MTHR_MACFA
ID MTHR_MACFA Reviewed; 656 AA.
AC Q60HE5;
DT 29-MAR-2005, integrated into UniProtKB/Swiss-Prot.
DT 23-NOV-2004, sequence version 1.
DT 03-AUG-2022, entry version 66.
DE RecName: Full=Methylenetetrahydrofolate reductase {ECO:0000305};
DE EC=1.5.1.20 {ECO:0000250|UniProtKB:P42898};
GN Name=MTHFR; ORFNames=QtrA-17780;
OS Macaca fascicularis (Crab-eating macaque) (Cynomolgus monkey).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini;
OC Cercopithecidae; Cercopithecinae; Macaca.
OX NCBI_TaxID=9541;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Temporal cortex;
RA Kusuda J., Osada N., Tanuma R., Hirata M., Sugano S., Hashimoto K.;
RT "Isolation and characterization of cDNA for macaque neurological disease
RT genes.";
RL Submitted (OCT-2003) to the EMBL/GenBank/DDBJ databases.
CC -!- FUNCTION: Catalyzes the conversion of 5,10-methylenetetrahydrofolate to
CC 5-methyltetrahydrofolate, a cosubstrate for homocysteine remethylation
CC to methionine. Represents a key regulatory connection between the
CC folate and methionine cycles. {ECO:0000250|UniProtKB:P42898}.
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 Evidence={ECO:0000250|UniProtKB:P42898};
CC PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:19819;
CC Evidence={ECO:0000250|UniProtKB:P42898};
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 Evidence={ECO:0000250|UniProtKB:P42898};
CC PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:19823;
CC Evidence={ECO:0000250|UniProtKB:P42898};
CC -!- COFACTOR:
CC Name=FAD; Xref=ChEBI:CHEBI:57692;
CC Evidence={ECO:0000250|UniProtKB:P42898};
CC -!- ACTIVITY REGULATION: Allosterically regulated by S-adenosylmethionine
CC (SAM). {ECO:0000250|UniProtKB:P42898}.
CC -!- PATHWAY: One-carbon metabolism; tetrahydrofolate interconversion.
CC {ECO:0000250|UniProtKB:P42898}.
CC -!- SUBUNIT: Homodimer. {ECO:0000250|UniProtKB:P42898}.
CC -!- DOMAIN: Contains a serine-rich phosphorylation region at the N-terminal
CC and an eukaryote-only S-adenosylmethionine (SAM)-binding domain at the
CC C-terminal. Through asymmetric homodimerization, the two regions are
CC positioned next to each other and N-terminal phosphorylation increases
CC sensitivity to SAM binding and inhibition.
CC {ECO:0000250|UniProtKB:P42898}.
CC -!- PTM: Phosphorylation of an N-terminal serine-rich phosphorylation
CC region increases sensitivity to S-adenosylmethionine and inhibition.
CC {ECO:0000250|UniProtKB:P42898}.
CC -!- SIMILARITY: Belongs to the methylenetetrahydrofolate reductase family.
CC {ECO:0000305}.
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DR EMBL; AB125182; BAD51970.1; -; mRNA.
DR RefSeq; NP_001271578.1; NM_001284649.1.
DR AlphaFoldDB; Q60HE5; -.
DR SMR; Q60HE5; -.
DR STRING; 9541.XP_005544833.1; -.
DR GeneID; 102117536; -.
DR CTD; 4524; -.
DR eggNOG; KOG0564; Eukaryota.
DR BRENDA; 1.5.1.20; 1793.
DR UniPathway; UPA00193; -.
DR Proteomes; UP000233100; Unplaced.
DR GO; GO:0004489; F:methylenetetrahydrofolate reductase (NAD(P)H) activity; ISS:UniProtKB.
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:0006555; P:methionine metabolic process; IEA:InterPro.
DR GO; GO:0035999; P:tetrahydrofolate interconversion; ISS:UniProtKB.
DR CDD; cd00537; MTHFR; 1.
DR InterPro; IPR029041; FAD-linked_oxidoreductase-like.
DR InterPro; IPR004621; Fadh2_euk.
DR InterPro; IPR003171; Mehydrof_redctse-like.
DR Pfam; PF02219; MTHFR; 1.
DR SUPFAM; SSF51730; SSF51730; 1.
DR TIGRFAMs; TIGR00677; fadh2_euk; 1.
PE 2: Evidence at transcript level;
KW Allosteric enzyme; FAD; Flavoprotein; NADP; Oxidoreductase; Phosphoprotein;
KW Reference proteome.
FT CHAIN 1..656
FT /note="Methylenetetrahydrofolate reductase"
FT /id="PRO_0000190246"
FT REGION 1..46
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 13..33
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 63
FT /note="Proton donor/acceptor"
FT /evidence="ECO:0000250"
FT BINDING 63..68
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000250"
FT BINDING 94..95
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:P42898"
FT BINDING 94..95
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000250"
FT BINDING 127
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:P42898"
FT BINDING 157..159
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:P42898"
FT BINDING 159
FT /ligand="substrate"
FT /evidence="ECO:0000250"
FT BINDING 174..175
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:P42898"
FT BINDING 197
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:P42898"
FT BINDING 201..204
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:P42898"
FT BINDING 210
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:P42898"
FT BINDING 217
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:P42898"
FT BINDING 228
FT /ligand="substrate"
FT /evidence="ECO:0000250"
FT BINDING 321
FT /ligand="substrate"
FT /evidence="ECO:0000250"
FT BINDING 325
FT /ligand="substrate"
FT /evidence="ECO:0000250"
FT BINDING 456
FT /ligand="S-adenosyl-L-methionine"
FT /ligand_id="ChEBI:CHEBI:59789"
FT /evidence="ECO:0000250|UniProtKB:P42898"
FT BINDING 461..464
FT /ligand="S-adenosyl-L-methionine"
FT /ligand_id="ChEBI:CHEBI:59789"
FT /evidence="ECO:0000250|UniProtKB:P42898"
FT BINDING 481..485
FT /ligand="S-adenosyl-L-methionine"
FT /ligand_id="ChEBI:CHEBI:59789"
FT /evidence="ECO:0000250|UniProtKB:P42898"
FT BINDING 560
FT /ligand="S-adenosyl-L-methionine"
FT /ligand_id="ChEBI:CHEBI:59789"
FT /evidence="ECO:0000250|UniProtKB:P42898"
FT BINDING 573
FT /ligand="S-adenosyl-L-methionine"
FT /ligand_id="ChEBI:CHEBI:59789"
FT /evidence="ECO:0000250|UniProtKB:P42898"
FT MOD_RES 10
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P42898"
FT MOD_RES 18
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P42898"
FT MOD_RES 20
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P42898"
FT MOD_RES 21
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P42898"
FT MOD_RES 23
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P42898"
FT MOD_RES 25
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P42898"
FT MOD_RES 26
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P42898"
FT MOD_RES 29
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P42898"
FT MOD_RES 30
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P42898"
FT MOD_RES 34
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:P42898"
FT MOD_RES 94
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:P42898"
FT MOD_RES 103
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P42898"
FT MOD_RES 394
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P42898"
FT MOD_RES 451
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:P42898"
SQ SEQUENCE 656 AA; 74656 MW; AFF7FA239B9520FB CRC64;
MVNEARGNDS LNPCLEGSAS SSSESSKDSS RCSTPGLDPE RHERLRDKMR RRMESGDKWF
SLEFFPPRTA EGAVNLISRF DRMAAGGPLF IDVTWHPAGD PGSDKETSSM MIASTAVNYC
GLETILHMTC CCQRLEEITG HLHKAKQLGL KNIMALRGDP IGDQWEEEEG GFNYAVDLVK
HIRSEFGDYF DLCVAGYPKG HPEAGSFEAD LKHLKEKVSA GADFIITQLF FEADTFFRFV
KACTDMGITC PIVPGIFPIQ GYHSLRQLVK QSKLEVPQEI KDVIEPIKDN DAAIRNYGIE
LAVSLCHELL ASGLVPGLHF YTLNREMATT EVLKRLGMWT EDPRRPLPWA LSAHPKRREE
DVRPIFWASR PKSYIYRTQE WDEFPNGRWG NSSSPAFGEL KDYYLFYLKS KSPRELLLKM
WGEELTSEES VFEVFVLYLS GEPNRNGHKV TCLPWNDEPL AAETSLLKEE LLRVNRQGIL
TINSQPNING KPSSDPVVGW GPSGGYVFQK AYLEFFTSRE TAEALLQVLK KYELRVNYHL
VNVKGENITN APELQPNAVT WGIFPGREII QPTVVDPISF MFWKDEAFAL WIEQWGKLYE
EESPSRTIIQ YIHDNYFLVN LVDNDFPLDN CLWQVVEDAL ELLNRPTQNE REMEAP
