NNMT_MOUSE
ID NNMT_MOUSE Reviewed; 264 AA.
AC O55239;
DT 01-DEC-2000, integrated into UniProtKB/Swiss-Prot.
DT 01-JUN-1998, sequence version 1.
DT 03-AUG-2022, entry version 148.
DE RecName: Full=Nicotinamide N-methyltransferase {ECO:0000303|PubMed:24717514};
DE EC=2.1.1.1 {ECO:0000269|PubMed:26168293, ECO:0000269|PubMed:29483571};
GN Name=Nnmt;
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=AKR/J, C3H/HeJ, C57BL/6J, C57BR/cdJ, and DBA/2J; TISSUE=Liver;
RX PubMed=9464457; DOI=10.1016/s0006-2952(97)00325-0;
RA Yan L., Otterness D.M., Craddock T.L., Weinshilboum R.M.;
RT "Mouse liver nicotinamide N-methyltransferase: cDNA cloning, expression,
RT and nucleotide sequence polymorphisms.";
RL Biochem. Pharmacol. 54:1139-1149(1997).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC STRAIN=C3H/HeJ;
RX PubMed=9726248; DOI=10.1089/dna.1998.17.659;
RA Yan L., Otterness D.M., Kozak C.A., Weinshilboum R.M.;
RT "Mouse nicotinamide N-methyltransferase gene: molecular cloning, structural
RT characterization, and chromosomal localization.";
RL DNA Cell Biol. 17:659-667(1998).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=C57BL/6J; TISSUE=Mammary gland;
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 FUNCTION, TISSUE SPECIFICITY, AND INDUCTION BY HIGH-FAT DIET.
RX PubMed=24717514; DOI=10.1038/nature13198;
RA Kraus D., Yang Q., Kong D., Banks A.S., Zhang L., Rodgers J.T., Pirinen E.,
RA Pulinilkunnil T.C., Gong F., Wang Y.C., Cen Y., Sauve A.A., Asara J.M.,
RA Peroni O.D., Monia B.P., Bhanot S., Alhonen L., Puigserver P., Kahn B.B.;
RT "Nicotinamide N-methyltransferase knockdown protects against diet-induced
RT obesity.";
RL Nature 508:258-262(2014).
RN [5]
RP FUNCTION, CATALYTIC ACTIVITY, AND MUTAGENESIS OF TYR-20 AND ALA-198.
RX PubMed=26168293; DOI=10.1038/nm.3882;
RA Hong S., Moreno-Navarrete J.M., Wei X., Kikukawa Y., Tzameli I., Prasad D.,
RA Lee Y., Asara J.M., Fernandez-Real J.M., Maratos-Flier E., Pissios P.;
RT "Nicotinamide N-methyltransferase regulates hepatic nutrient metabolism
RT through Sirt1 protein stabilization.";
RL Nat. Med. 21:887-894(2015).
RN [6] {ECO:0007744|PDB:2I62}
RP X-RAY CRYSTALLOGRAPHY (1.80 ANGSTROMS) IN COMPLEX WITH
RP S-ADENOSYL-L-METHIONINE.
RA Wu H., Min J., Zeng H., Loppnau P., Weigelt J., Sundstrom M.,
RA Arrowsmith C.H., Edwards A.M., Bochkarev A., Plotnikov A.N.;
RT "The Crystal Structure of Mouse Nicotinamide N-methyltransferase in complex
RT with SAH.";
RL Submitted (AUG-2006) to the PDB data bank.
RN [7]
RP X-RAY CRYSTALLOGRAPHY (1.99 ANGSTROMS) IN COMPLEX WITH
RP S-ADENOSYL-L-METHIONINE AND INHIBITOR, FUNCTION, CATALYTIC ACTIVITY, AND
RP ACTIVITY REGULATION.
RX PubMed=29483571; DOI=10.1038/s41598-018-22081-7;
RA Kannt A., Rajagopal S., Kadnur S.V., Suresh J., Bhamidipati R.K.,
RA Swaminathan S., Hallur M.S., Kristam R., Elvert R., Czech J.,
RA Pfenninger A., Rudolph C., Schreuder H., Chandrasekar D.V., Mane V.S.,
RA Birudukota S., Shaik S., Zope B.R., Burri R.R., Anand N.N., Thakur M.K.,
RA Singh M., Parveen R., Kandan S., Mullangi R., Yura T., Gosu R., Ruf S.,
RA Dhakshinamoorthy S.;
RT "A small molecule inhibitor of Nicotinamide N-methyltransferase for the
RT treatment of metabolic disorders.";
RL Sci. Rep. 8:3660-3660(2018).
CC -!- FUNCTION: Catalyzes the N-methylation of nicotinamide using the
CC universal methyl donor S-adenosyl-L-methionine to form N1-
CC methylnicotinamide and S-adenosyl-L-homocysteine, a predominant
CC nicotinamide/vitamin B3 clearance pathway (PubMed:26168293,
CC PubMed:29483571). Plays a central role in regulating cellular
CC methylation potential, by consuming S-adenosyl-L-methionine and
CC limiting its availability for other methyltransferases (By similarity).
CC Actively mediates genome-wide epigenetic and transcriptional changes
CC through hypomethylation of repressive chromatin marks, such as
CC H3K27me3. In a developmental context, contributes to low levels of the
CC repressive histone marks that characterize pluripotent embryonic stem
CC cell pre-implantation state (By similarity). Acts as a metabolic
CC regulator primarily on white adipose tissue energy expenditure as well
CC as hepatic gluconeogenesis and cholesterol biosynthesis
CC (PubMed:24717514, PubMed:26168293). In white adipocytes, regulates
CC polyamine flux by consuming S-adenosyl-L-methionine which provides for
CC propylamine group in polyamine biosynthesis, whereas by consuming
CC nicotinamide controls NAD(+) levels through the salvage pathway
CC (PubMed:24717514). Via its product N1-methylnicotinamide regulates
CC protein acetylation in hepatocytes, by repressing the ubiquitination
CC and increasing the stability of SIRT1 deacetylase (PubMed:26168293).
CC Can also N-methylate other pyridines structurally related to
CC nicotinamide and play a role in xenobiotic detoxification (By
CC similarity). {ECO:0000250|UniProtKB:P40261,
CC ECO:0000269|PubMed:24717514, ECO:0000269|PubMed:26168293,
CC ECO:0000269|PubMed:29483571}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=nicotinamide + S-adenosyl-L-methionine = 1-methylnicotinamide
CC + S-adenosyl-L-homocysteine; Xref=Rhea:RHEA:23884, ChEBI:CHEBI:16797,
CC ChEBI:CHEBI:17154, ChEBI:CHEBI:57856, ChEBI:CHEBI:59789; EC=2.1.1.1;
CC Evidence={ECO:0000269|PubMed:26168293, ECO:0000269|PubMed:29483571};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:23885;
CC Evidence={ECO:0000305|PubMed:26168293, ECO:0000305|PubMed:29483571};
CC -!- ACTIVITY REGULATION: Inhibited by 6-methoxynicotinamide (JBSNF-000088).
CC {ECO:0000269|PubMed:29483571}.
CC -!- PATHWAY: Cofactor metabolism. {ECO:0000250|UniProtKB:P40261}.
CC -!- PATHWAY: Amino-acid degradation. {ECO:0000250|UniProtKB:P40261}.
CC -!- SUBUNIT: Monomer. {ECO:0000250|UniProtKB:P40261}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm.
CC -!- TISSUE SPECIFICITY: Expressed in white adipose tissue and liver (at
CC protein level). {ECO:0000269|PubMed:24717514}.
CC -!- INDUCTION: Up-regulated in white adipose tissue and liver in response
CC to high-fat diet. {ECO:0000269|PubMed:24717514}.
CC -!- PTM: Deiminated by PADI1 and PADI2. {ECO:0000250|UniProtKB:P40261}.
CC -!- SIMILARITY: Belongs to the class I-like SAM-binding methyltransferase
CC superfamily. NNMT/PNMT/TEMT family. {ECO:0000305}.
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DR EMBL; U86105; AAB94331.1; -; mRNA.
DR EMBL; U86106; AAB94332.1; -; mRNA.
DR EMBL; U86108; AAB94334.1; -; mRNA.
DR EMBL; U86107; AAB94333.1; -; mRNA.
DR EMBL; AF044960; AAC77360.1; -; Genomic_DNA.
DR EMBL; AF029756; AAC77360.1; JOINED; Genomic_DNA.
DR EMBL; BC028757; AAH28757.1; -; mRNA.
DR CCDS; CCDS23157.1; -.
DR RefSeq; NP_035054.1; NM_010924.3.
DR RefSeq; XP_011240719.1; XM_011242417.1.
DR PDB; 2I62; X-ray; 1.80 A; A/B/C/D=1-264.
DR PDB; 5XVK; X-ray; 1.88 A; A/B=1-264.
DR PDB; 5YJI; X-ray; 1.99 A; A/B=1-264.
DR PDBsum; 2I62; -.
DR PDBsum; 5XVK; -.
DR PDBsum; 5YJI; -.
DR AlphaFoldDB; O55239; -.
DR SMR; O55239; -.
DR STRING; 10090.ENSMUSP00000034808; -.
DR BindingDB; O55239; -.
DR ChEMBL; CHEMBL4295666; -.
DR iPTMnet; O55239; -.
DR PhosphoSitePlus; O55239; -.
DR jPOST; O55239; -.
DR MaxQB; O55239; -.
DR PaxDb; O55239; -.
DR PeptideAtlas; O55239; -.
DR PRIDE; O55239; -.
DR ProteomicsDB; 293696; -.
DR Antibodypedia; 18379; 499 antibodies from 34 providers.
DR DNASU; 18113; -.
DR Ensembl; ENSMUST00000034808; ENSMUSP00000034808; ENSMUSG00000032271.
DR GeneID; 18113; -.
DR KEGG; mmu:18113; -.
DR UCSC; uc009pik.1; mouse.
DR CTD; 4837; -.
DR MGI; MGI:1099443; Nnmt.
DR VEuPathDB; HostDB:ENSMUSG00000032271; -.
DR eggNOG; KOG4564; Eukaryota.
DR GeneTree; ENSGT00390000011708; -.
DR HOGENOM; CLU_082526_1_1_1; -.
DR InParanoid; O55239; -.
DR OMA; YNFGSRH; -.
DR OrthoDB; 1054662at2759; -.
DR PhylomeDB; O55239; -.
DR TreeFam; TF313114; -.
DR BRENDA; 2.1.1.1; 3474.
DR Reactome; R-MMU-156581; Methylation.
DR Reactome; R-MMU-197264; Nicotinamide salvaging.
DR BioGRID-ORCS; 18113; 2 hits in 75 CRISPR screens.
DR ChiTaRS; Nnmt; mouse.
DR EvolutionaryTrace; O55239; -.
DR PRO; PR:O55239; -.
DR Proteomes; UP000000589; Chromosome 9.
DR RNAct; O55239; protein.
DR Bgee; ENSMUSG00000032271; Expressed in left lobe of liver and 125 other tissues.
DR ExpressionAtlas; O55239; baseline and differential.
DR Genevisible; O55239; MM.
DR GO; GO:0005829; C:cytosol; IDA:MGI.
DR GO; GO:0008170; F:N-methyltransferase activity; IBA:GO_Central.
DR GO; GO:0008112; F:nicotinamide N-methyltransferase activity; IDA:UniProtKB.
DR GO; GO:0031100; P:animal organ regeneration; IEA:Ensembl.
DR GO; GO:0032259; P:methylation; IDA:MGI.
DR GO; GO:0006769; P:nicotinamide metabolic process; IDA:UniProtKB.
DR GO; GO:0045722; P:positive regulation of gluconeogenesis; IMP:UniProtKB.
DR GO; GO:0090312; P:positive regulation of protein deacetylation; IMP:UniProtKB.
DR GO; GO:0051569; P:regulation of histone H3-K4 methylation; IMP:UniProtKB.
DR GO; GO:0031060; P:regulation of histone methylation; ISO:MGI.
DR GO; GO:0010967; P:regulation of polyamine biosynthetic process; IMP:UniProtKB.
DR GO; GO:0010243; P:response to organonitrogen compound; IEA:Ensembl.
DR GO; GO:0009410; P:response to xenobiotic stimulus; IEA:Ensembl.
DR Gene3D; 3.40.50.150; -; 1.
DR InterPro; IPR025820; NNMT/PNMT/TEMT_CS.
DR InterPro; IPR000940; NNMT_TEMT_trans.
DR InterPro; IPR029063; SAM-dependent_MTases_sf.
DR PANTHER; PTHR10867; PTHR10867; 1.
DR Pfam; PF01234; NNMT_PNMT_TEMT; 1.
DR PIRSF; PIRSF000384; PNMTase; 1.
DR SUPFAM; SSF53335; SSF53335; 1.
DR PROSITE; PS01100; NNMT_PNMT_TEMT; 1.
DR PROSITE; PS51681; SAM_MT_NNMT_PNMT_TEMT; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Citrullination; Cytoplasm; Methyltransferase;
KW Reference proteome; S-adenosyl-L-methionine; Transferase.
FT CHAIN 1..264
FT /note="Nicotinamide N-methyltransferase"
FT /id="PRO_0000159707"
FT BINDING 20
FT /ligand="S-adenosyl-L-methionine"
FT /ligand_id="ChEBI:CHEBI:59789"
FT /evidence="ECO:0000269|PubMed:29483571, ECO:0000269|Ref.6"
FT BINDING 25
FT /ligand="S-adenosyl-L-methionine"
FT /ligand_id="ChEBI:CHEBI:59789"
FT /evidence="ECO:0000269|PubMed:29483571, ECO:0000269|Ref.6"
FT BINDING 63
FT /ligand="S-adenosyl-L-methionine"
FT /ligand_id="ChEBI:CHEBI:59789"
FT /evidence="ECO:0000269|PubMed:29483571, ECO:0000269|Ref.6"
FT BINDING 69
FT /ligand="S-adenosyl-L-methionine"
FT /ligand_id="ChEBI:CHEBI:59789"
FT /evidence="ECO:0000269|PubMed:29483571, ECO:0000269|Ref.6"
FT BINDING 85
FT /ligand="S-adenosyl-L-methionine"
FT /ligand_id="ChEBI:CHEBI:59789"
FT /evidence="ECO:0000269|PubMed:29483571, ECO:0000269|Ref.6"
FT BINDING 87
FT /ligand="S-adenosyl-L-methionine"
FT /ligand_id="ChEBI:CHEBI:59789"
FT /evidence="ECO:0000269|PubMed:29483571, ECO:0000269|Ref.6"
FT BINDING 90
FT /ligand="S-adenosyl-L-methionine"
FT /ligand_id="ChEBI:CHEBI:59789"
FT /evidence="ECO:0000269|PubMed:29483571, ECO:0000269|Ref.6"
FT BINDING 142..143
FT /ligand="S-adenosyl-L-methionine"
FT /ligand_id="ChEBI:CHEBI:59789"
FT /evidence="ECO:0000269|PubMed:29483571, ECO:0000269|Ref.6"
FT BINDING 163
FT /ligand="S-adenosyl-L-methionine"
FT /ligand_id="ChEBI:CHEBI:59789"
FT /evidence="ECO:0000269|PubMed:29483571, ECO:0000269|Ref.6"
FT BINDING 197
FT /ligand="nicotinamide"
FT /ligand_id="ChEBI:CHEBI:17154"
FT /evidence="ECO:0000250|UniProtKB:P40261"
FT BINDING 213
FT /ligand="nicotinamide"
FT /ligand_id="ChEBI:CHEBI:17154"
FT /evidence="ECO:0000250|UniProtKB:P40261"
FT MOD_RES 18
FT /note="Citrulline; alternate"
FT /evidence="ECO:0000250|UniProtKB:P40261"
FT MOD_RES 132
FT /note="Citrulline; alternate"
FT /evidence="ECO:0000250|UniProtKB:P40261"
FT MOD_RES 181
FT /note="Citrulline; alternate"
FT /evidence="ECO:0000250|UniProtKB:P40261"
FT MUTAGEN 20
FT /note="Y->W: Loss of N-methyltransferase activity."
FT /evidence="ECO:0000269|PubMed:26168293"
FT MUTAGEN 198
FT /note="A->W: Loss of N-methyltransferase activity."
FT /evidence="ECO:0000269|PubMed:26168293"
FT HELIX 8..14
FT /evidence="ECO:0007829|PDB:2I62"
FT HELIX 17..25
FT /evidence="ECO:0007829|PDB:2I62"
FT STRAND 28..30
FT /evidence="ECO:0007829|PDB:5XVK"
FT HELIX 32..50
FT /evidence="ECO:0007829|PDB:2I62"
FT STRAND 51..53
FT /evidence="ECO:0007829|PDB:2I62"
FT STRAND 56..63
FT /evidence="ECO:0007829|PDB:2I62"
FT HELIX 69..71
FT /evidence="ECO:0007829|PDB:2I62"
FT HELIX 74..76
FT /evidence="ECO:0007829|PDB:2I62"
FT STRAND 78..86
FT /evidence="ECO:0007829|PDB:2I62"
FT HELIX 88..98
FT /evidence="ECO:0007829|PDB:2I62"
FT HELIX 108..117
FT /evidence="ECO:0007829|PDB:2I62"
FT TURN 118..120
FT /evidence="ECO:0007829|PDB:2I62"
FT HELIX 124..134
FT /evidence="ECO:0007829|PDB:2I62"
FT STRAND 135..140
FT /evidence="ECO:0007829|PDB:2I62"
FT STRAND 145..147
FT /evidence="ECO:0007829|PDB:2I62"
FT TURN 148..151
FT /evidence="ECO:0007829|PDB:2I62"
FT STRAND 157..164
FT /evidence="ECO:0007829|PDB:2I62"
FT HELIX 166..169
FT /evidence="ECO:0007829|PDB:2I62"
FT HELIX 173..184
FT /evidence="ECO:0007829|PDB:2I62"
FT STRAND 187..200
FT /evidence="ECO:0007829|PDB:2I62"
FT STRAND 203..206
FT /evidence="ECO:0007829|PDB:2I62"
FT STRAND 209..212
FT /evidence="ECO:0007829|PDB:2I62"
FT HELIX 218..227
FT /evidence="ECO:0007829|PDB:2I62"
FT STRAND 231..238
FT /evidence="ECO:0007829|PDB:2I62"
FT TURN 244..246
FT /evidence="ECO:0007829|PDB:2I62"
FT STRAND 252..258
FT /evidence="ECO:0007829|PDB:2I62"
SQ SEQUENCE 264 AA; 29598 MW; DC3FE92738B7EC90 CRC64;
MESGFTSKDT YLSHFNPRDY LEKYYSFGSR HCAENEILRH LLKNLFKIFC LGAVKGELLI
DIGSGPTIYQ LLSACESFTE IIVSDYTDQN LWELQKWLKK EPGAFDWSPV VTYVCDLEGN
RMKGPEKEEK LRRAIKQVLK CDVTQSQPLG GVSLPPADCL LSTLCLDAAC PDLPAYRTAL
RNLGSLLKPG GFLVMVDALK SSYYMIGEQK FSSLPLGWET VRDAVEEAGY TIEQFEVISQ
NYSSTTSNNE GLFSLVGRKP GRSE
