MTD2L_HUMAN
ID MTD2L_HUMAN Reviewed; 347 AA.
AC Q9H903; Q6P079; Q8N560;
DT 20-MAY-2008, integrated into UniProtKB/Swiss-Prot.
DT 19-OCT-2011, sequence version 3.
DT 03-AUG-2022, entry version 156.
DE RecName: Full=Bifunctional methylenetetrahydrofolate dehydrogenase/cyclohydrolase 2, mitochondrial {ECO:0000250|UniProtKB:D3ZUA0};
DE AltName: Full=NADP-dependent methylenetetrahydrofolate dehydrogenase 2-like protein {ECO:0000305|PubMed:21163947};
DE Short=MTHFD2-like {ECO:0000303|PubMed:21163947};
DE Includes:
DE RecName: Full=NAD-dependent methylenetetrahydrofolate dehydrogenase {ECO:0000250|UniProtKB:D3ZUA0};
DE EC=1.5.1.15 {ECO:0000250|UniProtKB:D3ZUA0};
DE EC=1.5.1.5 {ECO:0000250|UniProtKB:D3ZUA0};
DE Includes:
DE RecName: Full=Methenyltetrahydrofolate cyclohydrolase {ECO:0000250|UniProtKB:D3ZUA0};
DE EC=3.5.4.9 {ECO:0000250|UniProtKB:D3ZUA0};
GN Name=MTHFD2L {ECO:0000312|HGNC:HGNC:31865};
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 [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 [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.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 (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 2 AND 3).
RC TISSUE=Lung, and Testis;
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 [MRNA] OF 13-180 (ISOFORM 4).
RA Liou J.R.;
RT "Regulation of human tetrahydrofolate dehydrogenase/cyclohydrolase.";
RL Submitted (OCT-2003) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 152-347 (ISOFORM 1).
RC TISSUE=Teratocarcinoma;
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 [6]
RP ALTERNATIVE SPLICING (ISOFORMS 1; 4 AND 5), AND TISSUE SPECIFICITY.
RX PubMed=21163947; DOI=10.1074/jbc.m110.196840;
RA Bolusani S., Young B.A., Cole N.A., Tibbetts A.S., Momb J., Bryant J.D.,
RA Solmonson A., Appling D.R.;
RT "Mammalian MTHFD2L encodes a mitochondrial methylenetetrahydrofolate
RT dehydrogenase isozyme expressed in adult tissues.";
RL J. Biol. Chem. 286:5166-5174(2011).
CC -!- FUNCTION: Bifunctional mitochondrial folate-interconverting enzyme that
CC has both NAD/NADP-dependent methylenetetrahydrofolate dehydrogenase and
CC methenyltetrahydrofolate cyclohydrolase activities.
CC {ECO:0000250|UniProtKB:D3ZUA0}.
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:0000250|UniProtKB:D3ZUA0};
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:0000250|UniProtKB:D3ZUA0};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=(6R)-5,10-methylene-5,6,7,8-tetrahydrofolate + NADP(+) = 5,10-
CC methenyltetrahydrofolate + NADPH; Xref=Rhea:RHEA:22812,
CC ChEBI:CHEBI:15636, ChEBI:CHEBI:57455, ChEBI:CHEBI:57783,
CC ChEBI:CHEBI:58349; EC=1.5.1.5;
CC Evidence={ECO:0000250|UniProtKB:D3ZUA0};
CC -!- COFACTOR:
CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC Evidence={ECO:0000250|UniProtKB:D3ZUA0};
CC -!- PATHWAY: One-carbon metabolism; tetrahydrofolate interconversion.
CC {ECO:0000250|UniProtKB:D3ZUA0}.
CC -!- INTERACTION:
CC Q9H903-3; Q96HA8: NTAQ1; NbExp=3; IntAct=EBI-14202147, EBI-741158;
CC -!- SUBCELLULAR LOCATION: Mitochondrion inner membrane
CC {ECO:0000250|UniProtKB:D3ZUA0}; Peripheral membrane protein
CC {ECO:0000250|UniProtKB:D3ZUA0}; Matrix side
CC {ECO:0000250|UniProtKB:D3ZUA0}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=5;
CC Name=4;
CC IsoId=Q9H903-4; Sequence=Displayed;
CC Name=1;
CC IsoId=Q9H903-1; Sequence=VSP_041878;
CC Name=2;
CC IsoId=Q9H903-2; Sequence=VSP_041877;
CC Name=3;
CC IsoId=Q9H903-3; Sequence=VSP_041878, VSP_041880, VSP_041881;
CC Name=5;
CC IsoId=Q9H903-5; Sequence=VSP_041879;
CC -!- TISSUE SPECIFICITY: Isoform 1, isoform 4 and isoform 5 are expressed in
CC brain and placenta. {ECO:0000269|PubMed:21163947}.
CC -!- SIMILARITY: Belongs to the tetrahydrofolate
CC dehydrogenase/cyclohydrolase family. {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAH32771.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305};
CC Sequence=BAB14441.1; Type=Miscellaneous discrepancy; Note=Contaminating sequence. Sequence of unknown origin in the N-terminal part.; Evidence={ECO:0000305};
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DR EMBL; AC093677; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC097470; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471057; EAX05705.1; -; Genomic_DNA.
DR EMBL; AX794779; -; NOT_ANNOTATED_CDS; mRNA.
DR EMBL; BC032771; AAH32771.1; ALT_INIT; mRNA.
DR EMBL; BC065771; AAH65771.1; -; mRNA.
DR EMBL; AK023167; BAB14441.1; ALT_SEQ; mRNA.
DR CCDS; CCDS34009.1; -. [Q9H903-1]
DR CCDS; CCDS47075.1; -. [Q9H903-4]
DR RefSeq; NP_001138450.1; NM_001144978.1. [Q9H903-4]
DR AlphaFoldDB; Q9H903; -.
DR SMR; Q9H903; -.
DR BioGRID; 137092; 17.
DR IntAct; Q9H903; 7.
DR STRING; 9606.ENSP00000379108; -.
DR BindingDB; Q9H903; -.
DR ChEMBL; CHEMBL4105963; -.
DR iPTMnet; Q9H903; -.
DR PhosphoSitePlus; Q9H903; -.
DR BioMuta; MTHFD2L; -.
DR DMDM; 353526325; -.
DR jPOST; Q9H903; -.
DR MassIVE; Q9H903; -.
DR MaxQB; Q9H903; -.
DR PaxDb; Q9H903; -.
DR PeptideAtlas; Q9H903; -.
DR PRIDE; Q9H903; -.
DR ProteomicsDB; 81265; -. [Q9H903-4]
DR ProteomicsDB; 81266; -. [Q9H903-1]
DR ProteomicsDB; 81267; -. [Q9H903-2]
DR ProteomicsDB; 81268; -. [Q9H903-3]
DR ProteomicsDB; 81269; -. [Q9H903-5]
DR Antibodypedia; 24601; 152 antibodies from 27 providers.
DR DNASU; 441024; -.
DR Ensembl; ENST00000325278.7; ENSP00000321984.7; ENSG00000163738.19. [Q9H903-4]
DR Ensembl; ENST00000395759.6; ENSP00000379108.2; ENSG00000163738.19. [Q9H903-4]
DR Ensembl; ENST00000429519.5; ENSP00000391327.1; ENSG00000163738.19. [Q9H903-3]
DR GeneID; 441024; -.
DR KEGG; hsa:441024; -.
DR MANE-Select; ENST00000325278.7; ENSP00000321984.7; NM_001144978.3; NP_001138450.1.
DR UCSC; uc011cbj.3; human. [Q9H903-4]
DR CTD; 441024; -.
DR DisGeNET; 441024; -.
DR GeneCards; MTHFD2L; -.
DR HGNC; HGNC:31865; MTHFD2L.
DR HPA; ENSG00000163738; Low tissue specificity.
DR MIM; 614047; gene.
DR neXtProt; NX_Q9H903; -.
DR OpenTargets; ENSG00000163738; -.
DR PharmGKB; PA134943916; -.
DR VEuPathDB; HostDB:ENSG00000163738; -.
DR eggNOG; KOG0089; Eukaryota.
DR GeneTree; ENSGT00940000160901; -.
DR HOGENOM; CLU_034045_0_1_1; -.
DR InParanoid; Q9H903; -.
DR OrthoDB; 1004679at2759; -.
DR PhylomeDB; Q9H903; -.
DR TreeFam; TF323998; -.
DR BRENDA; 1.5.1.15; 2681.
DR BRENDA; 1.5.1.5; 2681.
DR BRENDA; 3.5.4.9; 2681.
DR PathwayCommons; Q9H903; -.
DR Reactome; R-HSA-196757; Metabolism of folate and pterines.
DR SignaLink; Q9H903; -.
DR SIGNOR; Q9H903; -.
DR UniPathway; UPA00193; -.
DR BioGRID-ORCS; 441024; 17 hits in 1054 CRISPR screens.
DR ChiTaRS; MTHFD2L; human.
DR GenomeRNAi; 441024; -.
DR Pharos; Q9H903; Tdark.
DR PRO; PR:Q9H903; -.
DR Proteomes; UP000005640; Chromosome 4.
DR RNAct; Q9H903; protein.
DR Bgee; ENSG00000163738; Expressed in corpus epididymis and 165 other tissues.
DR ExpressionAtlas; Q9H903; baseline and differential.
DR Genevisible; Q9H903; HS.
DR GO; GO:0005743; C:mitochondrial inner membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005759; C:mitochondrial matrix; TAS:Reactome.
DR GO; GO:0005739; C:mitochondrion; IBA:GO_Central.
DR GO; GO:0004477; F:methenyltetrahydrofolate cyclohydrolase activity; ISS:UniProtKB.
DR GO; GO:0004487; F:methylenetetrahydrofolate dehydrogenase (NAD+) activity; ISS:UniProtKB.
DR GO; GO:0004488; F:methylenetetrahydrofolate dehydrogenase (NADP+) activity; ISS:UniProtKB.
DR GO; GO:0009256; P:10-formyltetrahydrofolate metabolic process; IEA:Ensembl.
DR GO; GO:0046655; P:folic acid metabolic process; TAS:Reactome.
DR GO; GO:0000105; P:histidine biosynthetic process; IEA:UniProtKB-KW.
DR GO; GO:0009086; P:methionine biosynthetic process; IEA:UniProtKB-KW.
DR GO; GO:0006164; P:purine nucleotide biosynthetic process; IEA:UniProtKB-KW.
DR GO; GO:0035999; P:tetrahydrofolate interconversion; ISS: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; PS00767; THF_DHG_CYH_2; 1.
PE 1: Evidence at protein level;
KW Alternative splicing; Amino-acid biosynthesis; Histidine biosynthesis;
KW Hydrolase; Magnesium; Membrane; Methionine biosynthesis; Mitochondrion;
KW Mitochondrion inner membrane; Multifunctional enzyme; NAD;
KW One-carbon metabolism; Oxidoreductase; Purine biosynthesis;
KW Reference proteome.
FT CHAIN 1..347
FT /note="Bifunctional methylenetetrahydrofolate
FT dehydrogenase/cyclohydrolase 2, mitochondrial"
FT /id="PRO_0000337097"
FT BINDING 98..102
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:P13995"
FT BINDING 145..147
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:P13995"
FT BINDING 214..216
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000250|UniProtKB:P13995"
FT BINDING 247
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000250|UniProtKB:P13995"
FT BINDING 323..327
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:P13995"
FT VAR_SEQ 1..277
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_041877"
FT VAR_SEQ 1..58
FT /note="Missing (in isoform 1 and isoform 3)"
FT /evidence="ECO:0000303|PubMed:14702039,
FT ECO:0000303|PubMed:15489334"
FT /id="VSP_041878"
FT VAR_SEQ 269..310
FT /note="Missing (in isoform 5)"
FT /evidence="ECO:0000305"
FT /id="VSP_041879"
FT VAR_SEQ 269..281
FT /note="GIPKLITSDMVKE -> ERFHHFAQDLSNS (in isoform 3)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_041880"
FT VAR_SEQ 282..347
FT /note="Missing (in isoform 3)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_041881"
SQ SEQUENCE 347 AA; 37315 MW; 2A2C787BF7C89C2E CRC64;
MTVPVRGFSL LRGRLGRAPA LGRSTAPSVR APGEPGSAFR GFRSSGVRHE AIIISGTEMA
KHIQKEIQRG VESWVSLGNR RPHLSIILVG DNPASHTYVR NKIRAASAVG ICSELILKPK
DVSQEELLDV TDQLNMDPRV SGILVQLPLP DHVDERTICN GIAPEKDVDG FHIINIGRLC
LDQHSLIPAT ASAVWEIIKR TGIQTFGKNV VVAGRSKNVG MPIAMLLHTD GEHERPGGDA
TVTIAHRYTP KEQLKIHTQL ADIIIVAAGI PKLITSDMVK EGAAVIDVGI NYVHDPVTGK
TKLVGDVDFE AVKKKAGFIT PVPGGVGPMT VAMLLKNTLL AAKKIIY
