ID   C1TM_SCHPO              Reviewed;         972 AA.
AC   O43007;
DT   15-JAN-2008, integrated into UniProtKB/Swiss-Prot.
DT   03-OCT-2012, sequence version 3.
DT   27-MAR-2024, entry version 141.
DE   RecName: Full=C-1-tetrahydrofolate synthase, mitochondrial;
DE            Short=C1-THF synthase;
DE   Includes:
DE     RecName: Full=Methylenetetrahydrofolate dehydrogenase;
DE              EC=1.5.1.5;
DE   Includes:
DE     RecName: Full=Methenyltetrahydrofolate cyclohydrolase;
DE              EC=3.5.4.9;
DE   Includes:
DE     RecName: Full=Formyltetrahydrofolate synthetase;
DE              EC=6.3.4.3;
DE   Flags: Precursor;
GN   Name=ade9; ORFNames=SPBC2G2.08;
OS   Schizosaccharomyces pombe (strain 972 / ATCC 24843) (Fission yeast).
OC   Eukaryota; Fungi; Dikarya; Ascomycota; Taphrinomycotina;
OC   Schizosaccharomycetes; Schizosaccharomycetales; Schizosaccharomycetaceae;
OC   Schizosaccharomyces.
OX   NCBI_TaxID=284812;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC   STRAIN=972 / ATCC 24843;
RX   PubMed=11859360; DOI=10.1038/nature724;
RA   Wood V., Gwilliam R., Rajandream M.A., Lyne M.H., Lyne R., Stewart A.,
RA   Sgouros J.G., Peat N., Hayles J., Baker S.G., Basham D., Bowman S.,
RA   Brooks K., Brown D., Brown S., Chillingworth T., Churcher C.M., Collins M.,
RA   Connor R., Cronin A., Davis P., Feltwell T., Fraser A., Gentles S.,
RA   Goble A., Hamlin N., Harris D.E., Hidalgo J., Hodgson G., Holroyd S.,
RA   Hornsby T., Howarth S., Huckle E.J., Hunt S., Jagels K., James K.D.,
RA   Jones L., Jones M., Leather S., McDonald S., McLean J., Mooney P.,
RA   Moule S., Mungall K.L., Murphy L.D., Niblett D., Odell C., Oliver K.,
RA   O'Neil S., Pearson D., Quail M.A., Rabbinowitsch E., Rutherford K.M.,
RA   Rutter S., Saunders D., Seeger K., Sharp S., Skelton J., Simmonds M.N.,
RA   Squares R., Squares S., Stevens K., Taylor K., Taylor R.G., Tivey A.,
RA   Walsh S.V., Warren T., Whitehead S., Woodward J.R., Volckaert G., Aert R.,
RA   Robben J., Grymonprez B., Weltjens I., Vanstreels E., Rieger M.,
RA   Schaefer M., Mueller-Auer S., Gabel C., Fuchs M., Duesterhoeft A.,
RA   Fritzc C., Holzer E., Moestl D., Hilbert H., Borzym K., Langer I., Beck A.,
RA   Lehrach H., Reinhardt R., Pohl T.M., Eger P., Zimmermann W., Wedler H.,
RA   Wambutt R., Purnelle B., Goffeau A., Cadieu E., Dreano S., Gloux S.,
RA   Lelaure V., Mottier S., Galibert F., Aves S.J., Xiang Z., Hunt C.,
RA   Moore K., Hurst S.M., Lucas M., Rochet M., Gaillardin C., Tallada V.A.,
RA   Garzon A., Thode G., Daga R.R., Cruzado L., Jimenez J., Sanchez M.,
RA   del Rey F., Benito J., Dominguez A., Revuelta J.L., Moreno S.,
RA   Armstrong J., Forsburg S.L., Cerutti L., Lowe T., McCombie W.R.,
RA   Paulsen I., Potashkin J., Shpakovski G.V., Ussery D., Barrell B.G.,
RA   Nurse P.;
RT   "The genome sequence of Schizosaccharomyces pombe.";
RL   Nature 415:871-880(2002).
RN   [2]
RP   REVISION OF GENE MODEL.
RX   PubMed=21511999; DOI=10.1126/science.1203357;
RA   Rhind N., Chen Z., Yassour M., Thompson D.A., Haas B.J., Habib N.,
RA   Wapinski I., Roy S., Lin M.F., Heiman D.I., Young S.K., Furuya K., Guo Y.,
RA   Pidoux A., Chen H.M., Robbertse B., Goldberg J.M., Aoki K., Bayne E.H.,
RA   Berlin A.M., Desjardins C.A., Dobbs E., Dukaj L., Fan L., FitzGerald M.G.,
RA   French C., Gujja S., Hansen K., Keifenheim D., Levin J.Z., Mosher R.A.,
RA   Mueller C.A., Pfiffner J., Priest M., Russ C., Smialowska A., Swoboda P.,
RA   Sykes S.M., Vaughn M., Vengrova S., Yoder R., Zeng Q., Allshire R.,
RA   Baulcombe D., Birren B.W., Brown W., Ekwall K., Kellis M., Leatherwood J.,
RA   Levin H., Margalit H., Martienssen R., Nieduszynski C.A., Spatafora J.W.,
RA   Friedman N., Dalgaard J.Z., Baumann P., Niki H., Regev A., Nusbaum C.;
RT   "Comparative functional genomics of the fission yeasts.";
RL   Science 332:930-936(2011).
RN   [3]
RP   SUBCELLULAR LOCATION [LARGE SCALE ANALYSIS].
RX   PubMed=16823372; DOI=10.1038/nbt1222;
RA   Matsuyama A., Arai R., Yashiroda Y., Shirai A., Kamata A., Sekido S.,
RA   Kobayashi Y., Hashimoto A., Hamamoto M., Hiraoka Y., Horinouchi S.,
RA   Yoshida M.;
RT   "ORFeome cloning and global analysis of protein localization in the fission
RT   yeast Schizosaccharomyces pombe.";
RL   Nat. Biotechnol. 24:841-847(2006).
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.
CC       {ECO:0000250|UniProtKB:P09440}.
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:P09440};
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:P09440};
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:P09440};
CC   -!- PATHWAY: One-carbon metabolism; tetrahydrofolate interconversion.
CC   -!- SUBUNIT: Homodimer. {ECO:0000250|UniProtKB:P09440}.
CC   -!- SUBCELLULAR LOCATION: Mitochondrion {ECO:0000269|PubMed:16823372}.
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.
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; CU329671; CAA17888.3; -; Genomic_DNA.
DR   PIR; T40147; T40147.
DR   RefSeq; NP_596437.2; NM_001022356.2.
DR   AlphaFoldDB; O43007; -.
DR   SMR; O43007; -.
DR   BioGRID; 276831; 4.
DR   STRING; 284812.O43007; -.
DR   MaxQB; O43007; -.
DR   PaxDb; 4896-SPBC2G2-08-1; -.
DR   EnsemblFungi; SPBC2G2.08.1; SPBC2G2.08.1:pep; SPBC2G2.08.
DR   GeneID; 2540300; -.
DR   KEGG; spo:SPBC2G2.08; -.
DR   PomBase; SPBC2G2.08; ade9.
DR   VEuPathDB; FungiDB:SPBC2G2.08; -.
DR   eggNOG; KOG4230; Eukaryota.
DR   HOGENOM; CLU_003601_2_0_1; -.
DR   InParanoid; O43007; -.
DR   OMA; IKRVVDC; -.
DR   Reactome; R-SPO-196757; Metabolism of folate and pterines.
DR   UniPathway; UPA00193; -.
DR   PRO; PR:O43007; -.
DR   Proteomes; UP000002485; Chromosome II.
DR   GO; GO:0005829; C:cytosol; IBA:GO_Central.
DR   GO; GO:0005739; C:mitochondrion; HDA:PomBase.
DR   GO; GO:0005524; F:ATP binding; ISM:PomBase.
DR   GO; GO:0004329; F:formate-tetrahydrofolate ligase activity; ISS:PomBase.
DR   GO; GO:0004477; F:methenyltetrahydrofolate cyclohydrolase activity; IBA:GO_Central.
DR   GO; GO:0004488; F:methylenetetrahydrofolate dehydrogenase (NADP+) activity; IBA:GO_Central.
DR   GO; GO:0009257; P:10-formyltetrahydrofolate biosynthetic process; ISS:PomBase.
DR   GO; GO:0046656; P:folic acid biosynthetic process; ISO:PomBase.
DR   GO; GO:0009113; P:purine nucleobase biosynthetic process; ISO:PomBase.
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; 3.10.410.10; 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; C-1-TETRAHYDROFOLATE SYNTHASE, CYTOPLASMIC-RELATED; 1.
DR   PANTHER; PTHR48099:SF26; C-1-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; PS00767; THF_DHG_CYH_2; 1.
PE   3: Inferred from homology;
KW   ATP-binding; Hydrolase; Ligase; Mitochondrion; Multifunctional enzyme;
KW   NADP; Nucleotide-binding; One-carbon metabolism; Oxidoreductase;
KW   Reference proteome; Transit peptide.
FT   TRANSIT         1..55
FT                   /note="Mitochondrion"
FT                   /evidence="ECO:0000255"
FT   CHAIN           56..972
FT                   /note="C-1-tetrahydrofolate synthase, mitochondrial"
FT                   /id="PRO_0000315627"
FT   REGION          56..340
FT                   /note="Methylenetetrahydrofolate dehydrogenase and
FT                   cyclohydrolase"
FT   REGION          341..972
FT                   /note="Formyltetrahydrofolate synthetase"
FT   BINDING         84..88
FT                   /ligand="substrate"
FT                   /evidence="ECO:0000250|UniProtKB:P11586"
FT   BINDING         131..133
FT                   /ligand="substrate"
FT                   /evidence="ECO:0000250|UniProtKB:P11586"
FT   BINDING         202..204
FT                   /ligand="NADP(+)"
FT                   /ligand_id="ChEBI:CHEBI:58349"
FT                   /evidence="ECO:0000250|UniProtKB:P11586"
FT   BINDING         227
FT                   /ligand="NADP(+)"
FT                   /ligand_id="ChEBI:CHEBI:58349"
FT                   /evidence="ECO:0000250|UniProtKB:P11586"
FT   BINDING         299..303
FT                   /ligand="substrate"
FT                   /evidence="ECO:0000250|UniProtKB:P11586"
FT   BINDING         405..412
FT                   /ligand="ATP"
FT                   /ligand_id="ChEBI:CHEBI:30616"
SQ   SEQUENCE   972 AA;  105757 MW;  A14DFE32C0106F20 CRC64;
     MNVMVSFNQL RNYFLESNSL RPSKWLFQSY GTSSSANILN GKLLARKLQR SVAEEVQALK
     AKDRNFKPAL AIVQVGKRED SNVYVRMKEK AARLVGIDFK YCPFPETIQM PALLHELKKL
     NDDHTVHGVL VQLPLPKHLN ERTVTESITP PKDVDGFGAF NIGLLAKNDA TPIHYPCTPK
     GIMELLKDNK ISVAGLNAVV LGRSDIVGNP ISYLLRKDNA TVTVCHSKTK DLIQHISNAD
     LVIAALGKPE FVRGEWLKPG SVVVDVGINA VQRNGKRVLV GDVHFESASK VASSITPVPG
     GVGPMTVAML MENIVNAAKI ARTENIYRKI DLNPLELKKP VPSDIEIANS QEPKLISNLA
     KEMGIYDTEL ENYGNYKAKV NLAVYERLKH RKDGNYVVVS GITPTPFGEG KSTVVAGLVQ
     AMGHLGKLGI ACVRQPSQGP TFGVKGGAAG GGYAQFIPMD DFNLHMTGDI HAVTAANNLL
     VAALETRMFH ENTQSDAALI KRLIPVKNGR RVIPRGLIGR WNRICASHNM DPEDVNNASP
     ELLKEFVRLN VDPDTIECNR VLDVNDRFLR SIEVGKASTE KGHVRKTSFD ISVASECMSI
     LALSCDLNDM HSRLSRMVIA NDKYGNAITA GDLGVSGALT VLLKDAIKPN LMQTLEGTPA
     FVHAGPFANI SIGASSIIAD KIALKLAGTE SFDRPEDAGY VVTEAGFASD MGMEKFFNIK
     CRYSKLVPNT VVLVTTVKAL KLHGGGPKLK PGAPIPEEYL VENLDLVKNG CSNMVKHIQN
     CHKFNIPVVV AINSYKTDSS KEHEIIREAA LQAGAVDAVP SDHWAQGGKG AIELAKSVMT
     ACDQSSNSKF RLLYDSETSI EDKVNVIAKE MYGANGVEFS SLAKERINTF IKQGFGNLPI
     CMAKTQYSLS HNPEFRNVPK NFTVPIRDMR LNAGAGFIYP LAAEIQTIPG LPTAPAYLNI
     DICENGEIVG LS
//