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   27-MAR-2024, entry version 211.
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; 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; 18.
DR   DIP; DIP-61183N; -.
DR   IntAct; Q9UBK8; 9.
DR   STRING; 9606.ENSP00000402510; -.
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; 9606-ENSP00000264668; -.
DR   PeptideAtlas; Q9UBK8; -.
DR   ProteomicsDB; 83984; -. [Q9UBK8-1]
DR   ProteomicsDB; 83985; -. [Q9UBK8-2]
DR   Pumba; Q9UBK8; -.
DR   Antibodypedia; 22429; 97 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   AGR; HGNC:7473; -.
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; LFFGHQR; -.
DR   OrthoDB; 276396at2759; -.
DR   PhylomeDB; Q9UBK8; -.
DR   TreeFam; TF105716; -.
DR   BioCyc; MetaCyc:HS04756-MONOMER; -.
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; 42 hits in 1172 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 199 other cell types or tissues.
DR   ExpressionAtlas; Q9UBK8; baseline and differential.
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: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   CDD; cd06203; methionine_synthase_red; 1.
DR   Gene3D; 3.40.50.360; -; 1.
DR   Gene3D; 3.40.50.80; Nucleotide-binding domain of ferredoxin-NADP reductase (FNR) module; 1.
DR   Gene3D; 2.40.30.10; Translation factors; 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   PANTHER; PTHR19384:SF84; METHIONINE SYNTHASE REDUCTASE; 1.
DR   PANTHER; PTHR19384; NITRIC OXIDE SYNTHASE-RELATED; 1.
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; SSF52343; Ferredoxin reductase-like, C-terminal NADP-linked domain; 1.
DR   SUPFAM; SSF52218; Flavoproteins; 1.
DR   SUPFAM; SSF63380; Riboflavin synthase domain-like; 1.
DR   PROSITE; PS51384; FAD_FR; 1.
DR   PROSITE; PS50902; FLAVODOXIN_LIKE; 1.
DR   Genevisible; Q9UBK8; HS.
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
//