs1800584	TPMT		0.00	2
rs2518463	TPMT		0.00	0
rs2842934	TPMT		0.00	0
rs2842949	TPMT		0.00	0
rs3931660	TPMT	3	0.00	1	mercaptopurine
rs4449636	TPMT		0.00	0
rs6921269	TPMT		0.00	1
rs9333569	TPMT		0.00	1
rs9333570	TPMT		0.00	1
rs12201199	TPMT	3	2.25	2	cisplatin;mercaptopurine
rs12529220	TPMT		0.00	0
rs17839843	TPMT	3	0.00	1	mercaptopurine
rs56161402	TPMT		0.00	1
rs72552736	TPMT		0.00	2
rs72552737	TPMT		0.00	1
rs72552738	TPMT		0.00	0
rs72552739	TPMT		0.00	0
rs72552740	TPMT		0.00	1
rs72552742	TPMT		0.00	1
rs72556347	TPMT		0.00	0
rs74423290	TPMT		0.00	2
rs75543815	TPMT		0.00	3
rs79901429	TPMT		0.00	0
rs111901354	TPMT		0.00	6
rs112339338	TPMT		0.00	6
rs115106679	TPMT		0.00	2
rs144041067	TPMT		0.00	3
rs150900439	TPMT		0.00	1
rs151149760	TPMT		0.00	6
rs200220210	TPMT		0.00	3
rs200591577	TPMT		0.00	6
rs377085266	TPMT		0.00	1
rs398122996	TPMT		0.00	1
rs750424422	TPMT		0.00	1
rs281874771	TPMT		0.00	0
rs772832951	TPMT		0.00	0
rs139392616	TPMT		0.00	0

PharmGKB dosing guidelines

9 guidelines.

Source	Drug	Guideline	Dosing?	Recommendation?
CPIC	azathioprine	Annotation of CPIC Guideline for azathioprine and NUDT15, TPMT	yes	yes
CPIC	mercaptopurine	Annotation of CPIC Guideline for mercaptopurine and NUDT15, TPMT	yes	yes
CPIC	thioguanine	Annotation of CPIC Guideline for thioguanine and NUDT15, TPMT	yes	yes
DPWG	azathioprine	Annotation of DPWG Guideline for azathioprine and TPMT	yes	yes
DPWG	mercaptopurine	Annotation of DPWG Guideline for mercaptopurine and TPMT	yes	yes
DPWG	thioguanine	Annotation of DPWG Guideline for thioguanine and TPMT	yes	yes
CPNDS	cisplatin	Annotation of CPNDS Guideline for cisplatin and TPMT		yes
RNPGx	azathioprine	Annotation of RNPGx Guideline for azathioprine and TPMT	yes	yes
RNPGx	mercaptopurine	Annotation of RNPGx Guideline for mercaptopurine and TPMT		yes

ChEMBL bioactivities

7 potent at pChembl≥5 of 12 total, top 7 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.13	IC50	741.3	nM	CHEMBL415511
6.00	IC50	1000	nM	CHEMBL4591248
5.92	IC50	1202	nM	CHEMBL89875
5.59	IC50	2570	nM	CHEMBL327180
5.52	IC50	3020	nM	CHEMBL89826
5.05	IC50	8913	nM	CHEMBL90106
5.00	Kd	1e+04	nM	SINEFUNGIN

PubChem BioAssay actives

7 with measured affinity, of 45 total; 7 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
3,4,5-triiodobenzoic acid	213093: Inhibition of purified human kidney thiopurine methyltransferase (TPMT)	ic50	0.7413	uM
(2S,5S)-2-amino-5-[[(2R,3S,4R,5R)-5-(6-aminopurin-9-yl)-3,4-dihydroxyoxolan-2-yl]methyl]-7-(3-carbamoylphenyl)hept-6-ynoic acid	1616805: Inhibition of human TPMT expressed in Escherichia coli assessed as reduction in SAH level using 6-mercaptopurine as substrate in presence of SAM incubated for 30 mins by LC-MS/MS analysis	ic50	1.0000	uM
3-hydroxy-5-iodo-4-methoxybenzoic acid	213093: Inhibition of purified human kidney thiopurine methyltransferase (TPMT)	ic50	1.2023	uM
3-chloro-5-hydroxy-4-methoxybenzoic acid	213093: Inhibition of purified human kidney thiopurine methyltransferase (TPMT)	ic50	2.5704	uM
3-bromo-5-hydroxy-4-methoxybenzoic acid	213093: Inhibition of purified human kidney thiopurine methyltransferase (TPMT)	ic50	3.0200	uM
3-hydroxy-4-methoxy-5-nitrobenzoic acid	213093: Inhibition of purified human kidney thiopurine methyltransferase (TPMT)	ic50	8.9125	uM
(2S,5S)-2,5-diamino-6-[(2R,3S,4R,5R)-5-(6-aminopurin-9-yl)-3,4-dihydroxyoxolan-2-yl]hexanoic acid	1179566: Binding affinity to thiopurine methyltransferase (unknown origin) by NMR analysis	kd	10.0000	uM

CTD chemical–gene interactions

47 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Azathioprine	affects activity, affects response to substance, affects metabolic processing	22
Valproic Acid	affects expression, increases expression	5
bisphenol A	decreases expression, increases expression	2
sodium arsenite	affects cotreatment, increases abundance, increases expression	2
Vorinostat	increases expression	2
Arsenic	affects methylation, affects cotreatment, increases abundance, increases expression	2
Cisplatin	increases expression, affects response to substance	2
Mercaptopurine	affects response to substance, affects metabolic processing	2
Cyclosporine	decreases expression	2
FR900359	increases phosphorylation	1
dicrotophos	decreases expression	1
triphenyl phosphate	affects expression	1
pirinixic acid	affects binding, decreases expression, increases activity	1
senecionine	increases expression	1
trichostatin A	affects expression	1
perfluorooctanoic acid	decreases expression	1
manganese chloride	affects cotreatment, increases abundance, increases expression	1
4-aminophenylarsenoxide	decreases reaction, affects binding	1
2-hydroxychavicol	increases expression	1
di-n-butylphosphoric acid	affects expression	1
4-methylbenzenethiol	affects cotreatment, increases methylation	1
4-nitrobenzenthiol	increases methylation, decreases reaction, affects cotreatment	1
Irinotecan	increases expression, affects cotreatment, affects response to substance	1
Resveratrol	affects cotreatment, increases expression	1
Temozolomide	increases expression	1
Sunitinib	decreases expression	1
Arsenic Trioxide	decreases reaction, affects binding	1
Bendroflumethiazide	decreases activity	1
Diethylstilbestrol	decreases expression	1
Estradiol	decreases expression, affects cotreatment	1

ChEMBL screening assays

6 unique, capped per target: 3 binding, 3 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3369580	Binding	Binding affinity to thiopurine methyltransferase (unknown origin) by NMR analysis	Elements and modulation of functional dynamics. — J Med Chem
CHEMBL4416334	ADMET	Inhibition of human TPMT expressed in Escherichia coli assessed as reduction in SAH level at 10 uM using 6-mercaptopurine as substrate in presence of SAM incubated for 30 mins by LC-MS/MS analysis relative to control	High-Affinity Alkynyl Bisubstrate Inhibitors of Nicotinamide N-Methyltransferase (NNMT). — J Med Chem

Cellosaurus cell lines

5 cell lines: 5 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_D1R1	Abcam K-562 TPMT KO	Cancer cell line	Female
CVCL_D2MN	Abcam Raji TPMT KO	Cancer cell line	Male
CVCL_TT50	HAP1 TPMT (-) 1	Cancer cell line	Male
CVCL_TT51	HAP1 TPMT (-) 2	Cancer cell line	Male
CVCL_WQ71	Abcam Jurkat TPMT KO	Cancer cell line	Male

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.