MTDC_HUMAN
ID MTDC_HUMAN Reviewed; 350 AA.
AC P13995; Q53G90; Q53GV5; Q53S36; Q7Z650;
DT 01-JAN-1990, integrated into UniProtKB/Swiss-Prot.
DT 19-SEP-2006, sequence version 2.
DT 03-AUG-2022, entry version 219.
DE RecName: Full=Bifunctional methylenetetrahydrofolate dehydrogenase/cyclohydrolase, mitochondrial;
DE Includes:
DE RecName: Full=NAD-dependent methylenetetrahydrofolate dehydrogenase {ECO:0000303|PubMed:16100107};
DE EC=1.5.1.15 {ECO:0000269|PubMed:16100107, ECO:0000269|PubMed:8218174};
DE Includes:
DE RecName: Full=Methenyltetrahydrofolate cyclohydrolase;
DE EC=3.5.4.9 {ECO:0000305|PubMed:16100107};
DE Flags: Precursor;
GN Name=MTHFD2; Synonyms=NMDMC;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 3-350 (ISOFORM 1).
RX PubMed=2587219; DOI=10.1093/nar/17.21.8853;
RA Peri K.G., Belanger C., Mackenzie R.E.;
RT "Nucleotide sequence of the human NAD-dependent methylene tetrahydrofolate
RT dehydrogenase-cyclohydrolase.";
RL Nucleic Acids Res. 17:8853-8853(1989).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Liver, and Thyroid;
RA Suzuki Y., Sugano S., Totoki Y., Toyoda A., Takeda T., Sakaki Y.,
RA Tanaka A., Yokoyama S.;
RL Submitted (APR-2005) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15815621; DOI=10.1038/nature03466;
RA Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H., Minx P.,
RA Wagner-McPherson C., Layman D., Wylie K., Sekhon M., Becker M.C.,
RA Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Kremitzki C., Oddy L.,
RA Du H., Sun H., Bradshaw-Cordum H., Ali J., Carter J., Cordes M., Harris A.,
RA Isak A., van Brunt A., Nguyen C., Du F., Courtney L., Kalicki J.,
RA Ozersky P., Abbott S., Armstrong J., Belter E.A., Caruso L., Cedroni M.,
RA Cotton M., Davidson T., Desai A., Elliott G., Erb T., Fronick C., Gaige T.,
RA Haakenson W., Haglund K., Holmes A., Harkins R., Kim K., Kruchowski S.S.,
RA Strong C.M., Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K.,
RA McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C.,
RA Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N., Swearengen-Shahid S.,
RA Snider J., Strong J.T., Thompson J., Yoakum M., Leonard S., Pearman C.,
RA Trani L., Radionenko M., Waligorski J.E., Wang C., Rock S.M.,
RA Tin-Wollam A.-M., Maupin R., Latreille P., Wendl M.C., Yang S.-P., Pohl C.,
RA Wallis J.W., Spieth J., Bieri T.A., Berkowicz N., Nelson J.O., Osborne J.,
RA Ding L., Meyer R., Sabo A., Shotland Y., Sinha P., Wohldmann P.E.,
RA Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Jones T.A., She X.,
RA Ciccarelli F.D., Izaurralde E., Taylor J., Schmutz J., Myers R.M.,
RA Cox D.R., Huang X., McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C.,
RA Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S.,
RA Miller W., Eichler E.E., Bork P., Suyama M., Torrents D., Waterston R.H.,
RA Wilson R.K.;
RT "Generation and annotation of the DNA sequences of human chromosomes 2 and
RT 4.";
RL Nature 434:724-731(2005).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
RC TISSUE=Brain, Cervix, and Colon;
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 [7]
RP CATALYTIC ACTIVITY, AND COFACTOR.
RX PubMed=8218174; DOI=10.1021/bi00092a022;
RA Yang X.M., MacKenzie R.E.;
RT "NAD-dependent methylenetetrahydrofolate dehydrogenase-
RT methenyltetrahydrofolate cyclohydrolase is the mammalian homolog of the
RT mitochondrial enzyme encoded by the yeast MIS1 gene.";
RL Biochemistry 32:11118-11123(1993).
RN [8]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-50, AND IDENTIFICATION BY MASS
RP SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19608861; DOI=10.1126/science.1175371;
RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M., Walther T.C.,
RA Olsen J.V., Mann M.;
RT "Lysine acetylation targets protein complexes and co-regulates major
RT cellular functions.";
RL Science 325:834-840(2009).
RN [9]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T.,
RA Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [10]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=22814378; DOI=10.1073/pnas.1210303109;
RA Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A.,
RA Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E., Timmerman E.,
RA Prieto J., Arnesen T., Sherman F., Gevaert K., Aldabe R.;
RT "N-terminal acetylome analyses and functional insights of the N-terminal
RT acetyltransferase NatB.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012).
RN [11]
RP CLEAVAGE OF TRANSIT PEPTIDE [LARGE SCALE ANALYSIS] AFTER ASN-35, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=25944712; DOI=10.1002/pmic.201400617;
RA Vaca Jacome A.S., Rabilloud T., Schaeffer-Reiss C., Rompais M., Ayoub D.,
RA Lane L., Bairoch A., Van Dorsselaer A., Carapito C.;
RT "N-terminome analysis of the human mitochondrial proteome.";
RL Proteomics 15:2519-2524(2015).
RN [12]
RP SUMOYLATION [LARGE SCALE ANALYSIS] AT LYS-50, AND IDENTIFICATION BY MASS
RP SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=28112733; DOI=10.1038/nsmb.3366;
RA Hendriks I.A., Lyon D., Young C., Jensen L.J., Vertegaal A.C.,
RA Nielsen M.L.;
RT "Site-specific mapping of the human SUMO proteome reveals co-modification
RT with phosphorylation.";
RL Nat. Struct. Mol. Biol. 24:325-336(2017).
RN [13]
RP 3D-STRUCTURE MODELING OF 36-350 IN COMPLEX WITH NAD AND PHOSPHATE,
RP FUNCTION, CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES, AND
RP MUTAGENESIS OF ASP-168; ARG-201; ASP-225 AND ARG-233.
RX PubMed=16100107; DOI=10.1074/jbc.m505210200;
RA Christensen K.E., Mirza I.A., Berghuis A.M., Mackenzie R.E.;
RT "Magnesium and phosphate ions enable NAD binding to
RT methylenetetrahydrofolate dehydrogenase-methenyltetrahydrofolate
RT cyclohydrolase.";
RL J. Biol. Chem. 280:34316-34323(2005).
RN [14] {ECO:0007744|PDB:5TC4}
RP X-RAY CRYSTALLOGRAPHY (1.89 ANGSTROMS) OF 36-350 IN COMPLEX WITH PHOSPHATE;
RP NAD AND INHIBITOR, AND SUBUNIT.
RX PubMed=27899380; DOI=10.1158/0008-5472.can-16-1476;
RA Gustafsson R., Jemth A.S., Gustafsson N.M., Farnegardh K., Loseva O.,
RA Wiita E., Bonagas N., Dahllund L., Llona-Minguez S., Haggblad M.,
RA Henriksson M., Andersson Y., Homan E., Helleday T., Stenmark P.;
RT "Crystal structure of the emerging cancer target MTHFD2 in complex with a
RT substrate-based inhibitor.";
RL Cancer Res. 77:937-948(2017).
CC -!- FUNCTION: Although its dehydrogenase activity is NAD-specific, it can
CC also utilize NADP at a reduced efficiency.
CC {ECO:0000269|PubMed:16100107}.
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;
CC Evidence={ECO:0000269|PubMed:16100107, ECO:0000269|PubMed:8218174};
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;
CC Evidence={ECO:0000305|PubMed:16100107};
CC -!- COFACTOR:
CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC Evidence={ECO:0000269|PubMed:8218174};
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=202 uM for NAD {ECO:0000269|PubMed:16100107};
CC KM=352 uM for NADP {ECO:0000269|PubMed:16100107};
CC Vmax=22.5 umol/min/mg enzyme with NAD as substrate
CC {ECO:0000269|PubMed:16100107};
CC Vmax=2.92 umol/min/mg enzyme with NADP as substrate
CC {ECO:0000269|PubMed:16100107};
CC -!- SUBUNIT: Homodimer. {ECO:0000269|PubMed:27899380}.
CC -!- INTERACTION:
CC P13995; Q9UJ70-2: NAGK; NbExp=3; IntAct=EBI-1058895, EBI-11526455;
CC -!- SUBCELLULAR LOCATION: Mitochondrion.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=P13995-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P13995-2; Sequence=VSP_056188;
CC -!- DEVELOPMENTAL STAGE: Expressed only in developing normal tissues.
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}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAX93061.1; Type=Erroneous initiation; Evidence={ECO:0000305};
CC Sequence=BAD96546.1; Type=Erroneous initiation; Evidence={ECO:0000305};
CC Sequence=BAD96761.1; Type=Erroneous initiation; Evidence={ECO:0000305};
CC Sequence=CAA34431.1; Type=Erroneous initiation; Evidence={ECO:0000305};
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DR EMBL; X16396; CAA34431.1; ALT_INIT; mRNA.
DR EMBL; AK300035; BAG61846.1; -; mRNA.
DR EMBL; AK222826; BAD96546.1; ALT_INIT; mRNA.
DR EMBL; AK223041; BAD96761.1; ALT_INIT; mRNA.
DR EMBL; AC073263; AAX93061.1; ALT_INIT; Genomic_DNA.
DR EMBL; CH471053; EAW99671.1; -; Genomic_DNA.
DR EMBL; CH471053; EAW99672.1; -; Genomic_DNA.
DR EMBL; BC001548; AAH01548.2; -; mRNA.
DR EMBL; BC015062; AAH15062.1; -; mRNA.
DR EMBL; BC017054; AAH17054.2; -; mRNA.
DR CCDS; CCDS1935.2; -. [P13995-1]
DR PIR; S14902; DEHUMT.
DR RefSeq; NP_006627.2; NM_006636.3. [P13995-1]
DR RefSeq; XP_006711987.1; XM_006711924.2. [P13995-2]
DR PDB; 5TC4; X-ray; 1.89 A; A=36-350.
DR PDB; 6JIB; X-ray; 2.25 A; A/B=36-338.
DR PDB; 6JID; X-ray; 2.50 A; A/B=36-338.
DR PDB; 6KG2; X-ray; 2.25 A; A/B=36-338.
DR PDB; 6S4A; X-ray; 1.95 A; A/B=36-350.
DR PDB; 6S4E; X-ray; 1.90 A; A=36-350.
DR PDB; 6S4F; X-ray; 2.20 A; A/B=36-350.
DR PDB; 7EHJ; X-ray; 2.16 A; A/B=36-350.
DR PDB; 7EHM; X-ray; 2.13 A; A/B=36-350.
DR PDB; 7EHN; X-ray; 2.25 A; A/B=36-350.
DR PDB; 7EHV; X-ray; 2.61 A; A/B=36-350.
DR PDBsum; 5TC4; -.
DR PDBsum; 6JIB; -.
DR PDBsum; 6JID; -.
DR PDBsum; 6KG2; -.
DR PDBsum; 6S4A; -.
DR PDBsum; 6S4E; -.
DR PDBsum; 6S4F; -.
DR PDBsum; 7EHJ; -.
DR PDBsum; 7EHM; -.
DR PDBsum; 7EHN; -.
DR PDBsum; 7EHV; -.
DR AlphaFoldDB; P13995; -.
DR SMR; P13995; -.
DR BioGRID; 116011; 88.
DR IntAct; P13995; 25.
DR MINT; P13995; -.
DR STRING; 9606.ENSP00000377617; -.
DR BindingDB; P13995; -.
DR ChEMBL; CHEMBL3621036; -.
DR DrugBank; DB00157; NADH.
DR DrugBank; DB00116; Tetrahydrofolic acid.
DR GlyGen; P13995; 1 site, 1 O-linked glycan (1 site).
DR iPTMnet; P13995; -.
DR PhosphoSitePlus; P13995; -.
DR BioMuta; MTHFD2; -.
DR DMDM; 115311607; -.
DR EPD; P13995; -.
DR jPOST; P13995; -.
DR MassIVE; P13995; -.
DR MaxQB; P13995; -.
DR PaxDb; P13995; -.
DR PeptideAtlas; P13995; -.
DR PRIDE; P13995; -.
DR ProteomicsDB; 53016; -. [P13995-1]
DR ProteomicsDB; 69375; -.
DR Antibodypedia; 3292; 197 antibodies from 30 providers.
DR DNASU; 10797; -.
DR Ensembl; ENST00000394053.7; ENSP00000377617.2; ENSG00000065911.13. [P13995-1]
DR Ensembl; ENST00000677170.1; ENSP00000503486.1; ENSG00000065911.13. [P13995-2]
DR Ensembl; ENST00000678623.1; ENSP00000504392.1; ENSG00000065911.13. [P13995-2]
DR Ensembl; ENST00000678684.1; ENSP00000504687.1; ENSG00000065911.13. [P13995-2]
DR Ensembl; ENST00000678731.1; ENSP00000503927.1; ENSG00000065911.13. [P13995-2]
DR Ensembl; ENST00000679055.1; ENSP00000503701.1; ENSG00000065911.13. [P13995-2]
DR GeneID; 10797; -.
DR KEGG; hsa:10797; -.
DR MANE-Select; ENST00000394053.7; ENSP00000377617.2; NM_006636.4; NP_006627.2.
DR UCSC; uc002skk.4; human. [P13995-1]
DR CTD; 10797; -.
DR DisGeNET; 10797; -.
DR GeneCards; MTHFD2; -.
DR HGNC; HGNC:7434; MTHFD2.
DR HPA; ENSG00000065911; Low tissue specificity.
DR MIM; 604887; gene.
DR neXtProt; NX_P13995; -.
DR OpenTargets; ENSG00000065911; -.
DR PharmGKB; PA31238; -.
DR VEuPathDB; HostDB:ENSG00000065911; -.
DR eggNOG; KOG0089; Eukaryota.
DR GeneTree; ENSGT00940000154863; -.
DR HOGENOM; CLU_034045_0_1_1; -.
DR InParanoid; P13995; -.
DR OMA; HIVGRPM; -.
DR OrthoDB; 1004679at2759; -.
DR PhylomeDB; P13995; -.
DR TreeFam; TF323998; -.
DR BioCyc; MetaCyc:HS00858-MON; -.
DR BRENDA; 1.5.1.15; 2681.
DR BRENDA; 1.5.1.5; 2681.
DR BRENDA; 3.5.4.9; 2681.
DR PathwayCommons; P13995; -.
DR Reactome; R-HSA-196757; Metabolism of folate and pterines.
DR SABIO-RK; P13995; -.
DR SignaLink; P13995; -.
DR SIGNOR; P13995; -.
DR BioGRID-ORCS; 10797; 52 hits in 1095 CRISPR screens.
DR GeneWiki; MTHFD2; -.
DR GenomeRNAi; 10797; -.
DR Pharos; P13995; Tchem.
DR PRO; PR:P13995; -.
DR Proteomes; UP000005640; Chromosome 2.
DR RNAct; P13995; protein.
DR Bgee; ENSG00000065911; Expressed in cartilage tissue and 197 other tissues.
DR ExpressionAtlas; P13995; baseline and differential.
DR Genevisible; P13995; HS.
DR GO; GO:0005615; C:extracellular space; HDA:UniProtKB.
DR GO; GO:0005759; C:mitochondrial matrix; TAS:Reactome.
DR GO; GO:0005739; C:mitochondrion; IDA:HPA.
DR GO; GO:0000287; F:magnesium ion binding; IDA: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; IDA:UniProtKB.
DR GO; GO:0046655; P:folic acid metabolic process; TAS:Reactome.
DR GO; GO:0035999; P:tetrahydrofolate interconversion; IBA:GO_Central.
DR GO; GO:0046653; P:tetrahydrofolate metabolic process; IDA:UniProtKB.
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 3D-structure; Acetylation; Alternative splicing; Hydrolase;
KW Isopeptide bond; Magnesium; Mitochondrion; Multifunctional enzyme; NAD;
KW NADP; One-carbon metabolism; Oxidoreductase; Reference proteome;
KW Transit peptide; Ubl conjugation.
FT TRANSIT 1..35
FT /note="Mitochondrion"
FT /evidence="ECO:0007744|PubMed:25944712"
FT CHAIN 36..350
FT /note="Bifunctional methylenetetrahydrofolate
FT dehydrogenase/cyclohydrolase, mitochondrial"
FT /id="PRO_0000034049"
FT BINDING 84..88
FT /ligand="substrate"
FT /evidence="ECO:0000269|PubMed:27899380"
FT BINDING 131..133
FT /ligand="substrate"
FT /evidence="ECO:0000269|PubMed:27899380"
FT BINDING 200..202
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000269|PubMed:16100107,
FT ECO:0000269|PubMed:27899380"
FT BINDING 233
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000269|PubMed:16100107,
FT ECO:0000269|PubMed:27899380"
FT BINDING 309..313
FT /ligand="substrate"
FT /evidence="ECO:0000269|PubMed:27899380"
FT MOD_RES 50
FT /note="N6-acetyllysine; alternate"
FT /evidence="ECO:0007744|PubMed:19608861"
FT CROSSLNK 50
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO2); alternate"
FT /evidence="ECO:0007744|PubMed:28112733"
FT VAR_SEQ 1..102
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:14702039,
FT ECO:0000303|PubMed:15489334"
FT /id="VSP_056188"
FT MUTAGEN 168
FT /note="D->A: Significant loss of NAD and NADP-dependent
FT dehydrogenase specific activity."
FT /evidence="ECO:0000269|PubMed:16100107"
FT MUTAGEN 168
FT /note="D->E: Complete loss of NAD and NADP-dependent
FT dehydrogenase specific activity."
FT /evidence="ECO:0000269|PubMed:16100107"
FT MUTAGEN 168
FT /note="D->N: 80% decrease in NAD-dependent dehydrogenase
FT specific activity. 18% decrease in NADP-dependent
FT dehydrogenase specific activity. Reduced affinity for
FT magnesium."
FT /evidence="ECO:0000269|PubMed:16100107"
FT MUTAGEN 168
FT /note="D->S: 82% decrease in NAD-dependent dehydrogenase
FT specific activity. 65% decrease in NADP-dependent
FT dehydrogenase specific activity. Reduced affinity for
FT magnesium."
FT /evidence="ECO:0000269|PubMed:16100107"
FT MUTAGEN 201
FT /note="R->A,S,K: Complete loss of NAD and NADP-dependent
FT dehydrogenase specific activity."
FT /evidence="ECO:0000269|PubMed:16100107"
FT MUTAGEN 225
FT /note="D->A,S,E: Complete loss of NAD and NADP-dependent
FT dehydrogenase specific activity."
FT /evidence="ECO:0000269|PubMed:16100107"
FT MUTAGEN 225
FT /note="D->N: 84% decrease in NAD-dependent dehydrogenase
FT specific activity. 36% increase in NADP-dependent
FT dehydrogenase specific activity. Reduced affinity for
FT magnesium."
FT /evidence="ECO:0000269|PubMed:16100107"
FT MUTAGEN 233
FT /note="R->A: Significant loss of NAD and NADP-dependent
FT dehydrogenase specific activity."
FT /evidence="ECO:0000269|PubMed:16100107"
FT MUTAGEN 233
FT /note="R->K: 50% decrease in NAD and NADP-dependent
FT dehydrogenase specific activity. Reduced affinity for
FT magnesium."
FT /evidence="ECO:0000269|PubMed:16100107"
FT MUTAGEN 233
FT /note="R->S: Almost complete loss of NAD-dependent
FT dehydrogenase specific activity. 50% decrease in NADP-
FT dependent dehydrogenase specific activity."
FT /evidence="ECO:0000269|PubMed:16100107"
FT CONFLICT 75
FT /note="V -> A (in Ref. 3; BAD96546)"
FT /evidence="ECO:0000305"
FT CONFLICT 95
FT /note="V -> A (in Ref. 3; BAD96761)"
FT /evidence="ECO:0000305"
FT HELIX 42..62
FT /evidence="ECO:0007829|PDB:5TC4"
FT STRAND 69..76
FT /evidence="ECO:0007829|PDB:5TC4"
FT HELIX 79..95
FT /evidence="ECO:0007829|PDB:5TC4"
FT STRAND 98..104
FT /evidence="ECO:0007829|PDB:5TC4"
FT HELIX 110..122
FT /evidence="ECO:0007829|PDB:5TC4"
FT STRAND 128..131
FT /evidence="ECO:0007829|PDB:5TC4"
FT HELIX 141..147
FT /evidence="ECO:0007829|PDB:5TC4"
FT HELIX 150..152
FT /evidence="ECO:0007829|PDB:5TC4"
FT HELIX 159..166
FT /evidence="ECO:0007829|PDB:5TC4"
FT HELIX 175..187
FT /evidence="ECO:0007829|PDB:5TC4"
FT STRAND 195..199
FT /evidence="ECO:0007829|PDB:5TC4"
FT TURN 203..205
FT /evidence="ECO:0007829|PDB:5TC4"
FT HELIX 206..214
FT /evidence="ECO:0007829|PDB:5TC4"
FT STRAND 219..221
FT /evidence="ECO:0007829|PDB:5TC4"
FT STRAND 227..231
FT /evidence="ECO:0007829|PDB:5TC4"
FT HELIX 237..244
FT /evidence="ECO:0007829|PDB:5TC4"
FT STRAND 248..252
FT /evidence="ECO:0007829|PDB:5TC4"
FT HELIX 262..264
FT /evidence="ECO:0007829|PDB:5TC4"
FT STRAND 270..273
FT /evidence="ECO:0007829|PDB:5TC4"
FT STRAND 277..279
FT /evidence="ECO:0007829|PDB:5TC4"
FT TURN 282..285
FT /evidence="ECO:0007829|PDB:6S4F"
FT STRAND 288..290
FT /evidence="ECO:0007829|PDB:5TC4"
FT HELIX 295..298
FT /evidence="ECO:0007829|PDB:5TC4"
FT TURN 299..301
FT /evidence="ECO:0007829|PDB:5TC4"
FT STRAND 303..305
FT /evidence="ECO:0007829|PDB:5TC4"
FT STRAND 308..311
FT /evidence="ECO:0007829|PDB:5TC4"
FT HELIX 312..329
FT /evidence="ECO:0007829|PDB:5TC4"
FT TURN 330..332
FT /evidence="ECO:0007829|PDB:6JIB"
SQ SEQUENCE 350 AA; 37895 MW; 4DBD263CF7BE28F4 CRC64;
MAATSLMSAL AARLLQPAHS CSLRLRPFHL AAVRNEAVVI SGRKLAQQIK QEVRQEVEEW
VASGNKRPHL SVILVGENPA SHSYVLNKTR AAAVVGINSE TIMKPASISE EELLNLINKL
NNDDNVDGLL VQLPLPEHID ERRICNAVSP DKDVDGFHVI NVGRMCLDQY SMLPATPWGV
WEIIKRTGIP TLGKNVVVAG RSKNVGMPIA MLLHTDGAHE RPGGDATVTI SHRYTPKEQL
KKHTILADIV ISAAGIPNLI TADMIKEGAA VIDVGINRVH DPVTAKPKLV GDVDFEGVRQ
KAGYITPVPG GVGPMTVAML MKNTIIAAKK VLRLEEREVL KSKELGVATN
