ID C1TC_PONAB Reviewed; 935 AA. AC Q5R8P0; DT 12-DEC-2006, integrated into UniProtKB/Swiss-Prot. DT 23-JAN-2007, sequence version 3. DT 08-NOV-2023, entry version 97. 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; OS Pongo abelii (Sumatran orangutan) (Pongo pygmaeus abelii). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Pongo. OX NCBI_TaxID=9601; RN [1] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Kidney; RG The German cDNA consortium; RL Submitted (NOV-2004) to the EMBL/GenBank/DDBJ databases. 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}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; CR859711; CAH91870.1; -; mRNA. DR RefSeq; NP_001126083.1; NM_001132611.1. DR AlphaFoldDB; Q5R8P0; -. DR SMR; Q5R8P0; -. DR STRING; 9601.ENSPPYP00000006705; -. DR GeneID; 100173036; -. DR KEGG; pon:100173036; -. DR CTD; 4522; -. DR eggNOG; KOG4230; Eukaryota. DR InParanoid; Q5R8P0; -. DR OrthoDB; 651667at2759; -. DR UniPathway; UPA00193; -. DR Proteomes; UP000001595; Unplaced. DR GO; GO:0005737; C:cytoplasm; IEA:UniProtKB-SubCell. 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:0004488; F:methylenetetrahydrofolate dehydrogenase (NADP+) activity; ISS:UniProtKB. 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; ISS:UniProtKB. DR GO; GO:0035999; P:tetrahydrofolate interconversion; ISS:UniProtKB. DR CDD; cd00477; FTHFS; 1. DR CDD; cd01080; NAD_bind_m-THF_DH_Cyclohyd; 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 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 2: Evidence at transcript level; KW Acetylation; Amino-acid biosynthesis; ATP-binding; Cytoplasm; KW Histidine biosynthesis; Hydrolase; Ligase; Methionine biosynthesis; KW Multifunctional enzyme; NADP; Nucleotide-binding; One-carbon metabolism; KW Oxidoreductase; Phosphoprotein; Purine biosynthesis; Reference proteome. FT CHAIN 1..935 FT /note="C-1-tetrahydrofolate synthase, cytoplasmic" FT /id="PRO_0000265955" 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; 101341 MW; 4D98F58C5A908632 CRC64; MAPAEILNGR EISAQIRARL KNQVTQLKEQ VPGFTPGLAI LLVGNRDDSN LYINVKLKAA EEIGIKATHI KLPRTTTESE VIKYITSLNE DSTVHGFLVQ LPLDSENSIN TEEVINAIAP EKDVDGLTSI SAGKLARGDL NDCFIPCTPK GCLELIKETG VPIAGRHAVV VGRSKIVGAP MHDLLLWNNA TVTTCHSKTA NLDEEVNKGD ILVVATGRPE MVKGEWIKPG AIVIDCGINY VPDDKKPNGR KVVGDVAYDE AKERASFITP VPGGVGPMTV AMLMQSTVES AKRFLEKFKP GKWMIQYNNL NLKTPDPSDI DISRSCKPKP IGKLAREIGL LSEEVELYGE TKAKVLLSAL ERLKHRPDGK YVVVTGITPT PLGEGKSTTT VGLVQALGAH LYQNVFACVR QPSQGPTFGI KGGAAGGGYS QVIPMEEFNL HLTGDIHAFT AANNLVAAAI DARIFHELTQ TDKALFNRLV PSVNGVRKFS DIQIRRLKRL GIEKTDPTTL TDEEINRFAR LDIDPETITW QRVLDTNDRF LRKITIGQAP TEKGHTRTAQ FDISVASEIM AALALTTSLE DMRERLGKMV VASSKKGEPV SAEDLGVSGA LTVLMKDAIK PNLMQTLEGT PVFVHAGPFA NIAHGNSSII ADRIALKLVG PEGFVVTEAG FGADIGMEKF FNIKCRYSGL CPHVVVLVAT VRALKMHGGG PTVTAGLPLP KAYIEENLEL VEKGFSNLKK QIENARMFGI PVVVAVNAFK TDTEAELDLI SRLSREHGAF DAVKCTHWAE GGNGALALAQ AVQRAAQAPS SFQLLYDLKL PVEDKIRIIA QKIYGADDIE LLPEAQHKAE VYTKQGFGNL PVCMAKTHLS LSHNPEQKGV PTGFILPIRD IRASVGAGFL YPLVGTMSTM PGLPTRPCFY DIDLDPETQQ VNGLF //