MTD2L_RAT
ID MTD2L_RAT Reviewed; 338 AA.
AC D3ZUA0;
DT 19-OCT-2011, integrated into UniProtKB/Swiss-Prot.
DT 20-APR-2010, sequence version 1.
DT 03-AUG-2022, entry version 79.
DE RecName: Full=Bifunctional methylenetetrahydrofolate dehydrogenase/cyclohydrolase 2, mitochondrial {ECO:0000305|PubMed:21163947};
DE AltName: Full=NADP-dependent methylenetetrahydrofolate dehydrogenase 2-like protein {ECO:0000305|PubMed:21163947};
DE Short=MTHFD2-like {ECO:0000303|PubMed:21163947};
DE Includes:
DE RecName: Full=Methylenetetrahydrofolate dehydrogenase, mitochondrial {ECO:0000305|PubMed:21163947};
DE EC=1.5.1.15 {ECO:0000269|PubMed:24733394};
DE EC=1.5.1.5 {ECO:0000269|PubMed:21163947, ECO:0000269|PubMed:24733394};
DE Includes:
DE RecName: Full=Methenyltetrahydrofolate cyclohydrolase, mitochondrial {ECO:0000305|PubMed:24733394};
DE EC=3.5.4.9 {ECO:0000269|PubMed:24733394};
GN Name=Mthfd2l {ECO:0000312|RGD:1310879};
OS Rattus norvegicus (Rat).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Rattus.
OX NCBI_TaxID=10116;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Adams M.D., Myers E.W., Smith H.O., Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [2]
RP FUNCTION, CATALYTIC ACTIVITY, ALTERNATIVE SPLICING (ISOFORMS 1 AND 2),
RP SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY.
RX PubMed=21163947; DOI=10.1074/jbc.m110.196840;
RA Bolusani S., Young B.A., Cole N.A., Tibbetts A.S., Momb J., Bryant J.D.,
RA Solmonson A., Appling D.R.;
RT "Mammalian MTHFD2L encodes a mitochondrial methylenetetrahydrofolate
RT dehydrogenase isozyme expressed in adult tissues.";
RL J. Biol. Chem. 286:5166-5174(2011).
RN [3]
RP FUNCTION (ISOFORMS 1 AND 2), CATALYTIC ACTIVITY, PATHWAY, COFACTOR, AND
RP BIOPHYSICOCHEMICAL PROPERTIES.
RX PubMed=24733394; DOI=10.1074/jbc.m114.555573;
RA Shin M., Bryant J.D., Momb J., Appling D.R.;
RT "Mitochondrial MTHFD2L is a dual redox cofactor-specific
RT methylenetetrahydrofolate dehydrogenase/methenyltetrahydrofolate
RT cyclohydrolase expressed in both adult and embryonic tissues.";
RL J. Biol. Chem. 289:15507-15517(2014).
CC -!- FUNCTION: [Isoform 1]: Bifunctional mitochondrial folate-
CC interconverting enzyme that has both NAD/NADP-dependent
CC methylenetetrahydrofolate dehydrogenase and methenyltetrahydrofolate
CC cyclohydrolase activities. {ECO:0000269|PubMed:21163947,
CC ECO:0000269|PubMed:24733394}.
CC -!- FUNCTION: [Isoform 2]: Has no NAD/NADP-dependent
CC methylenetetrahydrofolate dehydrogenase activity.
CC {ECO:0000269|PubMed:24733394}.
CC -!- CATALYTIC ACTIVITY: [Isoform 1]:
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; Evidence={ECO:0000269|PubMed:21163947,
CC ECO:0000269|PubMed:24733394};
CC -!- CATALYTIC ACTIVITY: [Isoform 1]:
CC Reaction=(6R)-5,10-methylene-5,6,7,8-tetrahydrofolate + NAD(+) = 5,10-
CC methenyltetrahydrofolate + NADH; Xref=Rhea:RHEA:22892,
CC ChEBI:CHEBI:15636, ChEBI:CHEBI:57455, ChEBI:CHEBI:57540,
CC ChEBI:CHEBI:57945; EC=1.5.1.15;
CC Evidence={ECO:0000269|PubMed:24733394};
CC -!- CATALYTIC ACTIVITY: [Isoform 1]:
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:0000269|PubMed:24733394};
CC -!- COFACTOR:
CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC Evidence={ECO:0000269|PubMed:24733394};
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=147 uM for NAD(+) {ECO:0000269|PubMed:24733394};
CC KM=537 uM for NADP(+) {ECO:0000269|PubMed:24733394};
CC KM=40 uM for 5,10-methylenetetrahydrofolate (in presence of NAD(+))
CC {ECO:0000269|PubMed:24733394};
CC KM=42 uM for 5,10-methylenetetrahydrofolate (in presence of NADP(+))
CC {ECO:0000269|PubMed:24733394};
CC KM=130 uM for tetrahydropteroylpentaglutamate/H4PteGlu5 (in presence
CC of NAD(+)) {ECO:0000269|PubMed:24733394};
CC KM=153 uM for tetrahydropteroylpentaglutamate/H4PteGlu5 (in presence
CC of NADP(+)) {ECO:0000269|PubMed:24733394};
CC Note=Has similar catalytic efficiencies, at physiological
CC concentrations, with either NAD(+) or NADP(+) as substrates for the
CC dehydrogenation of (6R)-5,10-methylene-5,6,7,8-tetrahydrofolate.
CC {ECO:0000269|PubMed:24733394};
CC -!- PATHWAY: One-carbon metabolism; tetrahydrofolate interconversion.
CC {ECO:0000269|PubMed:24733394}.
CC -!- SUBCELLULAR LOCATION: Mitochondrion inner membrane
CC {ECO:0000269|PubMed:21163947}; Peripheral membrane protein
CC {ECO:0000269|PubMed:21163947}; Matrix side
CC {ECO:0000269|PubMed:21163947}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=D3ZUA0-1; Sequence=Displayed;
CC Name=2;
CC IsoId=D3ZUA0-2; Sequence=VSP_061393;
CC -!- TISSUE SPECIFICITY: Widely expressed. {ECO:0000269|PubMed:21163947}.
CC -!- SIMILARITY: Belongs to the tetrahydrofolate
CC dehydrogenase/cyclohydrolase family. {ECO:0000305}.
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DR EMBL; CH474060; EDL88577.1; -; Genomic_DNA.
DR RefSeq; NP_001100681.1; NM_001107211.1.
DR AlphaFoldDB; D3ZUA0; -.
DR SMR; D3ZUA0; -.
DR STRING; 10116.ENSRNOP00000044342; -.
DR PhosphoSitePlus; D3ZUA0; -.
DR PaxDb; D3ZUA0; -.
DR PRIDE; D3ZUA0; -.
DR Ensembl; ENSRNOT00000047708; ENSRNOP00000044342; ENSRNOG00000021347. [D3ZUA0-1]
DR GeneID; 305248; -.
DR KEGG; rno:305248; -.
DR UCSC; RGD:1310879; rat. [D3ZUA0-1]
DR CTD; 441024; -.
DR RGD; 1310879; Mthfd2l.
DR eggNOG; KOG0089; Eukaryota.
DR GeneTree; ENSGT00940000160901; -.
DR HOGENOM; CLU_034045_0_1_1; -.
DR InParanoid; D3ZUA0; -.
DR OMA; CKVITAE; -.
DR OrthoDB; 1004679at2759; -.
DR PhylomeDB; D3ZUA0; -.
DR TreeFam; TF323998; -.
DR BRENDA; 1.5.1.5; 5301.
DR Reactome; R-RNO-196757; Metabolism of folate and pterines.
DR UniPathway; UPA00193; -.
DR PRO; PR:D3ZUA0; -.
DR Proteomes; UP000002494; Chromosome 14.
DR Proteomes; UP000234681; Chromosome 14.
DR Bgee; ENSRNOG00000021347; Expressed in quadriceps femoris and 17 other tissues.
DR ExpressionAtlas; D3ZUA0; baseline and differential.
DR Genevisible; D3ZUA0; RN.
DR GO; GO:0005743; C:mitochondrial inner membrane; IDA:RGD.
DR GO; GO:0005759; C:mitochondrial matrix; IDA:RGD.
DR GO; GO:0005739; C:mitochondrion; IBA:GO_Central.
DR GO; GO:0004477; F:methenyltetrahydrofolate cyclohydrolase activity; IDA:UniProtKB.
DR GO; GO:0004487; F:methylenetetrahydrofolate dehydrogenase (NAD+) activity; IDA:UniProtKB.
DR GO; GO:0004488; F:methylenetetrahydrofolate dehydrogenase (NADP+) activity; IDA:UniProtKB.
DR GO; GO:0009256; P:10-formyltetrahydrofolate metabolic process; IDA:RGD.
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; IDA:UniProtKB.
DR CDD; cd01080; NAD_bind_m-THF_DH_Cyclohyd; 1.
DR HAMAP; MF_01576; THF_DHG_CYH; 1.
DR InterPro; IPR046346; Aminiacid_DH-like_N_sf.
DR InterPro; IPR036291; NAD(P)-bd_dom_sf.
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; PF00763; THF_DHG_CYH; 1.
DR Pfam; PF02882; THF_DHG_CYH_C; 1.
DR PRINTS; PR00085; THFDHDRGNASE.
DR SUPFAM; SSF51735; SSF51735; 1.
DR SUPFAM; SSF53223; SSF53223; 1.
DR PROSITE; PS00767; THF_DHG_CYH_2; 1.
PE 1: Evidence at protein level;
KW Alternative splicing; Amino-acid biosynthesis; Histidine biosynthesis;
KW Hydrolase; Magnesium; Membrane; Methionine biosynthesis; Mitochondrion;
KW Mitochondrion inner membrane; Multifunctional enzyme; NAD;
KW One-carbon metabolism; Oxidoreductase; Purine biosynthesis;
KW Reference proteome.
FT CHAIN 1..338
FT /note="Bifunctional methylenetetrahydrofolate
FT dehydrogenase/cyclohydrolase 2, mitochondrial"
FT /id="PRO_0000413329"
FT BINDING 89..93
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:P13995"
FT BINDING 136..138
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:P13995"
FT BINDING 205..207
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000250|UniProtKB:P13995"
FT BINDING 238
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000250|UniProtKB:P13995"
FT BINDING 314..318
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:P13995"
FT VAR_SEQ 260..301
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000305|PubMed:21163947,
FT ECO:0000305|PubMed:24733394"
FT /id="VSP_061393"
SQ SEQUENCE 338 AA; 36426 MW; D8E0CB282F9836B3 CRC64;
MATRARGLSL LRGRLGRGPA RAPGVAERAW RGFGSSSRRH EAVIISGTEM AKQIRRELQQ
GVESWLALGN RRPHLSIILV GDNPASHTYV RNKIRAASAV GICSELIVKP KNVSQEELLD
ITDQLNMDPR VSGILVQLPL PDHVDERTIC NGIAPEKDVD GFHIINIGRL CLDQHSLIPA
TASAVWEIIK RAGIETFGKN VVVAGRSKNV GMPIAMLLHT DGEHERPGGD ATVTIAHRHT
PREQLKAHTQ LAEIIIVAAG IPGLITADMV REGATVIDVG INYVQDPVTG KTKLVGDVDF
EAVKKKASFI TPVPGGVGPM TVAMLLKNTL LAAKNITY
