C1TM_MOUSE
ID C1TM_MOUSE Reviewed; 977 AA.
AC Q3V3R1; Q3TVQ0; Q3V402; Q80V98; Q8CAL0; Q8K2N5;
DT 01-JUL-2008, integrated into UniProtKB/Swiss-Prot.
DT 01-JUL-2008, sequence version 2.
DT 03-AUG-2022, entry version 130.
DE RecName: Full=Monofunctional C1-tetrahydrofolate synthase, mitochondrial {ECO:0000305|PubMed:15611115};
DE EC=6.3.4.3 {ECO:0000305|PubMed:15611115};
DE AltName: Full=Formyltetrahydrofolate synthetase;
DE Flags: Precursor;
GN Name=Mthfd1l; Synonyms=Fthfsdc1;
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 [LARGE SCALE MRNA].
RC STRAIN=C57BL/6J; TISSUE=Cerebellum, and Hypothalamus;
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 [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 167-977.
RC STRAIN=FVB/N-3; TISSUE=Mammary tumor;
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 [3]
RP FUNCTION, CATALYTIC ACTIVITY, PATHWAY, AND SUBCELLULAR LOCATION.
RX PubMed=15611115; DOI=10.1074/jbc.m409380200;
RA Christensen K.E., Patel H., Kuzmanov U., Mejia N.R., MacKenzie R.E.;
RT "Disruption of the mthfd1 gene reveals a monofunctional 10-
RT formyltetrahydrofolate synthetase in mammalian mitochondria.";
RL J. Biol. Chem. 280:7597-7602(2005).
RN [4]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Brain, Brown adipose tissue, Heart, Kidney, Liver, Lung, Pancreas,
RC 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).
RN [5]
RP SUCCINYLATION [LARGE SCALE ANALYSIS] AT LYS-188 AND LYS-595, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Embryonic fibroblast;
RX PubMed=23806337; DOI=10.1016/j.molcel.2013.06.001;
RA Park J., Chen Y., Tishkoff D.X., Peng C., Tan M., Dai L., Xie Z., Zhang Y.,
RA Zwaans B.M., Skinner M.E., Lombard D.B., Zhao Y.;
RT "SIRT5-mediated lysine desuccinylation impacts diverse metabolic
RT pathways.";
RL Mol. Cell 50:919-930(2013).
RN [6]
RP STRUCTURE BY NMR OF 510-573.
RG RIKEN structural genomics initiative (RSGI);
RT "Solution structure of the insertion region (510-573) of FTHFS domain from
RT mouse methylenetetrahydrofolate dehydrogenase (NADP+ dependent) 1-like
RT protein.";
RL Submitted (OCT-2007) to the PDB data bank.
CC -!- FUNCTION: May provide the missing metabolic reaction required to link
CC the mitochondria and the cytoplasm in the mammalian model of one-carbon
CC folate metabolism complementing thus the enzymatic activities of
CC MTHFD2. {ECO:0000269|PubMed:15611115}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=(6S)-5,6,7,8-tetrahydrofolate + ATP + formate = (6S)-10-
CC formyltetrahydrofolate + ADP + phosphate; Xref=Rhea:RHEA:20221,
CC ChEBI:CHEBI:15740, ChEBI:CHEBI:30616, ChEBI:CHEBI:43474,
CC ChEBI:CHEBI:57453, ChEBI:CHEBI:57454, ChEBI:CHEBI:456216; EC=6.3.4.3;
CC Evidence={ECO:0000305|PubMed:15611115};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:20222;
CC Evidence={ECO:0000305|PubMed:15611115};
CC -!- PATHWAY: One-carbon metabolism; tetrahydrofolate interconversion.
CC {ECO:0000305|PubMed:15611115}.
CC -!- SUBUNIT: Homodimer. {ECO:0000250|UniProtKB:Q6UB35}.
CC -!- SUBCELLULAR LOCATION: Mitochondrion {ECO:0000305|PubMed:15611115}.
CC -!- DOMAIN: This monofunctional enzyme consists of two major domains: an N-
CC terminal inactive methylene-THF dehydrogenase and cyclohydrolase domain
CC and an active larger formyl-THF synthetase C-terminal domain.
CC -!- SIMILARITY: In the N-terminal section; belongs to the tetrahydrofolate
CC dehydrogenase/cyclohydrolase family. {ECO:0000305}.
CC -!- SIMILARITY: In the C-terminal section; belongs to the formate--
CC tetrahydrofolate ligase family. {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAH30437.1; Type=Erroneous initiation; Evidence={ECO:0000305};
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DR EMBL; AK038579; BAC30053.1; -; mRNA.
DR EMBL; AK028211; BAE20438.1; -; mRNA.
DR EMBL; AK036284; BAE20500.1; -; mRNA.
DR EMBL; AK160025; BAE35568.1; -; mRNA.
DR EMBL; BC030437; AAH30437.1; ALT_INIT; mRNA.
DR EMBL; BC049936; AAH49936.1; -; mRNA.
DR CCDS; CCDS56672.1; -.
DR RefSeq; NP_001164256.1; NM_001170785.1.
DR RefSeq; NP_001164257.1; NM_001170786.1.
DR RefSeq; NP_758512.3; NM_172308.4.
DR PDB; 2EO2; NMR; -; A=510-573.
DR PDBsum; 2EO2; -.
DR AlphaFoldDB; Q3V3R1; -.
DR SMR; Q3V3R1; -.
DR BioGRID; 234813; 8.
DR IntAct; Q3V3R1; 7.
DR MINT; Q3V3R1; -.
DR STRING; 10090.ENSMUSP00000112897; -.
DR iPTMnet; Q3V3R1; -.
DR PhosphoSitePlus; Q3V3R1; -.
DR SwissPalm; Q3V3R1; -.
DR REPRODUCTION-2DPAGE; Q3V3R1; -.
DR EPD; Q3V3R1; -.
DR jPOST; Q3V3R1; -.
DR MaxQB; Q3V3R1; -.
DR PaxDb; Q3V3R1; -.
DR PeptideAtlas; Q3V3R1; -.
DR PRIDE; Q3V3R1; -.
DR ProteomicsDB; 273808; -.
DR Antibodypedia; 33330; 161 antibodies from 29 providers.
DR DNASU; 270685; -.
DR Ensembl; ENSMUST00000043735; ENSMUSP00000036178; ENSMUSG00000040675.
DR Ensembl; ENSMUST00000117291; ENSMUSP00000112870; ENSMUSG00000040675.
DR Ensembl; ENSMUST00000120585; ENSMUSP00000112897; ENSMUSG00000040675.
DR GeneID; 270685; -.
DR KEGG; mmu:270685; -.
DR UCSC; uc007ehj.2; mouse.
DR CTD; 25902; -.
DR MGI; MGI:1924836; Mthfd1l.
DR VEuPathDB; HostDB:ENSMUSG00000040675; -.
DR eggNOG; KOG4230; Eukaryota.
DR GeneTree; ENSGT00940000157477; -.
DR HOGENOM; CLU_003601_0_0_1; -.
DR InParanoid; Q3V3R1; -.
DR OMA; CGEIMTM; -.
DR OrthoDB; 690393at2759; -.
DR PhylomeDB; Q3V3R1; -.
DR TreeFam; TF300623; -.
DR BRENDA; 6.3.4.3; 3474.
DR Reactome; R-MMU-196757; Metabolism of folate and pterines.
DR UniPathway; UPA00193; -.
DR BioGRID-ORCS; 270685; 10 hits in 75 CRISPR screens.
DR ChiTaRS; Mthfd1l; mouse.
DR EvolutionaryTrace; Q3V3R1; -.
DR PRO; PR:Q3V3R1; -.
DR Proteomes; UP000000589; Chromosome 10.
DR RNAct; Q3V3R1; protein.
DR Bgee; ENSMUSG00000040675; Expressed in epiblast (generic) and 230 other tissues.
DR Genevisible; Q3V3R1; MM.
DR GO; GO:0005829; C:cytosol; IBA:GO_Central.
DR GO; GO:0005739; C:mitochondrion; IDA:BHF-UCL.
DR GO; GO:0005524; F:ATP binding; ISO:MGI.
DR GO; GO:0004329; F:formate-tetrahydrofolate ligase activity; ISO:MGI.
DR GO; GO:0004488; F:methylenetetrahydrofolate dehydrogenase (NADP+) activity; IEA:InterPro.
DR GO; GO:0042803; F:protein homodimerization activity; ISO:MGI.
DR GO; GO:0009257; P:10-formyltetrahydrofolate biosynthetic process; ISO:MGI.
DR GO; GO:0048702; P:embryonic neurocranium morphogenesis; IMP:BHF-UCL.
DR GO; GO:0048703; P:embryonic viscerocranium morphogenesis; IMP:BHF-UCL.
DR GO; GO:0006760; P:folic acid-containing compound metabolic process; ISO:MGI.
DR GO; GO:0015942; P:formate metabolic process; ISO:MGI.
DR GO; GO:0001843; P:neural tube closure; IMP:BHF-UCL.
DR GO; GO:0035999; P:tetrahydrofolate interconversion; IBA:GO_Central.
DR CDD; cd00477; FTHFS; 1.
DR Gene3D; 3.40.50.300; -; 2.
DR HAMAP; MF_01543; FTHFS; 1.
DR InterPro; IPR046346; Aminiacid_DH-like_N_sf.
DR InterPro; IPR000559; Formate_THF_ligase.
DR InterPro; IPR020628; Formate_THF_ligase_CS.
DR InterPro; IPR036291; NAD(P)-bd_dom_sf.
DR InterPro; IPR027417; P-loop_NTPase.
DR InterPro; IPR000672; THF_DH/CycHdrlase.
DR InterPro; IPR020630; THF_DH/CycHdrlase_cat_dom.
DR InterPro; IPR020631; THF_DH/CycHdrlase_NAD-bd_dom.
DR Pfam; PF01268; FTHFS; 1.
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; SSF52540; SSF52540; 1.
DR SUPFAM; SSF53223; SSF53223; 1.
DR PROSITE; PS00721; FTHFS_1; 1.
DR PROSITE; PS00722; FTHFS_2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; ATP-binding; Ligase; Mitochondrion;
KW Nucleotide-binding; One-carbon metabolism; Phosphoprotein;
KW Reference proteome; Transit peptide.
FT TRANSIT 1..31
FT /note="Mitochondrion"
FT /evidence="ECO:0000250|UniProtKB:Q6UB35"
FT CHAIN 32..977
FT /note="Monofunctional C1-tetrahydrofolate synthase,
FT mitochondrial"
FT /id="PRO_0000343178"
FT REGION 29..71
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 32..347
FT /note="Methylenetetrahydrofolate dehydrogenase and
FT cyclohydrolase"
FT REGION 348..977
FT /note="Formyltetrahydrofolate synthetase"
FT BINDING 422..429
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250"
FT MOD_RES 188
FT /note="N6-acetyllysine; alternate"
FT /evidence="ECO:0000250|UniProtKB:Q6UB35"
FT MOD_RES 188
FT /note="N6-succinyllysine; alternate"
FT /evidence="ECO:0007744|PubMed:23806337"
FT MOD_RES 356
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q6UB35"
FT MOD_RES 595
FT /note="N6-succinyllysine"
FT /evidence="ECO:0007744|PubMed:23806337"
FT CONFLICT 137
FT /note="D -> N (in Ref. 1; BAE35568)"
FT /evidence="ECO:0000305"
FT CONFLICT 279
FT /note="V -> A (in Ref. 1; BAE35568 and 2; AAH30437/
FT AAH49936)"
FT /evidence="ECO:0000305"
FT CONFLICT 353
FT /note="Q -> H (in Ref. 1; BAE35568)"
FT /evidence="ECO:0000305"
FT CONFLICT 369
FT /note="T -> N (in Ref. 1; BAE20500)"
FT /evidence="ECO:0000305"
FT CONFLICT 419
FT /note="I -> V (in Ref. 1; BAC30053)"
FT /evidence="ECO:0000305"
FT CONFLICT 422
FT /note="T -> S (in Ref. 1; BAE35568)"
FT /evidence="ECO:0000305"
FT CONFLICT 632
FT /note="V -> A (in Ref. 1; BAE35568)"
FT /evidence="ECO:0000305"
FT CONFLICT 963
FT /note="D -> G (in Ref. 1; BAE20438)"
FT /evidence="ECO:0000305"
FT HELIX 514..521
FT /evidence="ECO:0007829|PDB:2EO2"
FT STRAND 525..528
FT /evidence="ECO:0007829|PDB:2EO2"
FT HELIX 533..542
FT /evidence="ECO:0007829|PDB:2EO2"
FT TURN 549..551
FT /evidence="ECO:0007829|PDB:2EO2"
FT HELIX 554..562
FT /evidence="ECO:0007829|PDB:2EO2"
SQ SEQUENCE 977 AA; 105729 MW; 7275EF6F9A4292D6 CRC64;
MSVRLPLLLR QLGRQQLPSG PACRLRELCR SGSRSSSSGG GDPEGLRGRR LQDGQTFSSH
GPGNPEAPGM DSIVRDVIHN SKEVLSLLQE KNPAFKPVLV VIQAGDDNLM KDMNQNLAKE
AGLDITHICL PPDSGEDEII DEILKINEDP RVHGLTLQIS EDSLSNKVLN ALKPEKDVDG
VTDINLGKLV RGDAPECFVS PLAKAAVELV EKSGITLDGK KVLVVGAHGP LEAALQWLFQ
RKGSMTMSCP WATPQLPDKL READIVVLGS PKPEEIPAVW IPSGTTILNC FHDFLSGKLS
GGSPGVPVDK LIAEESVSLL AAALRIQNMV SSGRRWLREQ QHRRWRLHCL KLQPLSPVPS
DIEISRGQTP KAVDVLAKEI GLLADEIEIY GKSKAKVQLS LLERLKDQTD GKYVLVAGIT
PTPLGEGKST VTIGLVQALT AHLKVNSFAC LRQPSQGPTF GVKGGAAGGG YAQVIPMEEF
NLHLTGDIHA ITAANNLLAA AIDTRILHES TQTDKALYNR LVPLVNGVRE FSEIQLSRLK
KLGIHKTDPS TLTEEEVRKF ARLNIDPATI TWQRVLDTND RFLRKITIGQ GSTEKGYSRQ
AQFDIAVASE IMAVLALTDS LTDMKERLGR MVVASDKDGQ PVTAEDLGVT GALTVLMKDA
IKPNLMQTLE GTPVFVHAGP FANIAHGNSS VLADKIALKL VGEEGFVVTE AGFGADIGME
KFFNIKCRAS GLVPNVVVLV ATVRALKMHG GGPSVTAGVP LKKEYTEENI QLVADGCCNL
QKQIQIAQLF GVPVVVALNV FKTDTRAEID LVCELAKRAG AFDAVPCYHW SAGGKGSVDL
ARAVREAANK RSRFQFLYDV QLPIVEKIRV IAQTVYGAKD IELSPEAQSK IDRYTQQGFG
NLPICMAKTH LSLSHEPDKK GVPRDFTLPI SDVRASIGAG FIYPLVGTMS TMPGLPTRPC
FYDIDLDTET EQVKGLF
