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   27-MAR-2024, entry version 139.
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,
RC   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).
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 = (6R)-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:195366, ChEBI:CHEBI:456216;
CC         EC=6.3.4.3; 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
CC       formate--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; 9.
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; 10090-ENSMUSP00000112897; -.
DR   PeptideAtlas; Q3V3R1; -.
DR   ProteomicsDB; 273808; -.
DR   Pumba; Q3V3R1; -.
DR   Antibodypedia; 33330; 179 antibodies from 29 providers.
DR   DNASU; 270685; -.
DR   Ensembl; ENSMUST00000043735.8; ENSMUSP00000036178.8; ENSMUSG00000040675.18.
DR   Ensembl; ENSMUST00000117291.8; ENSMUSP00000112870.2; ENSMUSG00000040675.18.
DR   Ensembl; ENSMUST00000120585.8; ENSMUSP00000112897.2; ENSMUSG00000040675.18.
DR   GeneID; 270685; -.
DR   KEGG; mmu:270685; -.
DR   UCSC; uc007ehj.2; mouse.
DR   AGR; MGI:1924836; -.
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; KFWNLKC; -.
DR   OrthoDB; 651667at2759; -.
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 80 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 233 other cell types or tissues.
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; 1.10.8.770; -; 1.
DR   Gene3D; 3.10.410.10; Formyltetrahydrofolate synthetase, domain 3; 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   Gene3D; 3.40.50.300; P-loop containing nucleotide triphosphate hydrolases; 2.
DR   HAMAP; MF_01543; FTHFS; 1.
DR   InterPro; IPR046346; Aminoacid_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   PANTHER; PTHR48099; C-1-TETRAHYDROFOLATE SYNTHASE, CYTOPLASMIC-RELATED; 1.
DR   PANTHER; PTHR48099:SF12; MONOFUNCTIONAL C1-TETRAHYDROFOLATE SYNTHASE, MITOCHONDRIAL; 1.
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; SSF53223; Aminoacid dehydrogenase-like, N-terminal domain; 1.
DR   SUPFAM; SSF51735; NAD(P)-binding Rossmann-fold domains; 1.
DR   SUPFAM; SSF52540; P-loop containing nucleoside triphosphate hydrolases; 1.
DR   PROSITE; PS00721; FTHFS_1; 1.
DR   PROSITE; PS00722; FTHFS_2; 1.
DR   Genevisible; Q3V3R1; MM.
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;
FT                   AAH30437/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
//