TPMT_MOUSE
ID TPMT_MOUSE Reviewed; 240 AA.
AC O55060; Q9JIL7; Q9QUG7;
DT 15-JUL-1999, integrated into UniProtKB/Swiss-Prot.
DT 01-JUN-1998, sequence version 1.
DT 03-AUG-2022, entry version 154.
DE RecName: Full=Thiopurine S-methyltransferase {ECO:0000303|PubMed:18484748};
DE EC=2.1.1.67 {ECO:0000269|PubMed:18484748};
DE AltName: Full=Thiopurine methyltransferase;
GN Name=Tpmt;
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC STRAIN=C3H/HeJ;
RX PubMed=9539138; DOI=10.1016/s0014-5793(98)00159-8;
RA Fessing M.Y., Belkov V.M., Krynetski E.Y., Evans W.E.;
RT "Molecular cloning and functional characterization of the cDNA encoding the
RT murine thiopurine S-methyltransferase (TPMT).";
RL FEBS Lett. 424:143-145(1998).
RN [2]
RP NUCLEOTIDE SEQUENCE.
RC STRAIN=C57BL/6J, and DBA/2J;
RA Adjei A.A., Johnson G.B., Otterness D.M., Weinshilboum R.M.;
RT "Mouse thiopurine methyltransferase pharmacogenetics: cDNA cloning and
RT characterization and processed pseudogene cloning.";
RL Submitted (DEC-1997) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=FVB/N; TISSUE=Liver;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [4]
RP NUCLEOTIDE SEQUENCE OF 43-227.
RC STRAIN=129/Ola;
RA Krynetski E.Y., Fessing M.Y., Edick M.J., Evans W.E.;
RL Submitted (DEC-1999) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-34, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Brain, Brown adipose tissue, Heart, Kidney, Liver, Lung, Pancreas,
RC Spleen, and Testis;
RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001;
RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R.,
RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.;
RT "A tissue-specific atlas of mouse protein phosphorylation and expression.";
RL Cell 143:1174-1189(2010).
RN [6]
RP X-RAY CRYSTALLOGRAPHY (1.8 ANGSTROMS) IN COMPLEXES WITH
RP S-ADENOSYL-L-HOMOCYSTEINE AND 6-MERCAPTOPURINE, FUNCTION, CATALYTIC
RP ACTIVITY, AND SUBUNIT.
RX PubMed=18484748; DOI=10.1021/bi800102x;
RA Peng Y., Feng Q., Wilk D., Adjei A.A., Salavaggione O.E.,
RA Weinshilboum R.M., Yee V.C.;
RT "Structural basis of substrate recognition in thiopurine S-
RT methyltransferase.";
RL Biochemistry 47:6216-6225(2008).
CC -!- FUNCTION: Catalyzes the S-methylation of thiopurine drugs such as 6-
CC mercaptopurine (also called mercaptopurine, 6-MP or its brand name
CC Purinethol) using S-adenosyl-L-methionine as the methyl donor
CC (PubMed:18484748). TPMT activity modulates the cytotoxic effects of
CC thiopurine prodrugs. A natural substrate for this enzyme has yet to be
CC identified. {ECO:0000269|PubMed:18484748, ECO:0000305}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=S-adenosyl-L-methionine + a thiopurine = S-adenosyl-L-
CC homocysteine + a thiopurine S-methylether.; EC=2.1.1.67;
CC Evidence={ECO:0000269|PubMed:18484748};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=mercaptopurine + S-adenosyl-L-methionine = 6-methylthiopurine
CC + H(+) + S-adenosyl-L-homocysteine; Xref=Rhea:RHEA:12609,
CC ChEBI:CHEBI:15378, ChEBI:CHEBI:28279, ChEBI:CHEBI:50667,
CC ChEBI:CHEBI:57856, ChEBI:CHEBI:59789; EC=2.1.1.67;
CC Evidence={ECO:0000269|PubMed:18484748};
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=5.6 uM for S-adenosyl-L-methionine (at pH 6.5 and 37 degrees
CC Celsius) {ECO:0000269|PubMed:18484748};
CC KM=0.35 mM for 6-mercaptopurine (at pH 6.5 and 37 degrees Celsius)
CC {ECO:0000269|PubMed:18484748};
CC Vmax=0.604 nmol/sec/mg enzyme toward 6-mercaptopurine (at pH 6.5 and
CC 37 degrees Celsius) {ECO:0000269|PubMed:18484748};
CC -!- SUBUNIT: Monomer. {ECO:0000269|PubMed:18484748}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm.
CC -!- SIMILARITY: Belongs to the class I-like SAM-binding methyltransferase
CC superfamily. TPMT family. {ECO:0000305}.
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DR EMBL; AF046887; AAC25919.1; -; mRNA.
DR EMBL; AF037043; AAD02092.1; -; mRNA.
DR EMBL; AF037044; AAD02093.1; -; mRNA.
DR EMBL; AF104832; AAF06075.1; -; Genomic_DNA.
DR EMBL; AF104825; AAF06075.1; JOINED; Genomic_DNA.
DR EMBL; AF104826; AAF06075.1; JOINED; Genomic_DNA.
DR EMBL; AF104827; AAF06075.1; JOINED; Genomic_DNA.
DR EMBL; AF104828; AAF06075.1; JOINED; Genomic_DNA.
DR EMBL; AF104829; AAF06075.1; JOINED; Genomic_DNA.
DR EMBL; AF104830; AAF06075.1; JOINED; Genomic_DNA.
DR EMBL; AF104831; AAF06075.1; JOINED; Genomic_DNA.
DR EMBL; BC021598; AAH21598.1; -; mRNA.
DR EMBL; AH009424; AAF74424.1; -; Genomic_DNA.
DR CCDS; CCDS26488.1; -.
DR RefSeq; NP_058065.2; NM_016785.2.
DR RefSeq; XP_006516989.1; XM_006516926.2.
DR PDB; 2GB4; X-ray; 1.25 A; A/B=1-240.
DR PDB; 3BGD; X-ray; 2.00 A; A/B=1-240.
DR PDB; 3BGI; X-ray; 1.80 A; A/B=1-240.
DR PDBsum; 2GB4; -.
DR PDBsum; 3BGD; -.
DR PDBsum; 3BGI; -.
DR AlphaFoldDB; O55060; -.
DR SMR; O55060; -.
DR STRING; 10090.ENSMUSP00000021806; -.
DR iPTMnet; O55060; -.
DR PhosphoSitePlus; O55060; -.
DR jPOST; O55060; -.
DR MaxQB; O55060; -.
DR PaxDb; O55060; -.
DR PeptideAtlas; O55060; -.
DR PRIDE; O55060; -.
DR ProteomicsDB; 259168; -.
DR DNASU; 22017; -.
DR GeneID; 22017; -.
DR KEGG; mmu:22017; -.
DR UCSC; uc007qhq.2; mouse.
DR CTD; 7172; -.
DR MGI; MGI:98812; Tpmt.
DR eggNOG; ENOG502QSF5; Eukaryota.
DR InParanoid; O55060; -.
DR OrthoDB; 1590477at2759; -.
DR PhylomeDB; O55060; -.
DR TreeFam; TF328951; -.
DR BRENDA; 2.1.1.67; 3474.
DR Reactome; R-MMU-156581; Methylation.
DR Reactome; R-MMU-9748787; Azathioprine ADME.
DR BioGRID-ORCS; 22017; 3 hits in 73 CRISPR screens.
DR ChiTaRS; Tpmt; mouse.
DR EvolutionaryTrace; O55060; -.
DR PRO; PR:O55060; -.
DR Proteomes; UP000000589; Unplaced.
DR RNAct; O55060; protein.
DR GO; GO:0005737; C:cytoplasm; IEA:UniProtKB-SubCell.
DR GO; GO:1904047; F:S-adenosyl-L-methionine binding; ISO:MGI.
DR GO; GO:0008119; F:thiopurine S-methyltransferase activity; IDA:MGI.
DR GO; GO:0032259; P:methylation; IEA:UniProtKB-KW.
DR GO; GO:0006805; P:xenobiotic metabolic process; ISO:MGI.
DR Gene3D; 3.40.50.150; -; 1.
DR HAMAP; MF_00812; Thiopur_methtran; 1.
DR InterPro; IPR029063; SAM-dependent_MTases_sf.
DR InterPro; IPR025835; Thiopurine_S-MeTrfase.
DR InterPro; IPR008854; TPMT.
DR Pfam; PF05724; TPMT; 1.
DR PIRSF; PIRSF023956; Thiopurine_S-methyltransferase; 1.
DR SUPFAM; SSF53335; SSF53335; 1.
DR PROSITE; PS51585; SAM_MT_TPMT; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Cytoplasm; Methyltransferase; Phosphoprotein;
KW Reference proteome; S-adenosyl-L-methionine; Transferase.
FT CHAIN 1..240
FT /note="Thiopurine S-methyltransferase"
FT /id="PRO_0000220105"
FT BINDING 24..35
FT /ligand="S-adenosyl-L-methionine"
FT /ligand_id="ChEBI:CHEBI:59789"
FT BINDING 35
FT /ligand="substrate"
FT BINDING 64
FT /ligand="S-adenosyl-L-methionine"
FT /ligand_id="ChEBI:CHEBI:59789"
FT BINDING 85
FT /ligand="S-adenosyl-L-methionine"
FT /ligand_id="ChEBI:CHEBI:59789"
FT BINDING 129..130
FT /ligand="S-adenosyl-L-methionine"
FT /ligand_id="ChEBI:CHEBI:59789"
FT BINDING 147
FT /ligand="S-adenosyl-L-methionine"
FT /ligand_id="ChEBI:CHEBI:59789"
FT MOD_RES 34
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT MOD_RES 53
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:P51580"
FT VARIANT 69
FT /note="I -> V (in strain: C57BL/6J)"
FT TURN 11..16
FT /evidence="ECO:0007829|PDB:2GB4"
FT HELIX 21..30
FT /evidence="ECO:0007829|PDB:2GB4"
FT STRAND 38..40
FT /evidence="ECO:0007829|PDB:3BGI"
FT HELIX 42..52
FT /evidence="ECO:0007829|PDB:2GB4"
FT STRAND 59..62
FT /evidence="ECO:0007829|PDB:2GB4"
FT HELIX 70..76
FT /evidence="ECO:0007829|PDB:2GB4"
FT STRAND 80..84
FT /evidence="ECO:0007829|PDB:2GB4"
FT HELIX 88..97
FT /evidence="ECO:0007829|PDB:2GB4"
FT STRAND 102..106
FT /evidence="ECO:0007829|PDB:2GB4"
FT STRAND 114..118
FT /evidence="ECO:0007829|PDB:2GB4"
FT STRAND 121..128
FT /evidence="ECO:0007829|PDB:2GB4"
FT TURN 130..132
FT /evidence="ECO:0007829|PDB:2GB4"
FT HELIX 133..136
FT /evidence="ECO:0007829|PDB:2GB4"
FT STRAND 141..149
FT /evidence="ECO:0007829|PDB:2GB4"
FT TURN 150..152
FT /evidence="ECO:0007829|PDB:2GB4"
FT HELIX 155..157
FT /evidence="ECO:0007829|PDB:2GB4"
FT HELIX 158..167
FT /evidence="ECO:0007829|PDB:2GB4"
FT STRAND 169..181
FT /evidence="ECO:0007829|PDB:2GB4"
FT HELIX 184..186
FT /evidence="ECO:0007829|PDB:3BGI"
FT STRAND 189..191
FT /evidence="ECO:0007829|PDB:3BGD"
FT HELIX 196..203
FT /evidence="ECO:0007829|PDB:2GB4"
FT TURN 204..206
FT /evidence="ECO:0007829|PDB:2GB4"
FT STRAND 207..216
FT /evidence="ECO:0007829|PDB:2GB4"
FT HELIX 220..222
FT /evidence="ECO:0007829|PDB:2GB4"
FT TURN 223..226
FT /evidence="ECO:0007829|PDB:2GB4"
FT STRAND 231..239
FT /evidence="ECO:0007829|PDB:2GB4"
SQ SEQUENCE 240 AA; 27586 MW; 2BA57F30E8EB72D2 CRC64;
MSLDMKEHPD AEVQKNQVLT LEDWKEKWVT RHISFHQEQG HQLLKKHLDT FLKGQSGLRV
FFPLCGKAIE MKWFADRGHT VVGVEISEIG IREFFAEQNL SYTEEPLAEI AGAKVFKSSS
GSISLYCCSI FDLPRANIGK FDRIWDRGAL VAINPGDHDR YADIILSLLR KEFQYLVAVL
SYDPTKHAGP PFYVPSAELK RLFGTKCSMQ CLEEVDALEE RHKAWGLDYL FEKLYLLTEK
