C1TC_RAT
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 03-AUG-2022, entry version 154.
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(+) = 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:P11586};
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:P11586};
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: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 formate--
CC 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; P27653; -.
DR PRIDE; P27653; -.
DR GeneID; 64300; -.
DR KEGG; rno:64300; -.
DR UCSC; RGD:708531; rat.
DR CTD; 4522; -.
DR RGD; 708531; Mthfd1.
DR eggNOG; KOG4230; Eukaryota.
DR InParanoid; P27653; -.
DR OrthoDB; 690393at2759; -.
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:0005737; C:cytoplasm; TAS:RGD.
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:0009117; P:nucleotide metabolic process; IEP: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; 3.40.50.300; -; 2.
DR HAMAP; MF_01543; FTHFS; 1.
DR HAMAP; MF_01576; THF_DHG_CYH; 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; IPR020867; THF_DH/CycHdrlase_CS.
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.
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
