MTDC_MOUSE
ID MTDC_MOUSE Reviewed; 350 AA.
AC P18155; Q3TMN4;
DT 01-NOV-1990, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-1990, sequence version 1.
DT 03-AUG-2022, entry version 182.
DE RecName: Full=Bifunctional methylenetetrahydrofolate dehydrogenase/cyclohydrolase, mitochondrial;
DE Includes:
DE RecName: Full=NAD-dependent methylenetetrahydrofolate dehydrogenase;
DE EC=1.5.1.15 {ECO:0000269|PubMed:2647744, ECO:0000269|PubMed:3487546};
DE Includes:
DE RecName: Full=Methenyltetrahydrofolate cyclohydrolase;
DE EC=3.5.4.9 {ECO:0000269|PubMed:2647744, ECO:0000269|PubMed:3487546};
DE Flags: Precursor;
GN Name=Mthfd2; Synonyms=Nmdmc;
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], PROTEIN SEQUENCE OF 36-55, AND CATALYTIC
RP ACTIVITY.
RX PubMed=2647744; DOI=10.1016/s0021-9258(18)83667-5;
RA Belanger C., Mackenzie R.E.;
RT "Isolation and characterization of cDNA clones encoding the murine NAD-
RT dependent methylenetetrahydrofolate dehydrogenase-methenyltetrahydrofolate
RT cyclohydrolase.";
RL J. Biol. Chem. 264:4837-4843(1989).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=1999293; DOI=10.1016/0378-1119(91)90064-i;
RA Belanger C., Mackenzie R.E.;
RT "Structural organization of the murine gene encoding NAD-dependent
RT methylenetetrahydrofolate dehydrogenase-methenyltetrahydrofolate
RT cyclohydrolase.";
RL Gene 97:283-288(1991).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=C57BL/6J;
RX PubMed=16141072; DOI=10.1126/science.1112014;
RA Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N.,
RA Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K.,
RA Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J.,
RA Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R.,
RA Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T.,
RA Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A.,
RA Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B.,
RA Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M.,
RA Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S.,
RA Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E.,
RA Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D.,
RA Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M.,
RA Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H.,
RA Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V.,
RA Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S.,
RA Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H.,
RA Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N.,
RA Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F.,
RA Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G.,
RA Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z.,
RA Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C.,
RA Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y.,
RA Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S.,
RA Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K.,
RA Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R.,
RA van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H.,
RA Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M.,
RA Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C.,
RA Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S.,
RA Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K.,
RA Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M.,
RA Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C.,
RA Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A.,
RA Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.;
RT "The transcriptional landscape of the mammalian genome.";
RL Science 309:1559-1563(2005).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=FVB/N; TISSUE=Salivary 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 [5]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-34.
RX PubMed=1843253; DOI=10.1093/nar/19.16.4341;
RA Belanger C., Peri K.G., Mackenzie R.E.;
RT "Analysis of the promoter region of the gene encoding NAD-dependent
RT methylenetetrahydrofolate dehydrogenase-methenyltetrahydrofolate
RT cyclohydrolase.";
RL Nucleic Acids Res. 19:4341-4345(1991).
RN [6]
RP IDENTIFICATION, CATALYTIC ACTIVITY, AND COFACTOR.
RX PubMed=3487546; DOI=10.1016/s0021-9258(18)67686-0;
RA Mejia N.R., Rios-Orlandi E.M., MacKenzie R.E.;
RT "NAD-dependent methylenetetrahydrofolate dehydrogenase-
RT methenyltetrahydrofolate cyclohydrolase from ascites tumor cells.
RT Purification and properties.";
RL J. Biol. Chem. 261:9509-9513(1986).
RN [7]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Pancreas, 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).
CC -!- FUNCTION: Although its dehydrogenase activity is NAD-specific, it can
CC also utilize NADP at a reduced efficiency.
CC {ECO:0000250|UniProtKB:P13995}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=(6R)-5,10-methylene-5,6,7,8-tetrahydrofolate + NAD(+) = 5,10-
CC methenyltetrahydrofolate + NADH; Xref=Rhea:RHEA:22892,
CC ChEBI:CHEBI:15636, ChEBI:CHEBI:57455, ChEBI:CHEBI:57540,
CC ChEBI:CHEBI:57945; EC=1.5.1.15; Evidence={ECO:0000269|PubMed:2647744,
CC ECO:0000269|PubMed:3487546};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=5,10-methenyltetrahydrofolate + H2O = (6S)-10-
CC formyltetrahydrofolate + H(+); Xref=Rhea:RHEA:23700,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:57454,
CC ChEBI:CHEBI:57455; EC=3.5.4.9; Evidence={ECO:0000269|PubMed:2647744,
CC ECO:0000269|PubMed:3487546};
CC -!- COFACTOR:
CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC Evidence={ECO:0000269|PubMed:3487546};
CC -!- SUBUNIT: Homodimer. {ECO:0000250|UniProtKB:P13995}.
CC -!- SUBCELLULAR LOCATION: Mitochondrion.
CC -!- MISCELLANEOUS: This NAD-dependent bifunctional enzyme has very
CC different kinetic properties than the larger NADP-dependent
CC trifunctional enzyme and is unique in that it requires formation of an
CC enzyme-magnesium complex to allow binding of NAD.
CC -!- SIMILARITY: Belongs to the tetrahydrofolate
CC dehydrogenase/cyclohydrolase family. {ECO:0000305}.
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DR EMBL; J04627; AAA39827.1; -; mRNA.
DR EMBL; M63445; AAA39828.1; -; Genomic_DNA.
DR EMBL; M63415; AAA39828.1; JOINED; Genomic_DNA.
DR EMBL; M63439; AAA39828.1; JOINED; Genomic_DNA.
DR EMBL; M63440; AAA39828.1; JOINED; Genomic_DNA.
DR EMBL; M63441; AAA39828.1; JOINED; Genomic_DNA.
DR EMBL; M63442; AAA39828.1; JOINED; Genomic_DNA.
DR EMBL; M63443; AAA39828.1; JOINED; Genomic_DNA.
DR EMBL; M63444; AAA39828.1; JOINED; Genomic_DNA.
DR EMBL; AK076019; BAC36124.1; -; mRNA.
DR EMBL; AK159680; BAE35283.1; -; mRNA.
DR EMBL; AK165840; BAE38407.1; -; mRNA.
DR EMBL; BC019511; AAH19511.1; -; mRNA.
DR EMBL; S52980; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR CCDS; CCDS20277.1; -.
DR PIR; A33267; A33267.
DR RefSeq; NP_032664.1; NM_008638.2.
DR AlphaFoldDB; P18155; -.
DR SMR; P18155; -.
DR BioGRID; 201594; 2.
DR STRING; 10090.ENSMUSP00000005810; -.
DR iPTMnet; P18155; -.
DR PhosphoSitePlus; P18155; -.
DR EPD; P18155; -.
DR MaxQB; P18155; -.
DR PaxDb; P18155; -.
DR PeptideAtlas; P18155; -.
DR PRIDE; P18155; -.
DR ProteomicsDB; 290108; -.
DR Antibodypedia; 3292; 197 antibodies from 30 providers.
DR DNASU; 17768; -.
DR Ensembl; ENSMUST00000005810; ENSMUSP00000005810; ENSMUSG00000005667.
DR GeneID; 17768; -.
DR KEGG; mmu:17768; -.
DR UCSC; uc009cne.2; mouse.
DR CTD; 10797; -.
DR MGI; MGI:1338850; Mthfd2.
DR VEuPathDB; HostDB:ENSMUSG00000005667; -.
DR eggNOG; KOG0089; Eukaryota.
DR GeneTree; ENSGT00940000154863; -.
DR HOGENOM; CLU_034045_0_1_1; -.
DR InParanoid; P18155; -.
DR OMA; HIVGRPM; -.
DR OrthoDB; 1004679at2759; -.
DR PhylomeDB; P18155; -.
DR TreeFam; TF323998; -.
DR BRENDA; 1.5.1.15; 3474.
DR Reactome; R-MMU-196757; Metabolism of folate and pterines.
DR SABIO-RK; P18155; -.
DR BioGRID-ORCS; 17768; 9 hits in 74 CRISPR screens.
DR ChiTaRS; Mthfd2; mouse.
DR PRO; PR:P18155; -.
DR Proteomes; UP000000589; Chromosome 6.
DR RNAct; P18155; protein.
DR Bgee; ENSMUSG00000005667; Expressed in lacrimal gland and 246 other tissues.
DR ExpressionAtlas; P18155; baseline and differential.
DR Genevisible; P18155; MM.
DR GO; GO:0005739; C:mitochondrion; HDA:MGI.
DR GO; GO:0000287; F:magnesium ion binding; ISS:UniProtKB.
DR GO; GO:0004477; F:methenyltetrahydrofolate cyclohydrolase activity; IDA:UniProtKB.
DR GO; GO:0004487; F:methylenetetrahydrofolate dehydrogenase (NAD+) activity; IDA:UniProtKB.
DR GO; GO:0004488; F:methylenetetrahydrofolate dehydrogenase (NADP+) activity; IDA:UniProtKB.
DR GO; GO:0042301; F:phosphate ion binding; ISS:UniProtKB.
DR GO; GO:0035999; P:tetrahydrofolate interconversion; IBA:GO_Central.
DR GO; GO:0046653; P:tetrahydrofolate metabolic process; ISO:MGI.
DR CDD; cd01080; NAD_bind_m-THF_DH_Cyclohyd; 1.
DR HAMAP; MF_01576; THF_DHG_CYH; 1.
DR InterPro; IPR046346; Aminiacid_DH-like_N_sf.
DR InterPro; IPR036291; NAD(P)-bd_dom_sf.
DR InterPro; IPR000672; THF_DH/CycHdrlase.
DR InterPro; IPR020630; THF_DH/CycHdrlase_cat_dom.
DR InterPro; IPR020867; THF_DH/CycHdrlase_CS.
DR InterPro; IPR020631; THF_DH/CycHdrlase_NAD-bd_dom.
DR Pfam; PF00763; THF_DHG_CYH; 1.
DR Pfam; PF02882; THF_DHG_CYH_C; 1.
DR PRINTS; PR00085; THFDHDRGNASE.
DR SUPFAM; SSF51735; SSF51735; 1.
DR SUPFAM; SSF53223; SSF53223; 1.
DR PROSITE; PS00766; THF_DHG_CYH_1; 1.
DR PROSITE; PS00767; THF_DHG_CYH_2; 1.
PE 1: Evidence at protein level;
KW Acetylation; Direct protein sequencing; Hydrolase; Isopeptide bond;
KW Magnesium; Mitochondrion; Multifunctional enzyme; NAD; NADP;
KW One-carbon metabolism; Oxidoreductase; Reference proteome; Transit peptide;
KW Ubl conjugation.
FT TRANSIT 1..35
FT /note="Mitochondrion"
FT /evidence="ECO:0000269|PubMed:2647744"
FT CHAIN 36..350
FT /note="Bifunctional methylenetetrahydrofolate
FT dehydrogenase/cyclohydrolase, mitochondrial"
FT /id="PRO_0000034050"
FT BINDING 84..88
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:P13995"
FT BINDING 131..133
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:P13995"
FT BINDING 200..202
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000250|UniProtKB:P13995"
FT BINDING 233
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000250|UniProtKB:P13995"
FT BINDING 309..313
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:P13995"
FT MOD_RES 50
FT /note="N6-acetyllysine; alternate"
FT /evidence="ECO:0000250|UniProtKB:P13995"
FT CROSSLNK 50
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO2); alternate"
FT /evidence="ECO:0000250|UniProtKB:P13995"
SQ SEQUENCE 350 AA; 37863 MW; 896AD40D9154E9D7 CRC64;
MASVSLLSAL AVRLLRPTHG CHPRLQPFHL AAVRNEAVVI SGRKLAQQIK QEVQQEVEEW
VASGNKRPHL SVILVGDNPA SHSYVLNKTR AAAEVGINSE TIVKPASVSE EELLNSIRKL
NNDENVDGLL VQLPLPEHID ERKVCNAVSP DKDVDGFHVI NVGRMCLDQY SMLPATPWGV
WEIIKRTGIP TLGKNVVVAG RSKNVGMPIA MLLHTDGAHE RPGGDATVTI SHRYTPKEQL
KKHTILADIV ISAAGIPNLI TADMIKEGAA VIDVGINRVQ DPVTAKPKLV GDVDFEGVKK
KAGYITPVPG GVGPMTVAML MKNTIIAAKK VLRPEELEVF KSKQRGVATN
