ID C1TM_YEAST Reviewed; 975 AA. AC P09440; D6VQ83; DT 01-JUL-1989, integrated into UniProtKB/Swiss-Prot. DT 01-JUL-1989, sequence version 1. DT 27-MAR-2024, entry version 211. DE RecName: Full=C-1-tetrahydrofolate synthase, mitochondrial {ECO:0000305}; DE Short=C1-THF synthase; DE Includes: DE RecName: Full=Methylenetetrahydrofolate dehydrogenase; DE EC=1.5.1.5 {ECO:0000269|PubMed:3528153}; DE Includes: DE RecName: Full=Methenyltetrahydrofolate cyclohydrolase; DE EC=3.5.4.9 {ECO:0000269|PubMed:3528153}; DE Includes: DE RecName: Full=Formyltetrahydrofolate synthetase; DE EC=6.3.4.3 {ECO:0000269|PubMed:3528153}; DE Flags: Precursor; GN Name=MIS1 {ECO:0000303|PubMed:2836393}; OrderedLocusNames=YBR084W; GN ORFNames=YBR0751; OS Saccharomyces cerevisiae (strain ATCC 204508 / S288c) (Baker's yeast). OC Eukaryota; Fungi; Dikarya; Ascomycota; Saccharomycotina; Saccharomycetes; OC Saccharomycetales; Saccharomycetaceae; Saccharomyces. OX NCBI_TaxID=559292; RN [1] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RX PubMed=2836393; DOI=10.1016/s0021-9258(18)68558-8; RA Shannon K.W., Rabinowitz J.C.; RT "Isolation and characterization of the Saccharomyces cerevisiae MIS1 gene RT encoding mitochondrial C1-tetrahydrofolate synthase."; RL J. Biol. Chem. 263:7717-7725(1988). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RC STRAIN=ATCC 204508 / S288c; RX PubMed=7813418; DOI=10.1002/j.1460-2075.1994.tb06923.x; RA Feldmann H., Aigle M., Aljinovic G., Andre B., Baclet M.C., Barthe C., RA Baur A., Becam A.-M., Biteau N., Boles E., Brandt T., Brendel M., RA Brueckner M., Bussereau F., Christiansen C., Contreras R., Crouzet M., RA Cziepluch C., Demolis N., Delaveau T., Doignon F., Domdey H., RA Duesterhus S., Dubois E., Dujon B., El Bakkoury M., Entian K.-D., RA Feuermann M., Fiers W., Fobo G.M., Fritz C., Gassenhuber J., Glansdorff N., RA Goffeau A., Grivell L.A., de Haan M., Hein C., Herbert C.J., RA Hollenberg C.P., Holmstroem K., Jacq C., Jacquet M., Jauniaux J.-C., RA Jonniaux J.-L., Kallesoee T., Kiesau P., Kirchrath L., Koetter P., RA Korol S., Liebl S., Logghe M., Lohan A.J.E., Louis E.J., Li Z.Y., RA Maat M.J., Mallet L., Mannhaupt G., Messenguy F., Miosga T., Molemans F., RA Mueller S., Nasr F., Obermaier B., Perea J., Pierard A., Piravandi E., RA Pohl F.M., Pohl T.M., Potier S., Proft M., Purnelle B., Ramezani Rad M., RA Rieger M., Rose M., Schaaff-Gerstenschlaeger I., Scherens B., RA Schwarzlose C., Skala J., Slonimski P.P., Smits P.H.M., Souciet J.-L., RA Steensma H.Y., Stucka R., Urrestarazu L.A., van der Aart Q.J.M., RA Van Dyck L., Vassarotti A., Vetter I., Vierendeels F., Vissers S., RA Wagner G., de Wergifosse P., Wolfe K.H., Zagulski M., Zimmermann F.K., RA Mewes H.-W., Kleine K.; RT "Complete DNA sequence of yeast chromosome II."; RL EMBO J. 13:5795-5809(1994). RN [3] RP GENOME REANNOTATION. RC STRAIN=ATCC 204508 / S288c; RX PubMed=24374639; DOI=10.1534/g3.113.008995; RA Engel S.R., Dietrich F.S., Fisk D.G., Binkley G., Balakrishnan R., RA Costanzo M.C., Dwight S.S., Hitz B.C., Karra K., Nash R.S., Weng S., RA Wong E.D., Lloyd P., Skrzypek M.S., Miyasato S.R., Simison M., Cherry J.M.; RT "The reference genome sequence of Saccharomyces cerevisiae: Then and now."; RL G3 (Bethesda) 4:389-398(2014). RN [4] RP PROTEIN SEQUENCE OF 35-74, CATALYTIC ACTIVITY, SUBCELLULAR LOCATION, RP SUBUNIT, AND PATHWAY. RX PubMed=3528153; DOI=10.1016/s0021-9258(18)67234-5; RA Shannon K.W., Rabinowitz J.C.; RT "Purification and characterization of a mitochondrial isozyme of C1- RT tetrahydrofolate synthase from Saccharomyces cerevisiae."; RL J. Biol. Chem. 261:12266-12271(1986). RN [5] RP SUBCELLULAR LOCATION [LARGE SCALE ANALYSIS]. RX PubMed=14562095; DOI=10.1038/nature02026; RA Huh W.-K., Falvo J.V., Gerke L.C., Carroll A.S., Howson R.W., RA Weissman J.S., O'Shea E.K.; RT "Global analysis of protein localization in budding yeast."; RL Nature 425:686-691(2003). RN [6] RP LEVEL OF PROTEIN EXPRESSION [LARGE SCALE ANALYSIS]. RX PubMed=14562106; DOI=10.1038/nature02046; RA Ghaemmaghami S., Huh W.-K., Bower K., Howson R.W., Belle A., Dephoure N., RA O'Shea E.K., Weissman J.S.; RT "Global analysis of protein expression in yeast."; RL Nature 425:737-741(2003). RN [7] RP SUBCELLULAR LOCATION [LARGE SCALE ANALYSIS]. RC STRAIN=ATCC 76625 / YPH499; RX PubMed=14576278; DOI=10.1073/pnas.2135385100; RA Sickmann A., Reinders J., Wagner Y., Joppich C., Zahedi R.P., Meyer H.E., RA Schoenfisch B., Perschil I., Chacinska A., Guiard B., Rehling P., RA Pfanner N., Meisinger C.; RT "The proteome of Saccharomyces cerevisiae mitochondria."; RL Proc. Natl. Acad. Sci. U.S.A. 100:13207-13212(2003). CC -!- FUNCTION: Mitochondrial isozyme of C-1-tetrahydrofolate synthase. The CC trifunctional enzyme catalyzes the interconversion of the one-carbon CC derivatives of tetrahydrofolate (THF) between different oxidation CC states by the enzymatic activities 10-formyltetrahydrofolate CC synthetase, 5,lO-methenyltetrahydrofolate cyclohydrolase, and 5,lO- CC methylenetetrahydrofolate dehydrogenase. {ECO:0000269|PubMed:3528153}. 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; Evidence={ECO:0000269|PubMed:3528153}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:22813; CC Evidence={ECO:0000305|PubMed:3528153}; CC PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:22814; CC Evidence={ECO:0000305|PubMed:3528153}; 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:0000269|PubMed:3528153}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:23701; CC Evidence={ECO:0000305|PubMed:3528153}; CC PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:23702; CC Evidence={ECO:0000305|PubMed:3528153}; 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:0000269|PubMed:3528153}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:20222; CC Evidence={ECO:0000305|PubMed:3528153}; CC PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:20223; CC Evidence={ECO:0000305|PubMed:3528153}; CC -!- PATHWAY: One-carbon metabolism; tetrahydrofolate interconversion. CC {ECO:0000305|PubMed:3528153}. CC -!- SUBUNIT: Homodimer. {ECO:0000269|PubMed:3528153}. CC -!- SUBCELLULAR LOCATION: Mitochondrion {ECO:0000269|PubMed:14562095, CC ECO:0000269|PubMed:14576278, ECO:0000269|PubMed:3528153}. CC -!- DOMAIN: This trifunctional enzyme consists of two major domains: an N- CC terminal part containing the methylene-THF dehydrogenase and CC cyclohydrolase activities and a larger C-terminal part containing CC formyl-THF synthetase activity. {ECO:0000250|UniProtKB:P07245}. CC -!- MISCELLANEOUS: Present with 11400 molecules/cell in log phase SD CC medium. {ECO:0000269|PubMed:14562106}. 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; Z35953; CAA85029.1; -; Genomic_DNA. DR EMBL; J03724; AAA34781.1; -; Genomic_DNA. DR EMBL; BK006936; DAA07203.1; -; Genomic_DNA. DR PIR; A28174; A28174. DR RefSeq; NP_009640.1; NM_001178432.1. DR AlphaFoldDB; P09440; -. DR SMR; P09440; -. DR BioGRID; 32788; 343. DR DIP; DIP-6724N; -. DR IntAct; P09440; 51. DR MINT; P09440; -. DR STRING; 4932.YBR084W; -. DR iPTMnet; P09440; -. DR MaxQB; P09440; -. DR PaxDb; 4932-YBR084W; -. DR PeptideAtlas; P09440; -. DR EnsemblFungi; YBR084W_mRNA; YBR084W; YBR084W. DR GeneID; 852378; -. DR KEGG; sce:YBR084W; -. DR AGR; SGD:S000000288; -. DR SGD; S000000288; MIS1. DR VEuPathDB; FungiDB:YBR084W; -. DR eggNOG; KOG4230; Eukaryota. DR GeneTree; ENSGT01000000220033; -. DR HOGENOM; CLU_003601_2_0_1; -. DR InParanoid; P09440; -. DR OMA; IKRVVDC; -. DR OrthoDB; 651667at2759; -. DR BioCyc; YEAST:YBR084W-MONOMER; -. DR BRENDA; 3.5.4.9; 984. DR BRENDA; 6.3.4.3; 984. DR Reactome; R-SCE-196757; Metabolism of folate and pterines. DR UniPathway; UPA00193; -. DR BioGRID-ORCS; 852378; 0 hits in 10 CRISPR screens. DR PRO; PR:P09440; -. DR Proteomes; UP000002311; Chromosome II. DR RNAct; P09440; Protein. DR GO; GO:0005829; C:cytosol; IBA:GO_Central. DR GO; GO:0005739; C:mitochondrion; IDA:SGD. DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW. DR GO; GO:0004329; F:formate-tetrahydrofolate ligase activity; IDA:SGD. DR GO; GO:0004477; F:methenyltetrahydrofolate cyclohydrolase activity; IDA:SGD. DR GO; GO:0004488; F:methylenetetrahydrofolate dehydrogenase (NADP+) activity; IDA:SGD. DR GO; GO:0046656; P:folic acid biosynthetic process; IDA:SGD. DR GO; GO:0006139; P:nucleobase-containing compound metabolic process; IMP:SGD. DR GO; GO:0035999; P:tetrahydrofolate interconversion; IBA:GO_Central. 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:SF5; 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 ATP-binding; Direct protein sequencing; Hydrolase; Ligase; Mitochondrion; KW Multifunctional enzyme; NADP; Nucleotide-binding; One-carbon metabolism; KW Oxidoreductase; Reference proteome; Transit peptide. FT TRANSIT 1..34 FT /note="Mitochondrion" FT /evidence="ECO:0000269|PubMed:3528153" FT CHAIN 35..975 FT /note="C-1-tetrahydrofolate synthase, mitochondrial" FT /id="PRO_0000034052" FT REGION 35..343 FT /note="Methylenetetrahydrofolate dehydrogenase and FT cyclohydrolase" FT /evidence="ECO:0000250|UniProtKB:P07245" FT REGION 344..975 FT /note="Formyltetrahydrofolate synthetase" FT /evidence="ECO:0000250|UniProtKB:P07245" FT BINDING 83..87 FT /ligand="substrate" FT /evidence="ECO:0000250|UniProtKB:P11586" FT BINDING 130..132 FT /ligand="substrate" FT /evidence="ECO:0000250|UniProtKB:P11586" FT BINDING 201..203 FT /ligand="NADP(+)" FT /ligand_id="ChEBI:CHEBI:58349" FT /evidence="ECO:0000250|UniProtKB:P11586" FT BINDING 226 FT /ligand="NADP(+)" FT /ligand_id="ChEBI:CHEBI:58349" FT /evidence="ECO:0000250|UniProtKB:P11586" FT BINDING 301..305 FT /ligand="substrate" FT /evidence="ECO:0000250|UniProtKB:P11586" FT BINDING 408..415 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" SQ SEQUENCE 975 AA; 106217 MW; B9421D4F8981531F CRC64; MLSRLSLLSN SRAFQQARWR IYRLKVSPTV HASQYHILSG RKLAQSIREK ANDEIQAIKL KHPNFKPTLK IIQVGARPDS STYVRMKLKA SKDSNVDCII EKLPAEITEV ELLKKISDIN DDDSIHGLLI QLPLPRHLDE TTITNAVDFK KDVDGFHRYN AGELAKKGGK PYFIPCTPYG CMKLLEEAHV KLDGKNAVVL GRSSIVGNPI ASLLKNANAT VTVCHSHTRN IAEVVSQADI VIAACGIPQY VKSDWIKEGA VVIDVGINYV PDISKKSGQK LVGDVDFDSV KEKTSYITPV PGGVGPMTVA MLVSNVLLAA KRQFVESEKL PVIKPLPLHL ESPVPSDIDI SRAQSPKHIK QVAEELGIHS HELELYGHYK AKISPNIFKR LESRENGKYV LVAGITPTPL GEGKSTTTMG LVQALSAHLG KPSIANVRQP SLGPTLGVKG GAAGGGYAQV IPMDEFNLHL TGDIHAISAA NNLLAAAIDT RMFHEATQKN DSTFYKRLVP RKKGIRKFTP SMQRRLKRLD IEKEDPDALT PEEVKRFARL NINPDTITIR RVVDINDRML RQITIGEAAT EKGFTRTTGF DITVASELMA ILALSKSLHE MKERIGRMVI GADYDNKPVT VEDIGCTGAL TALLRDAIKP NLMQTLEGTP VMVHAGPFAN ISIGASSVIA DLMALKLVGS EKNPLNDKNI HEPGYVVTEA GFDFAMGGER FFDIKCRSSG LVPDAVVLVA TVRALKSHGG APNVKPGQSL PKEYTEENID FVAKGVSNLV KQIENIKTFG IPVVVAINRF ETDSQAEIEV IKKAALNAGA SHAVTSNHWM EGGKGAVELA HAVVDATKEP KNFNFLYDVN SSIEDKLTSI VQKMYGGAKI EVSPEAQKKI DTYKKQGFGN LPICIAKTQY SLSHDPSLKG VPRGFTFPIR DVRASIGAGY LYALAAEIQT IPGLSTYAGY MAVEVDDDGE IEGLF //