MTRR_HUMAN
ID MTRR_HUMAN Reviewed; 698 AA.
AC Q9UBK8; O60471; Q32MA9; Q7Z4M8;
DT 27-MAR-2002, integrated into UniProtKB/Swiss-Prot.
DT 16-JAN-2019, sequence version 4.
DT 03-AUG-2022, entry version 202.
DE RecName: Full=Methionine synthase reductase;
DE Short=MSR;
DE EC=1.16.1.8 {ECO:0000269|PubMed:17892308};
DE AltName: Full=Aquacobalamin reductase {ECO:0000303|PubMed:16769880};
DE Short=AqCbl reductase {ECO:0000303|PubMed:16769880};
GN Name=MTRR {ECO:0000312|HGNC:HGNC:7473};
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA] (ISOFORMS A AND B), AND VARIANT
RP LEU-175.
RX PubMed=10564814; DOI=10.1016/s0378-1119(99)00431-x;
RA Leclerc D., Odievre M.-H., Wu Q., Wilson A., Huizenga J., Rozen R.,
RA Scherer S.W., Gravel R.A.;
RT "Molecular cloning, expression and physical mapping of the human methionine
RT synthase reductase gene.";
RL Gene 240:75-88(1999).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM B), VARIANT LEU-175, AND VARIANT HMAE
RP LEU-576 DEL.
RX PubMed=9501215; DOI=10.1073/pnas.95.6.3059;
RA Leclerc D., Wilson A., Dumas R., Gafuik C., Song D., Watkins D.,
RA Heng H.H.Q., Rommens J.M., Scherer S.W., Rosenblatt D.S., Gravel R.A.;
RT "Cloning and mapping of a cDNA for methionine synthase reductase, a
RT flavoprotein defective in patients with homocystinuria.";
RL Proc. Natl. Acad. Sci. U.S.A. 95:3059-3064(1998).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15372022; DOI=10.1038/nature02919;
RA Schmutz J., Martin J., Terry A., Couronne O., Grimwood J., Lowry S.,
RA Gordon L.A., Scott D., Xie G., Huang W., Hellsten U., Tran-Gyamfi M.,
RA She X., Prabhakar S., Aerts A., Altherr M., Bajorek E., Black S.,
RA Branscomb E., Caoile C., Challacombe J.F., Chan Y.M., Denys M.,
RA Detter J.C., Escobar J., Flowers D., Fotopulos D., Glavina T., Gomez M.,
RA Gonzales E., Goodstein D., Grigoriev I., Groza M., Hammon N., Hawkins T.,
RA Haydu L., Israni S., Jett J., Kadner K., Kimball H., Kobayashi A.,
RA Lopez F., Lou Y., Martinez D., Medina C., Morgan J., Nandkeshwar R.,
RA Noonan J.P., Pitluck S., Pollard M., Predki P., Priest J., Ramirez L.,
RA Retterer J., Rodriguez A., Rogers S., Salamov A., Salazar A., Thayer N.,
RA Tice H., Tsai M., Ustaszewska A., Vo N., Wheeler J., Wu K., Yang J.,
RA Dickson M., Cheng J.-F., Eichler E.E., Olsen A., Pennacchio L.A.,
RA Rokhsar D.S., Richardson P., Lucas S.M., Myers R.M., Rubin E.M.;
RT "The DNA sequence and comparative analysis of human chromosome 5.";
RL Nature 431:268-274(2004).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS A AND B).
RC TISSUE=Lung;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [5]
RP FUNCTION, CATALYTIC ACTIVITY, AND BIOPHYSICOCHEMICAL PROPERTIES.
RX PubMed=16769880; DOI=10.1073/pnas.0603694103;
RA Yamada K., Gravel R.A., Toraya T., Matthews R.G.;
RT "Human methionine synthase reductase is a molecular chaperone for human
RT methionine synthase.";
RL Proc. Natl. Acad. Sci. U.S.A. 103:9476-9481(2006).
RN [6]
RP SUBCELLULAR LOCATION (ISOFORM A).
RX PubMed=18221906; DOI=10.1016/j.ymgme.2007.11.019;
RA Froese D.S., Wu X., Zhang J., Dumas R., Schoel W.M., Amrein M.,
RA Gravel R.A.;
RT "Restricted role for methionine synthase reductase defined by subcellular
RT localization.";
RL Mol. Genet. Metab. 94:68-77(2008).
RN [7]
RP FUNCTION.
RX PubMed=19243433; DOI=10.1111/j.1742-4658.2009.06919.x;
RA Wolthers K.R., Scrutton N.S.;
RT "Cobalamin uptake and reactivation occurs through specific protein
RT interactions in the methionine synthase-methionine synthase reductase
RT complex.";
RL FEBS J. 276:1942-1951(2009).
RN [8]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-171, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full phosphorylation
RT site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [9]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T.,
RA Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [10]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-171 AND SER-189, VARIANT
RP [LARGE SCALE ANALYSIS] LEU-175, AND IDENTIFICATION BY MASS SPECTROMETRY
RP [LARGE SCALE ANALYSIS].
RC TISSUE=Erythroleukemia;
RX PubMed=23186163; DOI=10.1021/pr300630k;
RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J.,
RA Mohammed S.;
RT "Toward a comprehensive characterization of a human cancer cell
RT phosphoproteome.";
RL J. Proteome Res. 12:260-271(2013).
RN [11]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-189, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Liver;
RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014;
RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L.,
RA Ye M., Zou H.;
RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver
RT phosphoproteome.";
RL J. Proteomics 96:253-262(2014).
RN [12]
RP FUNCTION, AND INTERACTION WITH MMACHC; MMADHC AND MTR.
RX PubMed=27771510; DOI=10.1016/j.bbadis.2016.10.016;
RA Bassila C., Ghemrawi R., Flayac J., Froese D.S., Baumgartner M.R.,
RA Gueant J.L., Coelho D.;
RT "Methionine synthase and methionine synthase reductase interact with MMACHC
RT and with MMADHC.";
RL Biochim. Biophys. Acta 1863:103-112(2017).
RN [13]
RP X-RAY CRYSTALLOGRAPHY (1.9 ANGSTROMS) OF 165-698 IN COMPLEX WITH FAD AND
RP NADP, COFACTOR, BIOPHYSICOCHEMICAL PROPERTIES, CATALYTIC ACTIVITY, AND
RP FUNCTION.
RX PubMed=17892308; DOI=10.1021/bi701209p;
RA Wolthers K.R., Lou X., Toogood H.S., Leys D., Scrutton N.S.;
RT "Mechanism of coenzyme binding to human methionine synthase reductase
RT revealed through the crystal structure of the FNR-like module and
RT isothermal titration calorimetry.";
RL Biochemistry 46:11833-11844(2007).
RN [14]
RP VARIANTS HMAE VAL-54 DEL; MET-56; THR-129; ARG-405; ARG-487 AND ARG-554,
RP AND VARIANT VAL-333.
RX PubMed=10484769; DOI=10.1093/hmg/8.11.2009;
RA Wilson A., Leclerc D., Rosenblatt D.S., Gravel R.A.;
RT "Molecular basis for methionine synthase reductase deficiency in patients
RT belonging to the cblE complementation group of disorders in
RT folate/cobalamin metabolism.";
RL Hum. Mol. Genet. 8:2009-2016(1999).
RN [15]
RP INVOLVEMENT IN SUSCEPTIBILITY TO NTDFS, AND VARIANT MET-22.
RX PubMed=10444342; DOI=10.1006/mgme.1999.2879;
RA Wilson A., Platt R., Wu Q., Leclerc D., Christensen B., Yang H.,
RA Gravel R.A., Rozen R.;
RT "A common variant in methionine synthase reductase combined with low
RT cobalamin (vitamin B12) increases risk for spina bifida.";
RL Mol. Genet. Metab. 67:317-323(1999).
RN [16]
RP INVOLVEMENT IN SUSCEPTIBILITY TO NTDFS, AND VARIANT MET-22.
RX PubMed=12375236; DOI=10.1086/344209;
RA Doolin M.-T., Barbaux S., McDonnell M., Hoess K., Whitehead A.S.,
RA Mitchell L.E.;
RT "Maternal genetic effects, exerted by genes involved in homocysteine
RT remethylation, influence the risk of spina bifida.";
RL Am. J. Hum. Genet. 71:1222-1226(2002).
RN [17]
RP VARIANTS MET-22; LEU-175 AND ARG-350.
RX PubMed=15979034; DOI=10.1016/j.ymgme.2005.02.003;
RA O'Leary V.B., Mills J.L., Pangilinan F., Kirke P.N., Cox C., Conley M.,
RA Weiler A., Peng K., Shane B., Scott J.M., Parle-McDermott A., Molloy A.M.,
RA Brody L.C.;
RT "Analysis of methionine synthase reductase polymorphisms for neural tube
RT defects risk association.";
RL Mol. Genet. Metab. 85:220-227(2005).
CC -!- FUNCTION: Key enzyme in methionine and folate homeostasis responsible
CC for the reactivation of methionine synthase (MTR/MS) activity by
CC catalyzing the reductive methylation of MTR-bound cob(II)alamin
CC (PubMed:17892308). Cobalamin (vitamin B12) forms a complex with MTR to
CC serve as an intermediary in methyl transfer reactions that cycles
CC between MTR-bound methylcob(III)alamin and MTR bound-cob(I)alamin
CC forms, and occasional oxidative escape of the cob(I)alamin intermediate
CC during the catalytic cycle leads to the inactive cob(II)alamin species
CC (Probable). The processing of cobalamin in the cytosol occurs in a
CC multiprotein complex composed of at least MMACHC, MMADHC, MTRR and MTR
CC which may contribute to shuttle safely and efficiently cobalamin
CC towards MTR in order to produce methionine (PubMed:27771510). Also
CC necessary for the utilization of methyl groups from the folate cycle,
CC thereby affecting transgenerational epigenetic inheritance (By
CC similarity). Also acts as a molecular chaperone for methionine synthase
CC by stabilizing apoMTR and incorporating methylcob(III)alamin into
CC apoMTR to form the holoenzyme (PubMed:16769880). Also serves as an
CC aquacob(III)alamin reductase by reducing aquacob(III)alamin to
CC cob(II)alamin; this reduction leads to stimulation of the conversion of
CC apoMTR and aquacob(III)alamin to MTR holoenzyme (PubMed:16769880).
CC {ECO:0000250|UniProtKB:Q8C1A3, ECO:0000269|PubMed:16769880,
CC ECO:0000269|PubMed:17892308, ECO:0000269|PubMed:27771510,
CC ECO:0000305|PubMed:19243433}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=H(+) + 2 methylcob(III)alamin-[methionine synthase] + NADP(+)
CC + 2 S-adenosyl-L-homocysteine = 2 cob(II)alamin-[methionine synthase]
CC + NADPH + 2 S-adenosyl-L-methionine; Xref=Rhea:RHEA:23908, Rhea:RHEA-
CC COMP:14714, Rhea:RHEA-COMP:14715, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:16304, ChEBI:CHEBI:28115, ChEBI:CHEBI:57783,
CC ChEBI:CHEBI:57856, ChEBI:CHEBI:58349, ChEBI:CHEBI:59789; EC=1.16.1.8;
CC Evidence={ECO:0000269|PubMed:17892308};
CC PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:23910;
CC Evidence={ECO:0000305|PubMed:17892308};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=A + 2 cob(II)alamin + 2 H(+) + 2 H2O = AH2 + 2
CC aquacob(III)alamin; Xref=Rhea:RHEA:20752, ChEBI:CHEBI:13193,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:15852,
CC ChEBI:CHEBI:16304, ChEBI:CHEBI:17499;
CC Evidence={ECO:0000269|PubMed:16769880};
CC PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:20754;
CC Evidence={ECO:0000305|PubMed:16769880};
CC -!- COFACTOR:
CC Name=FAD; Xref=ChEBI:CHEBI:57692;
CC Evidence={ECO:0000269|PubMed:17892308};
CC -!- COFACTOR:
CC Name=FMN; Xref=ChEBI:CHEBI:58210;
CC Evidence={ECO:0000269|PubMed:17892308};
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=2.89 uM for NADPH {ECO:0000269|PubMed:17892308};
CC KM=3540 uM for NADH {ECO:0000269|PubMed:17892308};
CC KM=3.7 uM for aquacob(III)alamin (at 37 degrees Celsius, pH 7.2)
CC {ECO:0000269|PubMed:16769880};
CC Note=kcat is 3.92 sec(-1) for the reduction of cytochrome c3 with
CC NADPH (PubMed:17892308). kcat is 0.24 sec(-1) for the reduction of
CC cytochrome c3 with NADH (PubMed:17892308). kcat is 220 min(-1) for
CC aquacob(III)alamin reduction (PubMed:16769880).
CC {ECO:0000269|PubMed:16769880, ECO:0000269|PubMed:17892308};
CC -!- SUBUNIT: Forms a multiprotein complex with MMACHC, MMADHC AND MTR.
CC {ECO:0000269|PubMed:27771510}.
CC -!- INTERACTION:
CC Q9UBK8; Q53SE7: FLJ13057; NbExp=3; IntAct=EBI-10319161, EBI-10172181;
CC -!- SUBCELLULAR LOCATION: [Isoform B]: Cytoplasm.
CC -!- SUBCELLULAR LOCATION: [Isoform A]: Cytoplasm
CC {ECO:0000269|PubMed:18221906}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=B;
CC IsoId=Q9UBK8-2; Sequence=Displayed;
CC Name=A;
CC IsoId=Q9UBK8-1; Sequence=VSP_060027;
CC -!- TISSUE SPECIFICITY: Found in all tissues tested, particularly abundant
CC in skeletal muscle.
CC -!- DISEASE: Homocystinuria-megaloblastic anemia, cblE complementation type
CC (HMAE) [MIM:236270]: An autosomal recessive inborn error of metabolism
CC resulting from defects in the cobalamin-dependent pathway that converts
CC homocysteine to methionine. It causes delayed psychomotor development,
CC megaloblastic anemia, homocystinuria, and hypomethioninemia. Cells from
CC patients with HMAE fail to incorporate methyltetrahydrofolate into
CC methionine in whole cells, but cell extracts show normal methionine
CC synthase activity in the presence of a reducing agent.
CC {ECO:0000269|PubMed:10484769, ECO:0000269|PubMed:9501215}. Note=The
CC disease is caused by variants affecting the gene represented in this
CC entry.
CC -!- DISEASE: Neural tube defects, folate-sensitive (NTDFS) [MIM:601634]:
CC The most common NTDs are open spina bifida (myelomeningocele) and
CC anencephaly. {ECO:0000269|PubMed:10444342,
CC ECO:0000269|PubMed:12375236}. Note=Disease susceptibility is associated
CC with variants affecting the gene represented in this entry.
CC -!- MISCELLANEOUS: It is debated whether the reduction of free
CC aquacob(II)alamin occurs spontaneously or is enzyme catalyzed.
CC {ECO:0000305}.
CC -!- WEB RESOURCE: Name=Protein Spotlight; Note=The hidden things - Issue
CC 166 of December 2014;
CC URL="https://web.expasy.org/spotlight/back_issues/166/";
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DR EMBL; AF121213; AAF17303.1; -; Genomic_DNA.
DR EMBL; AF121202; AAF17303.1; JOINED; Genomic_DNA.
DR EMBL; AF121203; AAF17303.1; JOINED; Genomic_DNA.
DR EMBL; AF121204; AAF17303.1; JOINED; Genomic_DNA.
DR EMBL; AF121205; AAF17303.1; JOINED; Genomic_DNA.
DR EMBL; AF121206; AAF17303.1; JOINED; Genomic_DNA.
DR EMBL; AF121207; AAF17303.1; JOINED; Genomic_DNA.
DR EMBL; AF121208; AAF17303.1; JOINED; Genomic_DNA.
DR EMBL; AF121209; AAF17303.1; JOINED; Genomic_DNA.
DR EMBL; AF121210; AAF17303.1; JOINED; Genomic_DNA.
DR EMBL; AF121211; AAF17303.1; JOINED; Genomic_DNA.
DR EMBL; AF121212; AAF17303.1; JOINED; Genomic_DNA.
DR EMBL; AF121214; AAF16876.1; -; mRNA.
DR EMBL; AF121213; AAF17304.1; -; Genomic_DNA.
DR EMBL; AF121202; AAF17304.1; JOINED; Genomic_DNA.
DR EMBL; AF121203; AAF17304.1; JOINED; Genomic_DNA.
DR EMBL; AF121204; AAF17304.1; JOINED; Genomic_DNA.
DR EMBL; AF121205; AAF17304.1; JOINED; Genomic_DNA.
DR EMBL; AF121206; AAF17304.1; JOINED; Genomic_DNA.
DR EMBL; AF121207; AAF17304.1; JOINED; Genomic_DNA.
DR EMBL; AF121208; AAF17304.1; JOINED; Genomic_DNA.
DR EMBL; AF121209; AAF17304.1; JOINED; Genomic_DNA.
DR EMBL; AF121210; AAF17304.1; JOINED; Genomic_DNA.
DR EMBL; AF121211; AAF17304.1; JOINED; Genomic_DNA.
DR EMBL; AF121212; AAF17304.1; JOINED; Genomic_DNA.
DR EMBL; AF025794; AAC39667.1; -; mRNA.
DR EMBL; AC010346; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC025174; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC054816; AAH54816.2; -; mRNA.
DR EMBL; BC109216; AAI09217.1; -; mRNA.
DR CCDS; CCDS3874.1; -. [Q9UBK8-2]
DR CCDS; CCDS47190.1; -. [Q9UBK8-2]
DR RefSeq; NP_002445.2; NM_002454.2. [Q9UBK8-2]
DR RefSeq; NP_076915.2; NM_024010.2. [Q9UBK8-2]
DR PDB; 2QTL; X-ray; 1.90 A; A=165-698.
DR PDB; 2QTZ; X-ray; 1.90 A; A=165-698.
DR PDBsum; 2QTL; -.
DR PDBsum; 2QTZ; -.
DR AlphaFoldDB; Q9UBK8; -.
DR SMR; Q9UBK8; -.
DR BioGRID; 110645; 15.
DR DIP; DIP-61183N; -.
DR IntAct; Q9UBK8; 9.
DR STRING; 9606.ENSP00000264668; -.
DR DrugBank; DB00115; Cyanocobalamin.
DR DrugBank; DB00134; Methionine.
DR DrugCentral; Q9UBK8; -.
DR GlyGen; Q9UBK8; 1 site, 1 O-linked glycan (1 site).
DR iPTMnet; Q9UBK8; -.
DR PhosphoSitePlus; Q9UBK8; -.
DR SwissPalm; Q9UBK8; -.
DR BioMuta; MTRR; -.
DR DMDM; 296439300; -.
DR EPD; Q9UBK8; -.
DR jPOST; Q9UBK8; -.
DR MassIVE; Q9UBK8; -.
DR MaxQB; Q9UBK8; -.
DR PaxDb; Q9UBK8; -.
DR PeptideAtlas; Q9UBK8; -.
DR PRIDE; Q9UBK8; -.
DR ProteomicsDB; 83984; -. [Q9UBK8-1]
DR ProteomicsDB; 83985; -. [Q9UBK8-2]
DR Antibodypedia; 22429; 91 antibodies from 20 providers.
DR DNASU; 4552; -.
DR Ensembl; ENST00000264668.6; ENSP00000264668.2; ENSG00000124275.15. [Q9UBK8-1]
DR Ensembl; ENST00000440940.7; ENSP00000402510.2; ENSG00000124275.15. [Q9UBK8-2]
DR GeneID; 4552; -.
DR KEGG; hsa:4552; -.
DR MANE-Select; ENST00000440940.7; ENSP00000402510.2; NM_002454.3; NP_002445.2.
DR UCSC; uc003jed.4; human. [Q9UBK8-2]
DR CTD; 4552; -.
DR DisGeNET; 4552; -.
DR GeneCards; MTRR; -.
DR GeneReviews; MTRR; -.
DR HGNC; HGNC:7473; MTRR.
DR HPA; ENSG00000124275; Low tissue specificity.
DR MalaCards; MTRR; -.
DR MIM; 236270; phenotype.
DR MIM; 601634; phenotype.
DR MIM; 602568; gene.
DR neXtProt; NX_Q9UBK8; -.
DR OpenTargets; ENSG00000124275; -.
DR Orphanet; 2169; Methylcobalamin deficiency type cblE.
DR PharmGKB; PA31277; -.
DR VEuPathDB; HostDB:ENSG00000124275; -.
DR eggNOG; KOG1158; Eukaryota.
DR GeneTree; ENSGT00940000155822; -.
DR HOGENOM; CLU_001570_17_7_1; -.
DR InParanoid; Q9UBK8; -.
DR OMA; TDRREHC; -.
DR OrthoDB; 318396at2759; -.
DR PhylomeDB; Q9UBK8; -.
DR TreeFam; TF105716; -.
DR BioCyc; MetaCyc:HS04756-MON; -.
DR BRENDA; 1.16.1.8; 2681.
DR PathwayCommons; Q9UBK8; -.
DR Reactome; R-HSA-156581; Methylation.
DR Reactome; R-HSA-1614635; Sulfur amino acid metabolism.
DR Reactome; R-HSA-3359467; Defective MTRR causes HMAE.
DR Reactome; R-HSA-3359469; Defective MTR causes HMAG.
DR Reactome; R-HSA-9759218; Cobalamin (Cbl) metabolism.
DR SABIO-RK; Q9UBK8; -.
DR SignaLink; Q9UBK8; -.
DR BioGRID-ORCS; 4552; 39 hits in 1092 CRISPR screens.
DR ChiTaRS; MTRR; human.
DR EvolutionaryTrace; Q9UBK8; -.
DR GeneWiki; MTRR_(gene); -.
DR GenomeRNAi; 4552; -.
DR Pharos; Q9UBK8; Tbio.
DR PRO; PR:Q9UBK8; -.
DR Proteomes; UP000005640; Chromosome 5.
DR RNAct; Q9UBK8; protein.
DR Bgee; ENSG00000124275; Expressed in endothelial cell and 197 other tissues.
DR ExpressionAtlas; Q9UBK8; baseline and differential.
DR Genevisible; Q9UBK8; HS.
DR GO; GO:0005829; C:cytosol; IDA:HPA.
DR GO; GO:0045111; C:intermediate filament cytoskeleton; IDA:HPA.
DR GO; GO:0005654; C:nucleoplasm; IDA:HPA.
DR GO; GO:0030586; F:[methionine synthase] reductase activity; IDA:BHF-UCL.
DR GO; GO:0071949; F:FAD binding; IDA:BHF-UCL.
DR GO; GO:0050660; F:flavin adenine dinucleotide binding; IDA:UniProtKB.
DR GO; GO:0010181; F:FMN binding; IDA:BHF-UCL.
DR GO; GO:0070402; F:NADPH binding; IDA:BHF-UCL.
DR GO; GO:0003958; F:NADPH-hemoprotein reductase activity; IDA:BHF-UCL.
DR GO; GO:0016491; F:oxidoreductase activity; IBA:GO_Central.
DR GO; GO:0016723; F:oxidoreductase activity, acting on metal ions, NAD or NADP as acceptor; IDA:UniProtKB.
DR GO; GO:0006306; P:DNA methylation; ISS:UniProtKB.
DR GO; GO:0046655; P:folic acid metabolic process; IDA:BHF-UCL.
DR GO; GO:0043418; P:homocysteine catabolic process; IDA:BHF-UCL.
DR GO; GO:0050667; P:homocysteine metabolic process; IBA:GO_Central.
DR GO; GO:0009086; P:methionine biosynthetic process; IDA:BHF-UCL.
DR GO; GO:1904042; P:negative regulation of cystathionine beta-synthase activity; IDA:BHF-UCL.
DR GO; GO:0033353; P:S-adenosylmethionine cycle; ISS:BHF-UCL.
DR Gene3D; 1.20.990.10; -; 1.
DR Gene3D; 3.40.50.360; -; 1.
DR Gene3D; 3.40.50.80; -; 1.
DR InterPro; IPR003097; CysJ-like_FAD-binding.
DR InterPro; IPR017927; FAD-bd_FR_type.
DR InterPro; IPR001094; Flavdoxin-like.
DR InterPro; IPR008254; Flavodoxin/NO_synth.
DR InterPro; IPR001709; Flavoprot_Pyr_Nucl_cyt_Rdtase.
DR InterPro; IPR029039; Flavoprotein-like_sf.
DR InterPro; IPR039261; FNR_nucleotide-bd.
DR InterPro; IPR023173; NADPH_Cyt_P450_Rdtase_alpha.
DR InterPro; IPR001433; OxRdtase_FAD/NAD-bd.
DR InterPro; IPR017938; Riboflavin_synthase-like_b-brl.
DR Pfam; PF00667; FAD_binding_1; 1.
DR Pfam; PF00258; Flavodoxin_1; 1.
DR Pfam; PF00175; NAD_binding_1; 1.
DR PRINTS; PR00369; FLAVODOXIN.
DR PRINTS; PR00371; FPNCR.
DR SUPFAM; SSF52218; SSF52218; 1.
DR SUPFAM; SSF52343; SSF52343; 1.
DR SUPFAM; SSF63380; SSF63380; 1.
DR PROSITE; PS51384; FAD_FR; 1.
DR PROSITE; PS50902; FLAVODOXIN_LIKE; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Amino-acid biosynthesis; Cytoplasm;
KW Disease variant; FAD; Flavoprotein; FMN; Methionine biosynthesis; NADP;
KW Oxidoreductase; Phosphoprotein; Reference proteome;
KW S-adenosyl-L-methionine.
FT CHAIN 1..698
FT /note="Methionine synthase reductase"
FT /id="PRO_0000021785"
FT DOMAIN 5..147
FT /note="Flavodoxin-like"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00088"
FT DOMAIN 271..533
FT /note="FAD-binding FR-type"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00716"
FT REGION 166..247
FT /note="Hinge"
FT BINDING 93..124
FT /ligand="FMN"
FT /ligand_id="ChEBI:CHEBI:58210"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00088"
FT BINDING 291
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000269|PubMed:17892308"
FT BINDING 451..454
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000269|PubMed:17892308"
FT BINDING 487..490
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000269|PubMed:17892308"
FT BINDING 610..611
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000269|PubMed:17892308"
FT BINDING 624..626
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000269|PubMed:17892308"
FT BINDING 659
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000269|PubMed:17892308"
FT BINDING 697
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000269|PubMed:17892308"
FT MOD_RES 171
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:20068231,
FT ECO:0007744|PubMed:23186163"
FT MOD_RES 189
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163,
FT ECO:0007744|PubMed:24275569"
FT VAR_SEQ 1
FT /note="M -> MGAASVRAGARLVEVALCSFTVTCLEVM (in isoform A)"
FT /evidence="ECO:0000303|PubMed:10564814,
FT ECO:0000303|PubMed:15489334, ECO:0000303|PubMed:9501215"
FT /id="VSP_060027"
FT VARIANT 22
FT /note="I -> M (may increase risk for spina bifida;
FT dbSNP:rs1801394)"
FT /evidence="ECO:0000269|PubMed:10444342,
FT ECO:0000269|PubMed:12375236, ECO:0000269|PubMed:15979034"
FT /id="VAR_012836"
FT VARIANT 54
FT /note="Missing (in HMAE)"
FT /evidence="ECO:0000269|PubMed:10484769"
FT /id="VAR_012837"
FT VARIANT 56
FT /note="V -> M (in HMAE; dbSNP:rs761061866)"
FT /evidence="ECO:0000269|PubMed:10484769"
FT /id="VAR_012838"
FT VARIANT 129
FT /note="A -> T (in HMAE)"
FT /evidence="ECO:0000269|PubMed:10484769"
FT /id="VAR_012839"
FT VARIANT 175
FT /note="S -> L (in dbSNP:rs1532268)"
FT /evidence="ECO:0000269|PubMed:10564814,
FT ECO:0000269|PubMed:15979034, ECO:0000269|PubMed:9501215,
FT ECO:0007744|PubMed:23186163"
FT /id="VAR_034595"
FT VARIANT 257
FT /note="S -> T (in dbSNP:rs2303080)"
FT /id="VAR_034596"
FT VARIANT 333
FT /note="L -> V (in dbSNP:rs10064631)"
FT /evidence="ECO:0000269|PubMed:10484769"
FT /id="VAR_012840"
FT VARIANT 350
FT /note="K -> R (in dbSNP:rs162036)"
FT /evidence="ECO:0000269|PubMed:15979034"
FT /id="VAR_034597"
FT VARIANT 405
FT /note="C -> R (in HMAE)"
FT /evidence="ECO:0000269|PubMed:10484769"
FT /id="VAR_012841"
FT VARIANT 415
FT /note="R -> C (in dbSNP:rs2287780)"
FT /id="VAR_034598"
FT VARIANT 450
FT /note="P -> R (in dbSNP:rs16879334)"
FT /id="VAR_034599"
FT VARIANT 487
FT /note="G -> R (in HMAE; dbSNP:rs137853061)"
FT /evidence="ECO:0000269|PubMed:10484769"
FT /id="VAR_012842"
FT VARIANT 515
FT /note="A -> V (in dbSNP:rs16879355)"
FT /id="VAR_056947"
FT VARIANT 554
FT /note="G -> R (in HMAE)"
FT /evidence="ECO:0000269|PubMed:10484769"
FT /id="VAR_015731"
FT VARIANT 576
FT /note="Missing (in HMAE)"
FT /evidence="ECO:0000269|PubMed:9501215"
FT /id="VAR_012843"
FT VARIANT 595
FT /note="H -> Y (in dbSNP:rs10380)"
FT /id="VAR_014944"
FT HELIX 235..237
FT /evidence="ECO:0007829|PDB:2QTL"
FT STRAND 250..255
FT /evidence="ECO:0007829|PDB:2QTL"
FT STRAND 274..283
FT /evidence="ECO:0007829|PDB:2QTL"
FT STRAND 293..299
FT /evidence="ECO:0007829|PDB:2QTL"
FT STRAND 312..316
FT /evidence="ECO:0007829|PDB:2QTL"
FT HELIX 321..330
FT /evidence="ECO:0007829|PDB:2QTL"
FT HELIX 334..336
FT /evidence="ECO:0007829|PDB:2QTL"
FT STRAND 339..345
FT /evidence="ECO:0007829|PDB:2QTL"
FT HELIX 366..372
FT /evidence="ECO:0007829|PDB:2QTL"
FT HELIX 382..389
FT /evidence="ECO:0007829|PDB:2QTL"
FT HELIX 395..405
FT /evidence="ECO:0007829|PDB:2QTL"
FT HELIX 410..416
FT /evidence="ECO:0007829|PDB:2QTL"
FT TURN 417..421
FT /evidence="ECO:0007829|PDB:2QTL"
FT HELIX 424..430
FT /evidence="ECO:0007829|PDB:2QTL"
FT HELIX 438..444
FT /evidence="ECO:0007829|PDB:2QTL"
FT STRAND 451..454
FT /evidence="ECO:0007829|PDB:2QTL"
FT TURN 459..461
FT /evidence="ECO:0007829|PDB:2QTL"
FT STRAND 465..471
FT /evidence="ECO:0007829|PDB:2QTL"
FT STRAND 474..476
FT /evidence="ECO:0007829|PDB:2QTL"
FT STRAND 483..486
FT /evidence="ECO:0007829|PDB:2QTL"
FT HELIX 488..496
FT /evidence="ECO:0007829|PDB:2QTL"
FT TURN 497..500
FT /evidence="ECO:0007829|PDB:2QTL"
FT STRAND 519..524
FT /evidence="ECO:0007829|PDB:2QTL"
FT STRAND 540..543
FT /evidence="ECO:0007829|PDB:2QTL"
FT HELIX 546..549
FT /evidence="ECO:0007829|PDB:2QTL"
FT HELIX 550..565
FT /evidence="ECO:0007829|PDB:2QTL"
FT STRAND 574..581
FT /evidence="ECO:0007829|PDB:2QTL"
FT TURN 583..585
FT /evidence="ECO:0007829|PDB:2QTL"
FT HELIX 590..598
FT /evidence="ECO:0007829|PDB:2QTL"
FT STRAND 604..612
FT /evidence="ECO:0007829|PDB:2QTL"
FT HELIX 625..631
FT /evidence="ECO:0007829|PDB:2QTL"
FT HELIX 633..642
FT /evidence="ECO:0007829|PDB:2QTL"
FT STRAND 646..652
FT /evidence="ECO:0007829|PDB:2QTL"
FT HELIX 654..672
FT /evidence="ECO:0007829|PDB:2QTL"
FT HELIX 676..688
FT /evidence="ECO:0007829|PDB:2QTL"
FT STRAND 691..696
FT /evidence="ECO:0007829|PDB:2QTL"
SQ SEQUENCE 698 AA; 77674 MW; D4B394F0B24A07E5 CRC64;
MRRFLLLYAT QQGQAKAIAE EICEQAVVHG FSADLHCISE SDKYDLKTET APLVVVVSTT
GTGDPPDTAR KFVKEIQNQT LPVDFFAHLR YGLLGLGDSE YTYFCNGGKI IDKRLQELGA
RHFYDTGHAD DCVGLELVVE PWIAGLWPAL RKHFRSSRGQ EEISGALPVA SPASSRTDLV
KSELLHIESQ VELLRFDDSG RKDSEVLKQN AVNSNQSNVV IEDFESSLTR SVPPLSQASL
NIPGLPPEYL QVHLQESLGQ EESQVSVTSA DPVFQVPISK AVQLTTNDAI KTTLLVELDI
SNTDFSYQPG DAFSVICPNS DSEVQSLLQR LQLEDKREHC VLLKIKADTK KKGATLPQHI
PAGCSLQFIF TWCLEIRAIP KKAFLRALVD YTSDSAEKRR LQELCSKQGA ADYSRFVRDA
CACLLDLLLA FPSCQPPLSL LLEHLPKLQP RPYSCASSSL FHPGKLHFVF NIVEFLSTAT
TEVLRKGVCT GWLALLVASV LQPNIHASHE DSGKALAPKI SISPRTTNSF HLPDDPSIPI
IMVGPGTGIA PFIGFLQHRE KLQEQHPDGN FGAMWLFFGC RHKDRDYLFR KELRHFLKHG
ILTHLKVSFS RDAPVGEEEA PAKYVQDNIQ LHGQQVARIL LQENGHIYVC GDAKNMAKDV
HDALVQIISK EVGVEKLEAM KTLATLKEEK RYLQDIWS
