C1TC_DROME
ID C1TC_DROME Reviewed; 968 AA.
AC O96553; A4V2N7; A4V2N9; Q5BIE6; Q8T0P2;
DT 19-SEP-2003, integrated into UniProtKB/Swiss-Prot.
DT 19-JUL-2004, sequence version 4.
DT 03-AUG-2022, entry version 166.
DE RecName: Full=C-1-tetrahydrofolate synthase, cytoplasmic;
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;
GN Name=pug; ORFNames=CG4067;
OS Drosophila melanogaster (Fruit fly).
OC Eukaryota; Metazoa; Ecdysozoa; Arthropoda; Hexapoda; Insecta; Pterygota;
OC Neoptera; Endopterygota; Diptera; Brachycera; Muscomorpha; Ephydroidea;
OC Drosophilidae; Drosophila; Sophophora.
OX NCBI_TaxID=7227;
RN [1] {ECO:0000305}
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND TISSUE SPECIFICITY.
RX PubMed=9832531; DOI=10.1093/genetics/150.4.1551;
RA Rong Y.S., Golic K.G.;
RT "Dominant defects in Drosophila eye pigmentation resulting from a
RT euchromatin-heterochromatin fusion gene.";
RL Genetics 150:1551-1566(1998).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=Berkeley {ECO:0000269|PubMed:10731132};
RX PubMed=10731132; DOI=10.1126/science.287.5461.2185;
RA Adams M.D., Celniker S.E., Holt R.A., Evans C.A., Gocayne J.D.,
RA Amanatides P.G., Scherer S.E., Li P.W., Hoskins R.A., Galle R.F.,
RA George R.A., Lewis S.E., Richards S., Ashburner M., Henderson S.N.,
RA Sutton G.G., Wortman J.R., Yandell M.D., Zhang Q., Chen L.X., Brandon R.C.,
RA Rogers Y.-H.C., Blazej R.G., Champe M., Pfeiffer B.D., Wan K.H., Doyle C.,
RA Baxter E.G., Helt G., Nelson C.R., Miklos G.L.G., Abril J.F., Agbayani A.,
RA An H.-J., Andrews-Pfannkoch C., Baldwin D., Ballew R.M., Basu A.,
RA Baxendale J., Bayraktaroglu L., Beasley E.M., Beeson K.Y., Benos P.V.,
RA Berman B.P., Bhandari D., Bolshakov S., Borkova D., Botchan M.R., Bouck J.,
RA Brokstein P., Brottier P., Burtis K.C., Busam D.A., Butler H., Cadieu E.,
RA Center A., Chandra I., Cherry J.M., Cawley S., Dahlke C., Davenport L.B.,
RA Davies P., de Pablos B., Delcher A., Deng Z., Mays A.D., Dew I.,
RA Dietz S.M., Dodson K., Doup L.E., Downes M., Dugan-Rocha S., Dunkov B.C.,
RA Dunn P., Durbin K.J., Evangelista C.C., Ferraz C., Ferriera S.,
RA Fleischmann W., Fosler C., Gabrielian A.E., Garg N.S., Gelbart W.M.,
RA Glasser K., Glodek A., Gong F., Gorrell J.H., Gu Z., Guan P., Harris M.,
RA Harris N.L., Harvey D.A., Heiman T.J., Hernandez J.R., Houck J., Hostin D.,
RA Houston K.A., Howland T.J., Wei M.-H., Ibegwam C., Jalali M., Kalush F.,
RA Karpen G.H., Ke Z., Kennison J.A., Ketchum K.A., Kimmel B.E., Kodira C.D.,
RA Kraft C.L., Kravitz S., Kulp D., Lai Z., Lasko P., Lei Y., Levitsky A.A.,
RA Li J.H., Li Z., Liang Y., Lin X., Liu X., Mattei B., McIntosh T.C.,
RA McLeod M.P., McPherson D., Merkulov G., Milshina N.V., Mobarry C.,
RA Morris J., Moshrefi A., Mount S.M., Moy M., Murphy B., Murphy L.,
RA Muzny D.M., Nelson D.L., Nelson D.R., Nelson K.A., Nixon K., Nusskern D.R.,
RA Pacleb J.M., Palazzolo M., Pittman G.S., Pan S., Pollard J., Puri V.,
RA Reese M.G., Reinert K., Remington K., Saunders R.D.C., Scheeler F.,
RA Shen H., Shue B.C., Siden-Kiamos I., Simpson M., Skupski M.P., Smith T.J.,
RA Spier E., Spradling A.C., Stapleton M., Strong R., Sun E., Svirskas R.,
RA Tector C., Turner R., Venter E., Wang A.H., Wang X., Wang Z.-Y.,
RA Wassarman D.A., Weinstock G.M., Weissenbach J., Williams S.M., Woodage T.,
RA Worley K.C., Wu D., Yang S., Yao Q.A., Ye J., Yeh R.-F., Zaveri J.S.,
RA Zhan M., Zhang G., Zhao Q., Zheng L., Zheng X.H., Zhong F.N., Zhong W.,
RA Zhou X., Zhu S.C., Zhu X., Smith H.O., Gibbs R.A., Myers E.W., Rubin G.M.,
RA Venter J.C.;
RT "The genome sequence of Drosophila melanogaster.";
RL Science 287:2185-2195(2000).
RN [3]
RP GENOME REANNOTATION, AND ALTERNATIVE SPLICING.
RC STRAIN=Berkeley;
RX PubMed=12537572; DOI=10.1186/gb-2002-3-12-research0083;
RA Misra S., Crosby M.A., Mungall C.J., Matthews B.B., Campbell K.S.,
RA Hradecky P., Huang Y., Kaminker J.S., Millburn G.H., Prochnik S.E.,
RA Smith C.D., Tupy J.L., Whitfield E.J., Bayraktaroglu L., Berman B.P.,
RA Bettencourt B.R., Celniker S.E., de Grey A.D.N.J., Drysdale R.A.,
RA Harris N.L., Richter J., Russo S., Schroeder A.J., Shu S.Q., Stapleton M.,
RA Yamada C., Ashburner M., Gelbart W.M., Rubin G.M., Lewis S.E.;
RT "Annotation of the Drosophila melanogaster euchromatic genome: a systematic
RT review.";
RL Genome Biol. 3:RESEARCH0083.1-RESEARCH0083.22(2002).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM A).
RC STRAIN=Berkeley; TISSUE=Embryo;
RA Stapleton M., Carlson J.W., Chavez C., Frise E., George R.A., Pacleb J.M.,
RA Park S., Wan K.H., Yu C., Rubin G.M., Celniker S.E.;
RL Submitted (MAR-2005) to the EMBL/GenBank/DDBJ databases.
RN [5] {ECO:0000305}
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 604-968.
RC STRAIN=Berkeley {ECO:0000269|PubMed:12537569};
RC TISSUE=Head {ECO:0000269|PubMed:12537569};
RX PubMed=12537569; DOI=10.1186/gb-2002-3-12-research0080;
RA Stapleton M., Carlson J.W., Brokstein P., Yu C., Champe M., George R.A.,
RA Guarin H., Kronmiller B., Pacleb J.M., Park S., Wan K.H., Rubin G.M.,
RA Celniker S.E.;
RT "A Drosophila full-length cDNA resource.";
RL Genome Biol. 3:RESEARCH0080.1-RESEARCH0080.8(2002).
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 -!- SUBUNIT: Homodimer. {ECO:0000250|UniProtKB:P11586}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=B; Synonyms=D;
CC IsoId=O96553-1; Sequence=Displayed;
CC Name=A; Synonyms=C;
CC IsoId=O96553-2; Sequence=VSP_010883;
CC -!- TISSUE SPECIFICITY: Present in all tissues.
CC {ECO:0000269|PubMed:9832531}.
CC -!- DOMAIN: This trifunctional enzyme consists of two major domains: a N-
CC terminal part, containing the methylene-THF dehydrogenase and the
CC methenyl-THF cyclohydrolase activities and a larger formyl-THF
CC synthetase domain.
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}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAL39291.1; Type=Erroneous initiation; Evidence={ECO:0000305};
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DR EMBL; AF082097; AAC78847.1; -; Genomic_DNA.
DR EMBL; AE014297; AAG22140.2; -; Genomic_DNA.
DR EMBL; AE014297; AAN13478.1; -; Genomic_DNA.
DR EMBL; AE014297; AAN13479.1; -; Genomic_DNA.
DR EMBL; AE014297; AAX52944.1; -; Genomic_DNA.
DR EMBL; BT021278; AAX33426.1; -; mRNA.
DR EMBL; AY069146; AAL39291.1; ALT_INIT; mRNA.
DR RefSeq; NP_001014614.1; NM_001014614.2. [O96553-1]
DR RefSeq; NP_477254.1; NM_057906.4. [O96553-2]
DR RefSeq; NP_731489.2; NM_169350.3. [O96553-1]
DR RefSeq; NP_731490.1; NM_169351.2. [O96553-2]
DR AlphaFoldDB; O96553; -.
DR SMR; O96553; -.
DR BioGRID; 66423; 2.
DR IntAct; O96553; 4.
DR STRING; 7227.FBpp0081741; -.
DR PaxDb; O96553; -.
DR DNASU; 41279; -.
DR EnsemblMetazoa; FBtr0082264; FBpp0081741; FBgn0020385. [O96553-1]
DR EnsemblMetazoa; FBtr0082265; FBpp0081742; FBgn0020385. [O96553-2]
DR EnsemblMetazoa; FBtr0082266; FBpp0081743; FBgn0020385. [O96553-2]
DR EnsemblMetazoa; FBtr0100144; FBpp0099494; FBgn0020385. [O96553-1]
DR GeneID; 41279; -.
DR KEGG; dme:Dmel_CG4067; -.
DR UCSC; CG4067-RA; d. melanogaster. [O96553-1]
DR CTD; 41279; -.
DR FlyBase; FBgn0020385; pug.
DR VEuPathDB; VectorBase:FBgn0020385; -.
DR eggNOG; KOG4230; Eukaryota.
DR GeneTree; ENSGT00940000167165; -.
DR InParanoid; O96553; -.
DR PhylomeDB; O96553; -.
DR Reactome; R-DME-196757; Metabolism of folate and pterines.
DR SignaLink; O96553; -.
DR UniPathway; UPA00193; -.
DR BioGRID-ORCS; 41279; 0 hits in 3 CRISPR screens.
DR GenomeRNAi; 41279; -.
DR PRO; PR:O96553; -.
DR Proteomes; UP000000803; Chromosome 3R.
DR Bgee; FBgn0020385; Expressed in head capsule and 34 other tissues.
DR ExpressionAtlas; O96553; baseline and differential.
DR Genevisible; O96553; DM.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
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; NAS:UniProtKB.
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:0008652; P:cellular amino acid biosynthetic process; NAS: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; IEA:UniProtKB-KW.
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; 3.40.50.300; -; 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 2: Evidence at transcript level;
KW Alternative splicing; Amino-acid biosynthesis; ATP-binding; Cytoplasm;
KW Histidine biosynthesis; Hydrolase; Ligase; Methionine biosynthesis;
KW Multifunctional enzyme; NADP; Nucleotide-binding; One-carbon metabolism;
KW Oxidoreductase; Purine biosynthesis; Reference proteome.
FT CHAIN 1..968
FT /note="C-1-tetrahydrofolate synthase, cytoplasmic"
FT /id="PRO_0000199324"
FT REGION 1..338
FT /note="Methylenetetrahydrofolate dehydrogenase and
FT cyclohydrolase"
FT REGION 339..968
FT /note="Formyltetrahydrofolate synthetase"
FT BINDING 86..90
FT /ligand="substrate"
FT /evidence="ECO:0000250"
FT BINDING 133..135
FT /ligand="substrate"
FT /evidence="ECO:0000250"
FT BINDING 205..207
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250"
FT BINDING 230
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250"
FT BINDING 305..309
FT /ligand="substrate"
FT /evidence="ECO:0000250"
FT BINDING 413..420
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250"
FT VAR_SEQ 1..34
FT /note="Missing (in isoform A)"
FT /evidence="ECO:0000303|Ref.4"
FT /id="VSP_010883"
FT CONFLICT 879
FT /note="E -> K (in Ref. 4; AAX33426)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 968 AA; 103504 MW; D65EC8455DD8AF2C CRC64;
MSAQYQRFLK VLEKWPAEKS KVGSGEWTAE PAIKMSGAKI ISGTAVAKSI REELRNEVTA
MSKQLADFVP GLRIVQVGGR EDSNVYIRMK IKAATEIGID AAHVQLPRSI TEVELLDKIN
DLNEDPRVHG IIVQMPLDCD TPIDSHRITD AVSPEKDVDG LHTVNEGRLA IGDLGGFLPC
TPWGCLELIR RSGVEIAGAR AVVLGRSKIV GTPAAELLKW ANATVTVCHS KTRNLEEITR
SADILVVGIG VAEMVKGSWI KPGAVVIDCG INVKPDASKA SGSKLVGDVD YAEALQVAGH
LTPVPGGVGP MTVAMLMKNT VRSAARFLER LAKSQWALQT LPLKPQRPVP SDIVIARAQK
PKDIAVLAKE IGLEAREVSL YGNKKAKISL SVLERLKDKE VGHYVVVAGM TPTPLGEGKT
TTLMGLVQAL GAHKLRNTMA ALRQPSQGPT FGIKGGAAGG GYAQVIPMEE FNLHLTGDIH
AVSAANNLLA AQLDTRIFHE NTQKDKALYD RLVPAIKGQR KFSPIQLRRL QKLGITKTDP
DTLTADEYGP FARLDIDPDT IMWERVVDIN DRYLRTITVG QSPTEKGISR ETRFSISVAS
EIMAVLALSR SLEDMKQRLA DMVVAFDKRG KPVTADDLGV TGALAVLLKD ALEPNLMQSL
EGTPVLVHAG PFANIAHGCN SIIADEVGLK LVGKNGFVCT EAGFGSDIGM EKFCNIKCRT
SGRKPNAMVL VATVRAIKMH GGGAPVTPGA PLNKQYTEEN LELVQKGLPN LLQHIENGKA
FGMPVVVSLN AHSADTPAEH ELVKKAALEA GAFAAVVSTH WADGGAGAVQ LADAVIKACE
QGNQFRLLYD LELPLVDKMN KIATTMYGAG KVVLSPAAEE KVKRLTDAGF GNLPICMSKV
SGSFTGDAKI KGAPKGFTLD VEDVYVSAGA GFVVAMCGEV TKMPGLPTRP AIYDIDLNTE
TGEIEGLF
