ID   C1TC_RAT                Reviewed;         935 AA.
AC   P27653; Q62808;
DT   01-AUG-1992, integrated into UniProtKB/Swiss-Prot.
DT   23-JAN-2007, sequence version 3.
DT   08-NOV-2023, entry version 160.
DE   RecName: Full=C-1-tetrahydrofolate synthase, cytoplasmic {ECO:0000250|UniProtKB:P11586};
DE            Short=C1-THF synthase;
DE   Includes:
DE     RecName: Full=Methylenetetrahydrofolate dehydrogenase {ECO:0000250|UniProtKB:P11586};
DE              EC=1.5.1.5 {ECO:0000250|UniProtKB:P11586};
DE   Includes:
DE     RecName: Full=Methenyltetrahydrofolate cyclohydrolase {ECO:0000250|UniProtKB:P11586};
DE              EC=3.5.4.9 {ECO:0000250|UniProtKB:P11586};
DE   Includes:
DE     RecName: Full=Formyltetrahydrofolate synthetase {ECO:0000250|UniProtKB:P11586};
DE              EC=6.3.4.3 {ECO:0000250|UniProtKB:P11586};
GN   Name=Mthfd1; Synonyms=Mthfd;
OS   Rattus norvegicus (Rat).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC   Murinae; Rattus.
OX   NCBI_TaxID=10116;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA].
RC   TISSUE=Liver;
RX   PubMed=2186031; DOI=10.1016/s0021-9258(19)39017-9;
RA   Thigpen A.E., West M.G., Appling D.R.;
RT   "Rat C1-tetrahydrofolate synthase. cDNA isolation, tissue-specific levels
RT   of the mRNA, and expression of the protein in yeast.";
RL   J. Biol. Chem. 265:7907-7913(1990).
RN   [2]
RP   SEQUENCE REVISION TO 19 AND 24.
RA   Appling D.R.;
RL   Submitted (JUL-1995) to the EMBL/GenBank/DDBJ databases.
RN   [3]
RP   PROTEIN SEQUENCE OF 521-532, AND IDENTIFICATION BY MASS SPECTROMETRY.
RC   STRAIN=Sprague-Dawley; TISSUE=Spinal cord;
RA   Lubec G., Afjehi-Sadat L.;
RL   Submitted (NOV-2006) to UniProtKB.
CC   -!- FUNCTION: Trifunctional enzyme that catalyzes the interconversion of
CC       three forms of one-carbon-substituted tetrahydrofolate: (6R)-5,10-
CC       methylene-5,6,7,8-tetrahydrofolate, 5,10-methenyltetrahydrofolate and
CC       (6S)-10-formyltetrahydrofolate. These derivatives of tetrahydrofolate
CC       are differentially required in nucleotide and amino acid biosynthesis,
CC       (6S)-10-formyltetrahydrofolate being required for purine biosynthesis
CC       while (6R)-5,10-methylene-5,6,7,8-tetrahydrofolate is used for serine
CC       and methionine biosynthesis for instance.
CC       {ECO:0000250|UniProtKB:P11586}.
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=(6R)-5,10-methylene-5,6,7,8-tetrahydrofolate + NADP(+) = (6R)-
CC         5,10-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:P11586};
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:0000250|UniProtKB:P11586};
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:0000250|UniProtKB:P11586};
CC   -!- PATHWAY: One-carbon metabolism; tetrahydrofolate interconversion.
CC       {ECO:0000250|UniProtKB:P11586}.
CC   -!- SUBUNIT: Homodimer. {ECO:0000250|UniProtKB:P11586}.
CC   -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250|UniProtKB:P11586}.
CC   -!- DOMAIN: The N-terminal methylenetetrahydrofolate dehydrogenase and
CC       methenyltetrahydrofolate cyclohydrolase (D/C) domain carries both the
CC       methylenetetrahydrofolate dehydrogenase and methenyltetrahydrofolate
CC       cyclohydrolase activities. {ECO:0000250|UniProtKB:P11586}.
CC   -!- DOMAIN: The larger C-terminal formyltetrahydrofolate synthetase domain
CC       carries a third formyltetrahydrofolate synthetase activity.
CC       {ECO:0000250|UniProtKB:P11586}.
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}.
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DR   EMBL; J05519; AAA74248.1; -; mRNA.
DR   EMBL; U31032; AAA74744.1; -; Genomic_DNA.
DR   PIR; A35367; A35367.
DR   RefSeq; NP_071953.1; NM_022508.1.
DR   AlphaFoldDB; P27653; -.
DR   SMR; P27653; -.
DR   BioGRID; 249015; 1.
DR   IntAct; P27653; 1.
DR   STRING; 10116.ENSRNOP00000008374; -.
DR   iPTMnet; P27653; -.
DR   PhosphoSitePlus; P27653; -.
DR   jPOST; P27653; -.
DR   PaxDb; 10116-ENSRNOP00000008374; -.
DR   GeneID; 64300; -.
DR   KEGG; rno:64300; -.
DR   UCSC; RGD:708531; rat.
DR   AGR; RGD:708531; -.
DR   CTD; 4522; -.
DR   RGD; 708531; Mthfd1.
DR   eggNOG; KOG4230; Eukaryota.
DR   InParanoid; P27653; -.
DR   OrthoDB; 651667at2759; -.
DR   PhylomeDB; P27653; -.
DR   Reactome; R-RNO-196757; Metabolism of folate and pterines.
DR   UniPathway; UPA00193; -.
DR   PRO; PR:P27653; -.
DR   Proteomes; UP000002494; Unplaced.
DR   GO; GO:0005829; C:cytosol; IBA:GO_Central.
DR   GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR   GO; GO:0004329; F:formate-tetrahydrofolate ligase activity; ISS:UniProtKB.
DR   GO; GO:0004477; F:methenyltetrahydrofolate cyclohydrolase activity; ISS:UniProtKB.
DR   GO; GO:0004487; F:methylenetetrahydrofolate dehydrogenase (NAD+) activity; ISO:RGD.
DR   GO; GO:0004488; F:methylenetetrahydrofolate dehydrogenase (NADP+) activity; ISS:UniProtKB.
DR   GO; GO:0004486; F:methylenetetrahydrofolate dehydrogenase [NAD(P)+] activity; ISO:RGD.
DR   GO; GO:0009257; P:10-formyltetrahydrofolate biosynthetic process; ISO:RGD.
DR   GO; GO:0007507; P:heart development; ISO:RGD.
DR   GO; GO:0000105; P:histidine biosynthetic process; IEA:UniProtKB-KW.
DR   GO; GO:0009086; P:methionine biosynthetic process; ISO:RGD.
DR   GO; GO:0006555; P:methionine metabolic process; ISO:RGD.
DR   GO; GO:0001843; P:neural tube closure; ISO:RGD.
DR   GO; GO:0001780; P:neutrophil homeostasis; ISO:RGD.
DR   GO; GO:0006730; P:one-carbon metabolic process; IEP:RGD.
DR   GO; GO:0006164; P:purine nucleotide biosynthetic process; ISS:UniProtKB.
DR   GO; GO:0009152; P:purine ribonucleotide biosynthetic process; ISO:RGD.
DR   GO; GO:0035713; P:response to nitrogen dioxide; IEP:RGD.
DR   GO; GO:0009070; P:serine family amino acid biosynthetic process; ISO:RGD.
DR   GO; GO:0009069; P:serine family amino acid metabolic process; ISO:RGD.
DR   GO; GO:0061053; P:somite development; ISO:RGD.
DR   GO; GO:0035999; P:tetrahydrofolate interconversion; ISS:UniProtKB.
DR   GO; GO:0046653; P:tetrahydrofolate metabolic process; TAS:RGD.
DR   GO; GO:0019346; P:transsulfuration; ISO:RGD.
DR   CDD; cd00477; FTHFS; 1.
DR   CDD; cd01080; NAD_bind_m-THF_DH_Cyclohyd; 1.
DR   Gene3D; 3.30.1510.10; Domain 2, N(10)-formyltetrahydrofolate synthetase; 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   HAMAP; MF_01576; THF_DHG_CYH; 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; IPR020867; THF_DH/CycHdrlase_CS.
DR   InterPro; IPR020631; THF_DH/CycHdrlase_NAD-bd_dom.
DR   PANTHER; PTHR48099:SF1; C-1-TETRAHYDROFOLATE SYNTHASE, CYTOPLASMIC; 1.
DR   PANTHER; PTHR48099; C-1-TETRAHYDROFOLATE SYNTHASE, CYTOPLASMIC-RELATED; 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   PROSITE; PS00766; THF_DHG_CYH_1; 1.
DR   PROSITE; PS00767; THF_DHG_CYH_2; 1.
PE   1: Evidence at protein level;
KW   Acetylation; Amino-acid biosynthesis; ATP-binding; Cytoplasm;
KW   Direct protein sequencing; Histidine biosynthesis; Hydrolase; Ligase;
KW   Methionine biosynthesis; Multifunctional enzyme; NADP; Nucleotide-binding;
KW   One-carbon metabolism; Oxidoreductase; Phosphoprotein; Purine biosynthesis;
KW   Reference proteome.
FT   CHAIN           1..935
FT                   /note="C-1-tetrahydrofolate synthase, cytoplasmic"
FT                   /id="PRO_0000199323"
FT   REGION          2..291
FT                   /note="Methylenetetrahydrofolate dehydrogenase and
FT                   methenyltetrahydrofolate cyclohydrolase (D/C) domain"
FT                   /evidence="ECO:0000250|UniProtKB:P11586"
FT   REGION          310..935
FT                   /note="Formyltetrahydrofolate synthetase domain"
FT                   /evidence="ECO:0000250|UniProtKB:P11586"
FT   ACT_SITE        56
FT                   /evidence="ECO:0000250|UniProtKB:P11586"
FT   BINDING         52..56
FT                   /ligand="substrate"
FT                   /evidence="ECO:0000250|UniProtKB:P11586"
FT   BINDING         99..101
FT                   /ligand="substrate"
FT                   /evidence="ECO:0000250|UniProtKB:P11586"
FT   BINDING         172..174
FT                   /ligand="NADP(+)"
FT                   /ligand_id="ChEBI:CHEBI:58349"
FT                   /evidence="ECO:0000250|UniProtKB:P11586"
FT   BINDING         197
FT                   /ligand="NADP(+)"
FT                   /ligand_id="ChEBI:CHEBI:58349"
FT                   /evidence="ECO:0000250|UniProtKB:P11586"
FT   BINDING         272..276
FT                   /ligand="substrate"
FT                   /evidence="ECO:0000250|UniProtKB:P11586"
FT   BINDING         380..387
FT                   /ligand="ATP"
FT                   /ligand_id="ChEBI:CHEBI:30616"
FT                   /evidence="ECO:0000250"
FT   MOD_RES         1
FT                   /note="N-acetylmethionine"
FT                   /evidence="ECO:0000250|UniProtKB:P11586"
FT   MOD_RES         318
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:P11586"
FT   MOD_RES         413
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:P11586"
FT   MOD_RES         490
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:P11586"
SQ   SEQUENCE   935 AA;  100996 MW;  6E42A56C10A4059E CRC64;
     MAPAGILNGK VVSAQIRNRL KTQVTQMQEQ VPGFTPGLAI LQVGDRDDSN LYINVKLKAA
     QEIGIKATHI KLPRTSTESE VLKYVISLNE DATVHGFIVQ LPLDSENSIN TEAVINAIAP
     EKDVDGLTSI NAGKLARGDL KDCFIPCTPK GCLELIKETG VQIAGRHAVV VGRSKIVGAP
     MHDLLLWNNA TVTTCHSKTA DLDKEVNKGD ILVVATGQPE MVKGEWIKPG AVVIDCGINY
     VPDDTKPNGR KVVGDVAYDE AKEKASFITP VPGGVGPMTV AMLMQSTVES AQRFLKKFKP
     GKWTIQYNKL NLKTPVPSDI AISRSCKPKL IGNLAREIGL LTEEVELYGE TKAKVLLSAL
     DRLKHQPDGK YVVVTGITPT PLGEGKSTTT IGLVQALGAH LHQNVFACVR QPSQGPTFGI
     KGGAAGGGYS QVIPMEEFNL HLTGDIHAIT AANNLVAAAI DARIFHELTQ TDKALFNRLV
     PSVNGVRKFS DIQIRRLRRL GIEKTDPAAL TDDEINRFAR LDIDPETITW QRVLDTNDRF
     LRKITIGQAP TEKGHTRTAQ FDISVASEIM AVLALTSSLE DMRARLGKMV VASSKKGEPI
     SCEDLGVSGA LTVLMKDAIK PNLMQTLEGT PVFVHAGPFA NIAHGNSSII ADRIALKLVG
     PEGFVVTEAG FGADIGMEKF FNIKCRYSGL QPHVVVLVAT VRALKMHGGG PTVTAGLPLP
     KAYTEEDLDL VEKGFSNLRK QIENARMFGV PVVVAMNAFK TDTDTELDLI GRLSREHGAF
     DAVKCTHWAE GGQGALALAQ AVQRASQAPS SFQLLYDLKL SVEDKIRIIA QKIYGADDIE
     LLPEAQNKAE IYTKQGFGNL PICMAKTHLS LSHNPEQKGV PTGFVLPIRD IRASVGAGFL
     YPLVGTMSTM PGLPTRPCFY DIDLDPETEQ VNGLF
//