ID   MTHR1_YEAST             Reviewed;         657 AA.
AC   P46151; D6W3Y9;
DT   01-NOV-1995, integrated into UniProtKB/Swiss-Prot.
DT   01-OCT-1996, sequence version 2.
DT   27-MAR-2024, entry version 187.
DE   RecName: Full=Methylenetetrahydrofolate reductase 1;
DE            EC=1.5.1.20;
GN   Name=MET12; OrderedLocusNames=YPL023C; ORFNames=LPB8C;
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 [LARGE SCALE GENOMIC DNA].
RC   STRAIN=ATCC 204508 / S288c;
RX   PubMed=9169875;
RA   Bussey H., Storms R.K., Ahmed A., Albermann K., Allen E., Ansorge W.,
RA   Araujo R., Aparicio A., Barrell B.G., Badcock K., Benes V., Botstein D.,
RA   Bowman S., Brueckner M., Carpenter J., Cherry J.M., Chung E.,
RA   Churcher C.M., Coster F., Davis K., Davis R.W., Dietrich F.S., Delius H.,
RA   DiPaolo T., Dubois E., Duesterhoeft A., Duncan M., Floeth M., Fortin N.,
RA   Friesen J.D., Fritz C., Goffeau A., Hall J., Hebling U., Heumann K.,
RA   Hilbert H., Hillier L.W., Hunicke-Smith S., Hyman R.W., Johnston M.,
RA   Kalman S., Kleine K., Komp C., Kurdi O., Lashkari D., Lew H., Lin A.,
RA   Lin D., Louis E.J., Marathe R., Messenguy F., Mewes H.-W., Mirtipati S.,
RA   Moestl D., Mueller-Auer S., Namath A., Nentwich U., Oefner P., Pearson D.,
RA   Petel F.X., Pohl T.M., Purnelle B., Rajandream M.A., Rechmann S.,
RA   Rieger M., Riles L., Roberts D., Schaefer M., Scharfe M., Scherens B.,
RA   Schramm S., Schroeder M., Sdicu A.-M., Tettelin H., Urrestarazu L.A.,
RA   Ushinsky S., Vierendeels F., Vissers S., Voss H., Walsh S.V., Wambutt R.,
RA   Wang Y., Wedler E., Wedler H., Winnett E., Zhong W.-W., Zollner A.,
RA   Vo D.H., Hani J.;
RT   "The nucleotide sequence of Saccharomyces cerevisiae chromosome XVI.";
RL   Nature 387:103-105(1997).
RN   [2]
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   [3]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-131.
RX   PubMed=6095044; DOI=10.1128/mcb.4.10.2161-2169.1984;
RA   Yang E., Friedberg E.C.;
RT   "Molecular cloning and nucleotide sequence analysis of the Saccharomyces
RT   cerevisiae RAD1 gene.";
RL   Mol. Cell. Biol. 4:2161-2169(1984).
RN   [4]
RP   IDENTIFICATION.
RX   PubMed=7920641; DOI=10.1038/ng0694-195;
RA   Goyette P., Sumner J.S., Milos R., Duncan A.M.V., Rosenblatt D.S.,
RA   Matthews R.G., Rozen R.;
RT   "Human methylenetetrahydrofolate reductase: isolation of cDNA, mapping and
RT   mutation identification.";
RL   Nat. Genet. 7:195-200(1994).
RN   [5]
RP   ERRATUM OF PUBMED:7920641.
RX   PubMed=7951330;
RA   Goyette P., Sumner J.S., Milos R., Duncan A.M.V., Rosenblatt D.S.,
RA   Matthews R.G., Rozen R.;
RL   Nat. Genet. 7:551-551(1994).
RN   [6]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-120 AND SER-301, AND
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX   PubMed=18407956; DOI=10.1074/mcp.m700468-mcp200;
RA   Albuquerque C.P., Smolka M.B., Payne S.H., Bafna V., Eng J., Zhou H.;
RT   "A multidimensional chromatography technology for in-depth phosphoproteome
RT   analysis.";
RL   Mol. Cell. Proteomics 7:1389-1396(2008).
RN   [7]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-358, AND IDENTIFICATION BY
RP   MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX   PubMed=19779198; DOI=10.1126/science.1172867;
RA   Holt L.J., Tuch B.B., Villen J., Johnson A.D., Gygi S.P., Morgan D.O.;
RT   "Global analysis of Cdk1 substrate phosphorylation sites provides insights
RT   into evolution.";
RL   Science 325:1682-1686(2009).
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=(6S)-5-methyl-5,6,7,8-tetrahydrofolate + NADP(+) = (6R)-5,10-
CC         methylene-5,6,7,8-tetrahydrofolate + H(+) + NADPH;
CC         Xref=Rhea:RHEA:19817, ChEBI:CHEBI:15378, ChEBI:CHEBI:15636,
CC         ChEBI:CHEBI:18608, ChEBI:CHEBI:57783, ChEBI:CHEBI:58349; EC=1.5.1.20;
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=(6S)-5-methyl-5,6,7,8-tetrahydrofolate + NAD(+) = (6R)-5,10-
CC         methylene-5,6,7,8-tetrahydrofolate + H(+) + NADH;
CC         Xref=Rhea:RHEA:19821, ChEBI:CHEBI:15378, ChEBI:CHEBI:15636,
CC         ChEBI:CHEBI:18608, ChEBI:CHEBI:57540, ChEBI:CHEBI:57945; EC=1.5.1.20;
CC   -!- COFACTOR:
CC       Name=FAD; Xref=ChEBI:CHEBI:57692; Evidence={ECO:0000250};
CC   -!- PATHWAY: One-carbon metabolism; tetrahydrofolate interconversion.
CC   -!- INTERACTION:
CC       P46151; P53128: MET13; NbExp=2; IntAct=EBI-11567, EBI-11572;
CC   -!- SIMILARITY: Belongs to the methylenetetrahydrofolate reductase family.
CC       {ECO:0000305}.
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DR   EMBL; U36624; AAB68164.1; -; Genomic_DNA.
DR   EMBL; K02070; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; BK006949; DAA11405.1; -; Genomic_DNA.
DR   PIR; S63459; S63459.
DR   RefSeq; NP_015302.1; NM_001183837.1.
DR   PDB; 6FNU; X-ray; 1.56 A; A=1-302.
DR   PDBsum; 6FNU; -.
DR   AlphaFoldDB; P46151; -.
DR   SMR; P46151; -.
DR   BioGRID; 36154; 140.
DR   DIP; DIP-2825N; -.
DR   IntAct; P46151; 5.
DR   MINT; P46151; -.
DR   STRING; 4932.YPL023C; -.
DR   iPTMnet; P46151; -.
DR   MaxQB; P46151; -.
DR   PaxDb; 4932-YPL023C; -.
DR   PeptideAtlas; P46151; -.
DR   EnsemblFungi; YPL023C_mRNA; YPL023C; YPL023C.
DR   GeneID; 856084; -.
DR   KEGG; sce:YPL023C; -.
DR   AGR; SGD:S000005944; -.
DR   SGD; S000005944; MET12.
DR   VEuPathDB; FungiDB:YPL023C; -.
DR   eggNOG; KOG0564; Eukaryota.
DR   HOGENOM; CLU_025841_2_2_1; -.
DR   InParanoid; P46151; -.
DR   OMA; GVFKTIP; -.
DR   OrthoDB; 1381745at2759; -.
DR   BioCyc; YEAST:YPL023C-MONOMER; -.
DR   UniPathway; UPA00193; -.
DR   BioGRID-ORCS; 856084; 4 hits in 10 CRISPR screens.
DR   PRO; PR:P46151; -.
DR   Proteomes; UP000002311; Chromosome XVI.
DR   RNAct; P46151; Protein.
DR   GO; GO:0071949; F:FAD binding; IBA:GO_Central.
DR   GO; GO:0004489; F:methylenetetrahydrofolate reductase (NAD(P)H) activity; IDA:SGD.
DR   GO; GO:0106312; F:methylenetetrahydrofolate reductase NADH activity; IEA:RHEA.
DR   GO; GO:0106313; F:methylenetetrahydrofolate reductase NADPH activity; IEA:RHEA.
DR   GO; GO:0009086; P:methionine biosynthetic process; IBA:GO_Central.
DR   GO; GO:0035999; P:tetrahydrofolate interconversion; IBA:GO_Central.
DR   CDD; cd00537; MTHFR; 1.
DR   Gene3D; 3.20.20.220; -; 1.
DR   InterPro; IPR029041; FAD-linked_oxidoreductase-like.
DR   InterPro; IPR004621; Fadh2_euk.
DR   InterPro; IPR003171; Mehydrof_redctse-like.
DR   NCBIfam; TIGR00677; fadh2_euk; 1.
DR   PANTHER; PTHR45754; METHYLENETETRAHYDROFOLATE REDUCTASE; 1.
DR   PANTHER; PTHR45754:SF1; METHYLENETETRAHYDROFOLATE REDUCTASE 1; 1.
DR   Pfam; PF02219; MTHFR; 1.
DR   SUPFAM; SSF51730; FAD-linked oxidoreductase; 1.
PE   1: Evidence at protein level;
KW   3D-structure; FAD; Flavoprotein; NADP; Oxidoreductase; Phosphoprotein;
KW   Reference proteome.
FT   CHAIN           1..657
FT                   /note="Methylenetetrahydrofolate reductase 1"
FT                   /id="PRO_0000190255"
FT   REGION          308..329
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   ACT_SITE        18
FT                   /note="Proton donor/acceptor"
FT                   /evidence="ECO:0000250"
FT   BINDING         18..23
FT                   /ligand="NAD(+)"
FT                   /ligand_id="ChEBI:CHEBI:57540"
FT                   /evidence="ECO:0000250"
FT   BINDING         49..50
FT                   /ligand="FAD"
FT                   /ligand_id="ChEBI:CHEBI:57692"
FT                   /evidence="ECO:0000250"
FT   BINDING         49..50
FT                   /ligand="NAD(+)"
FT                   /ligand_id="ChEBI:CHEBI:57540"
FT                   /evidence="ECO:0000250"
FT   BINDING         78
FT                   /ligand="FAD"
FT                   /ligand_id="ChEBI:CHEBI:57692"
FT                   /evidence="ECO:0000250"
FT   BINDING         108..110
FT                   /ligand="FAD"
FT                   /ligand_id="ChEBI:CHEBI:57692"
FT                   /evidence="ECO:0000250"
FT   BINDING         110
FT                   /ligand="substrate"
FT                   /evidence="ECO:0000250"
FT   BINDING         129..130
FT                   /ligand="FAD"
FT                   /ligand_id="ChEBI:CHEBI:57692"
FT                   /evidence="ECO:0000250"
FT   BINDING         152
FT                   /ligand="FAD"
FT                   /ligand_id="ChEBI:CHEBI:57692"
FT                   /evidence="ECO:0000250"
FT   BINDING         171
FT                   /ligand="FAD"
FT                   /ligand_id="ChEBI:CHEBI:57692"
FT                   /evidence="ECO:0000250"
FT   BINDING         178
FT                   /ligand="FAD"
FT                   /ligand_id="ChEBI:CHEBI:57692"
FT                   /evidence="ECO:0000250"
FT   BINDING         189
FT                   /ligand="substrate"
FT                   /evidence="ECO:0000250"
FT   BINDING         286
FT                   /ligand="substrate"
FT                   /evidence="ECO:0000250"
FT   MOD_RES         120
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0007744|PubMed:18407956"
FT   MOD_RES         301
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0007744|PubMed:18407956"
FT   MOD_RES         358
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0007744|PubMed:19779198"
FT   CONFLICT        110..111
FT                   /note="DP -> NL (in Ref. 3; K02070)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        115..116
FT                   /note="ED -> VV (in Ref. 3; K02070)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        119
FT                   /note="D -> V (in Ref. 3; K02070)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        124..131
FT                   /note="ESPFKYAV -> RLLNMRLF (in Ref. 3; K02070)"
FT                   /evidence="ECO:0000305"
FT   HELIX           3..9
FT                   /evidence="ECO:0007829|PDB:6FNU"
FT   STRAND          14..19
FT                   /evidence="ECO:0007829|PDB:6FNU"
FT   HELIX           25..38
FT                   /evidence="ECO:0007829|PDB:6FNU"
FT   HELIX           39..41
FT                   /evidence="ECO:0007829|PDB:6FNU"
FT   STRAND          46..48
FT                   /evidence="ECO:0007829|PDB:6FNU"
FT   HELIX           52..54
FT                   /evidence="ECO:0007829|PDB:6FNU"
FT   HELIX           57..71
FT                   /evidence="ECO:0007829|PDB:6FNU"
FT   STRAND          75..80
FT                   /evidence="ECO:0007829|PDB:6FNU"
FT   HELIX           86..98
FT                   /evidence="ECO:0007829|PDB:6FNU"
FT   STRAND          103..107
FT                   /evidence="ECO:0007829|PDB:6FNU"
FT   HELIX           116..118
FT                   /evidence="ECO:0007829|PDB:6FNU"
FT   HELIX           130..141
FT                   /evidence="ECO:0007829|PDB:6FNU"
FT   HELIX           142..144
FT                   /evidence="ECO:0007829|PDB:6FNU"
FT   STRAND          145..151
FT                   /evidence="ECO:0007829|PDB:6FNU"
FT   HELIX           168..180
FT                   /evidence="ECO:0007829|PDB:6FNU"
FT   STRAND          185..190
FT                   /evidence="ECO:0007829|PDB:6FNU"
FT   HELIX           194..207
FT                   /evidence="ECO:0007829|PDB:6FNU"
FT   STRAND          210..212
FT                   /evidence="ECO:0007829|PDB:6FNU"
FT   STRAND          214..218
FT                   /evidence="ECO:0007829|PDB:6FNU"
FT   HELIX           224..234
FT                   /evidence="ECO:0007829|PDB:6FNU"
FT   HELIX           240..243
FT                   /evidence="ECO:0007829|PDB:6FNU"
FT   HELIX           248..251
FT                   /evidence="ECO:0007829|PDB:6FNU"
FT   HELIX           254..275
FT                   /evidence="ECO:0007829|PDB:6FNU"
FT   TURN            276..278
FT                   /evidence="ECO:0007829|PDB:6FNU"
FT   STRAND          282..286
FT                   /evidence="ECO:0007829|PDB:6FNU"
FT   HELIX           292..300
FT                   /evidence="ECO:0007829|PDB:6FNU"
SQ   SEQUENCE   657 AA;  73942 MW;  D75612EA92D67500 CRC64;
     MSIRDLYHAR ASPFISLEFF PPKTELGTRN LMERMHRMTA LDPLFITVTW GAGGTTAEKT
     LTLASLAQQT LNIPVCMHLT CTNTEKAIID DALDRCYNAG IRNILALRGD PPIGEDWLDS
     QSNESPFKYA VDLVRYIKQS YGDKFCVGVA AYPEGHCEGE AEGHEQDPLK DLVYLKEKVE
     AGADFVITQL FYDVEKFLTF EMLFRERISQ DLPLFPGLMP INSYLLFHRA AKLSHASIPP
     AILSRFPPEI QSDDNAVKSI GVDILIELIQ EIYQRTSGRI KGFHFYTLNL EKAIAQIVSQ
     SPVLSHIVNE SSEEEGEDET SGEIGSIENV PIEDADGDIV LDDSNEETVA NRKRRRHSSL
     DSAKLIFNRA IVTEKGLRYN NENGSMPSKK ALISISKGHG TLGRDATWDE FPNGRFGDSR
     SPAYGEIDGY GPSIKVSKSK ALELWGIPKT IGDLKDIFIK YLEGSTDAIP WSDLGLSAET
     ALIQEELIQL NYRGYLTLAS QPATNATLSS DKIFGWGPAK GRLYQKAFVE MFIHRQQWET
     TLKPKLDHYG RRKFSYYAGD SSGSFETNLD PHSSSVVTWG VFPNSPVKQT TIIEEESFKA
     WRDEAFSIWS EWAKLFPRNT PANILLRLVH KDYCLVSIVH HDFKETDELW EMLLDQA
//