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 29-MAY-2024, entry version 229. 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(+) = (6R)- CC 5,10-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=(6R)-5,10-methenyltetrahydrofolate + H2O = (6R)-10- CC formyltetrahydrofolate + H(+); Xref=Rhea:RHEA:23700, CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:57455, CC ChEBI:CHEBI:195366; 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}; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- 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; 111. DR IntAct; P13995; 29. 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; 9606-ENSP00000377617; -. DR PeptideAtlas; P13995; -. DR ProteomicsDB; 53016; -. [P13995-1] DR ProteomicsDB; 69375; -. DR Pumba; P13995; -. DR Antibodypedia; 3292; 221 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 AGR; HGNC:7434; -. 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; VCHILTK; -. DR OrthoDB; 5386942at2759; -. DR PhylomeDB; P13995; -. DR TreeFam; TF323998; -. DR BioCyc; MetaCyc:HS00858-MONOMER; -. 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; 54 hits in 1176 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 199 other cell types or tissues. DR ExpressionAtlas; P13995; baseline and differential. 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 Gene3D; 3.40.50.10860; Leucine Dehydrogenase, chain A, domain 1; 1. DR Gene3D; 3.40.50.720; NAD(P)-binding Rossmann-like Domain; 1. DR HAMAP; MF_01576; THF_DHG_CYH; 1. DR InterPro; IPR046346; Aminoacid_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 PANTHER; PTHR48099:SF15; BIFUNCTIONAL METHYLENETETRAHYDROFOLATE DEHYDROGENASE_CYCLOHYDROLASE, MITOCHONDRIAL; 1. DR PANTHER; PTHR48099; C-1-TETRAHYDROFOLATE SYNTHASE, CYTOPLASMIC-RELATED; 1. DR Pfam; PF00763; THF_DHG_CYH; 1. DR Pfam; PF02882; THF_DHG_CYH_C; 1. DR PRINTS; PR00085; THFDHDRGNASE. DR SUPFAM; SSF53223; Aminoacid dehydrogenase-like, N-terminal domain; 1. DR SUPFAM; SSF51735; NAD(P)-binding Rossmann-fold domains; 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 //