UniProtKB - Q9UBK8 (MTRR_HUMAN)
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Protein
Methionine synthase reductase
Gene
MTRR
Organism
Homo sapiens (Human)
Status
Functioni
Involved in the reductive regeneration of cob(I)alamin (vitamin B12) cofactor required for the maintenance of methionine synthase in a functional state. Necessary for utilization of methylgroups from the folate cycle, thereby affecting transgenerational epigenetic inheritance. Folate pathway donates methyl groups necessary for cellular methylation and affects different pathways such as DNA methylation, possibly explaining the transgenerational epigenetic inheritance effects.1 Publication
Catalytic activityi
2 [methionine synthase]-methylcob(I)alamin + 2 S-adenosylhomocysteine + NADP+ = 2 [methionine synthase]-cob(II)alamin + NADPH + 2 S-adenosyl-L-methionine.1 Publication
Cofactori
Protein has several cofactor binding sites:Kineticsi
- KM=2.89 µM for NADPH1 Publication
- KM=3540 µM for NADH1 Publication
Sites
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Binding sitei | 318 | NADP1 Publication | 1 | |
Binding sitei | 686 | NADP1 Publication | 1 | |
Binding sitei | 724 | FAD1 Publication | 1 |
Regions
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Nucleotide bindingi | 120 – 151 | FMNPROSITE-ProRule annotationAdd BLAST | 32 | |
Nucleotide bindingi | 478 – 481 | FAD1 Publication | 4 | |
Nucleotide bindingi | 514 – 517 | FAD1 Publication | 4 | |
Nucleotide bindingi | 637 – 638 | NADP1 Publication | 2 | |
Nucleotide bindingi | 651 – 653 | NADP1 Publication | 3 |
GO - Molecular functioni
- [methionine synthase] reductase activity Source: BHF-UCL
- aquacobalamin reductase (NADPH) activity Source: CACAO
- FAD binding Source: BHF-UCL
- flavin adenine dinucleotide binding Source: UniProtKB
- FMN binding Source: BHF-UCL
- NADP binding Source: UniProtKB
- NADPH binding Source: BHF-UCL
- NADPH-hemoprotein reductase activity Source: BHF-UCL
- oxidoreductase activity, oxidizing metal ions, NAD or NADP as acceptor Source: UniProtKB
GO - Biological processi
- cobalamin metabolic process Source: Reactome
- DNA methylation Source: UniProtKB
- folic acid metabolic process Source: BHF-UCL
- homocysteine catabolic process Source: BHF-UCL
- methionine biosynthetic process Source: BHF-UCL
- methionine metabolic process Source: UniProtKB
- methylation Source: Reactome
- negative regulation of cystathionine beta-synthase activity Source: BHF-UCL
- oxidation-reduction process Source: UniProtKB
- S-adenosylmethionine cycle Source: BHF-UCL
- sulfur amino acid metabolic process Source: Reactome
Keywordsi
Molecular function | Oxidoreductase |
Biological process | Amino-acid biosynthesis, Methionine biosynthesis |
Ligand | FAD, Flavoprotein, FMN, NADP, S-adenosyl-L-methionine |
Enzyme and pathway databases
BioCyci | MetaCyc:HS04756-MONOMER. |
BRENDAi | 1.16.1.8. 2681. |
Reactomei | R-HSA-156581. Methylation. R-HSA-1614635. Sulfur amino acid metabolism. R-HSA-196741. Cobalamin (Cbl, vitamin B12) transport and metabolism. R-HSA-3359467. Defective MTRR causes methylmalonic aciduria and homocystinuria type cblE. R-HSA-3359469. Defective MTR causes methylmalonic aciduria and homocystinuria type cblG. |
SABIO-RKi | Q9UBK8. |
Names & Taxonomyi
Protein namesi | |
Gene namesi | Name:MTRR |
Organismi | Homo sapiens (Human) |
Taxonomic identifieri | 9606 [NCBI] |
Taxonomic lineagei | Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo |
Proteomesi |
|
Organism-specific databases
EuPathDBi | HostDB:ENSG00000124275.14. |
HGNCi | HGNC:7473. MTRR. |
MIMi | 602568. gene. |
neXtProti | NX_Q9UBK8. |
Pathology & Biotechi
Involvement in diseasei
Homocystinuria-megaloblastic anemia, cblE complementation type (HMAE)2 Publications
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionAn autosomal recessive inborn error of metabolism resulting from defects in the cobalamin-dependent pathway that converts homocysteine to methionine. It causes delayed psychomotor development, megaloblastic anemia, homocystinuria, and hypomethioninemia. Cells from patients with HMAE fail to incorporate methyltetrahydrofolate into methionine in whole cells, but cell extracts show normal methionine synthase activity in the presence of a reducing agent.
See also OMIM:236270Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Natural variantiVAR_012837 | 81 | Missing in HMAE. 1 Publication | 1 | |
Natural variantiVAR_012838 | 83 | V → M in HMAE. 1 PublicationCorresponds to variant dbSNP:rs761061866Ensembl. | 1 | |
Natural variantiVAR_012839 | 156 | A → T in HMAE. 1 Publication | 1 | |
Natural variantiVAR_012841 | 432 | C → R in HMAE. 1 Publication | 1 | |
Natural variantiVAR_012842 | 514 | G → R in HMAE. 1 PublicationCorresponds to variant dbSNP:rs137853061Ensembl. | 1 | |
Natural variantiVAR_015731 | 581 | G → R in HMAE. 1 Publication | 1 | |
Natural variantiVAR_012843 | 603 | Missing in HMAE. 1 Publication | 1 |
Neural tube defects, folate-sensitive (NTDFS)2 Publications
Disease susceptibility is associated with variations affecting the gene represented in this entry.
Disease descriptionThe most common NTDs are open spina bifida (myelomeningocele) and anencephaly.
See also OMIM:601634Keywords - Diseasei
Disease mutationOrganism-specific databases
DisGeNETi | 4552. |
GeneReviewsi | MTRR. |
MalaCardsi | MTRR. |
MIMi | 236270. phenotype. 601634. phenotype. |
OpenTargetsi | ENSG00000124275. |
Orphaneti | 2169. Methylcobalamin deficiency type cblE. |
PharmGKBi | PA31277. |
Chemistry databases
DrugBanki | DB00115. Cyanocobalamin. DB00200. Hydroxocobalamin. DB00134. L-Methionine. |
Polymorphism and mutation databases
BioMutai | MTRR. |
DMDMi | 296439300. |
PTM / Processingi
Molecule processing
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
ChainiPRO_0000021785 | 1 – 725 | Methionine synthase reductaseAdd BLAST | 725 |
Amino acid modifications
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Modified residuei | 198 | PhosphoserineCombined sources | 1 | |
Modified residuei | 216 | PhosphoserineCombined sources | 1 |
Keywords - PTMi
PhosphoproteinProteomic databases
EPDi | Q9UBK8. |
MaxQBi | Q9UBK8. |
PaxDbi | Q9UBK8. |
PeptideAtlasi | Q9UBK8. |
PRIDEi | Q9UBK8. |
PTM databases
iPTMneti | Q9UBK8. |
PhosphoSitePlusi | Q9UBK8. |
SwissPalmi | Q9UBK8. |
Expressioni
Tissue specificityi
Found in all tissues tested, particularly abundant in skeletal muscle.
Gene expression databases
Bgeei | ENSG00000124275. |
CleanExi | HS_MTRR. |
ExpressionAtlasi | Q9UBK8. baseline and differential. |
Genevisiblei | Q9UBK8. HS. |
Organism-specific databases
HPAi | HPA038113. |
Interactioni
Binary interactionsi
With | Entry | #Exp. | IntAct | Notes |
---|---|---|---|---|
FLJ13057 | Q53SE7 | 3 | EBI-10319161,EBI-10172181 |
Protein-protein interaction databases
BioGridi | 110645. 14 interactors. |
DIPi | DIP-61183N. |
IntActi | Q9UBK8. 9 interactors. |
STRINGi | 9606.ENSP00000264668. |
Structurei
Secondary structure
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more detailsFeature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Helixi | 262 – 264 | Combined sources | 3 | |
Beta strandi | 277 – 282 | Combined sources | 6 | |
Beta strandi | 301 – 310 | Combined sources | 10 | |
Beta strandi | 320 – 326 | Combined sources | 7 | |
Beta strandi | 339 – 343 | Combined sources | 5 | |
Helixi | 348 – 357 | Combined sources | 10 | |
Helixi | 361 – 363 | Combined sources | 3 | |
Beta strandi | 366 – 372 | Combined sources | 7 | |
Helixi | 393 – 399 | Combined sources | 7 | |
Helixi | 409 – 416 | Combined sources | 8 | |
Helixi | 422 – 432 | Combined sources | 11 | |
Helixi | 437 – 443 | Combined sources | 7 | |
Turni | 444 – 448 | Combined sources | 5 | |
Helixi | 451 – 457 | Combined sources | 7 | |
Helixi | 465 – 471 | Combined sources | 7 | |
Beta strandi | 478 – 481 | Combined sources | 4 | |
Turni | 486 – 488 | Combined sources | 3 | |
Beta strandi | 492 – 498 | Combined sources | 7 | |
Beta strandi | 501 – 503 | Combined sources | 3 | |
Beta strandi | 510 – 513 | Combined sources | 4 | |
Helixi | 515 – 523 | Combined sources | 9 | |
Turni | 524 – 527 | Combined sources | 4 | |
Beta strandi | 546 – 551 | Combined sources | 6 | |
Beta strandi | 567 – 570 | Combined sources | 4 | |
Helixi | 573 – 576 | Combined sources | 4 | |
Helixi | 577 – 592 | Combined sources | 16 | |
Beta strandi | 601 – 608 | Combined sources | 8 | |
Turni | 610 – 612 | Combined sources | 3 | |
Helixi | 617 – 625 | Combined sources | 9 | |
Beta strandi | 631 – 639 | Combined sources | 9 | |
Helixi | 652 – 658 | Combined sources | 7 | |
Helixi | 660 – 669 | Combined sources | 10 | |
Beta strandi | 673 – 679 | Combined sources | 7 | |
Helixi | 681 – 699 | Combined sources | 19 | |
Helixi | 703 – 715 | Combined sources | 13 | |
Beta strandi | 718 – 723 | Combined sources | 6 |
3D structure databases
Select the link destinations: PDBei RCSB PDBi PDBji Links Updated | PDB entry | Method | Resolution (Å) | Chain | Positions | PDBsum |
2QTL | X-ray | 1.90 | A | 192-725 | [»] | |
2QTZ | X-ray | 1.90 | A | 192-725 | [»] | |
ProteinModelPortali | Q9UBK8. | |||||
SMRi | Q9UBK8. | |||||
ModBasei | Search... | |||||
MobiDBi | Search... |
Miscellaneous databases
EvolutionaryTracei | Q9UBK8. |
Family & Domainsi
Domains and Repeats
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Domaini | 32 – 174 | Flavodoxin-likePROSITE-ProRule annotationAdd BLAST | 143 | |
Domaini | 298 – 560 | FAD-binding FR-typePROSITE-ProRule annotationAdd BLAST | 263 |
Region
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Regioni | 193 – 274 | HingeAdd BLAST | 82 |
Phylogenomic databases
eggNOGi | KOG1158. Eukaryota. COG0369. LUCA. |
GeneTreei | ENSGT00840000129757. |
HOGENOMi | HOG000007485. |
HOVERGENi | HBG108376. |
InParanoidi | Q9UBK8. |
KOi | K00597. |
OMAi | PWIAGLW. |
OrthoDBi | EOG091G045Q. |
PhylomeDBi | Q9UBK8. |
TreeFami | TF105716. |
Family and domain databases
Gene3Di | 1.20.990.10. 2 hits. 3.40.50.360. 1 hit. |
InterProi | View protein in InterPro IPR003097. FAD-binding_1. IPR017927. Fd_Rdtase_FAD-bd. IPR001094. Flavdoxin-like. IPR008254. Flavodoxin/NO_synth. IPR001709. Flavoprot_Pyr_Nucl_cyt_Rdtase. IPR029039. Flavoprotein-like_sf. IPR023173. NADPH_Cyt_P450_Rdtase_alpha. IPR001433. OxRdtase_FAD/NAD-bd. IPR017938. Riboflavin_synthase-like_b-brl. |
Pfami | View protein in Pfam PF00667. FAD_binding_1. 1 hit. PF00258. Flavodoxin_1. 1 hit. PF00175. NAD_binding_1. 1 hit. |
PRINTSi | PR00369. FLAVODOXIN. PR00371. FPNCR. |
SUPFAMi | SSF52218. SSF52218. 1 hit. SSF63380. SSF63380. 1 hit. |
PROSITEi | View protein in PROSITE PS51384. FAD_FR. 1 hit. PS50902. FLAVODOXIN_LIKE. 1 hit. |
s (3)i Sequence
Sequence statusi: Complete.
This entry describes 3 produced by isoformsialternative splicing. AlignAdd to basket
Isoform A (identifier: Q9UBK8-1) [UniParc]FASTAAdd to basket
This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.
10 20 30 40 50
MGAASVRAGA RLVEVALCSF TVTCLEVMRR FLLLYATQQG QAKAIAEEIC
60 70 80 90 100
EQAVVHGFSA DLHCISESDK YDLKTETAPL VVVVSTTGTG DPPDTARKFV
110 120 130 140 150
KEIQNQTLPV DFFAHLRYGL LGLGDSEYTY FCNGGKIIDK RLQELGARHF
160 170 180 190 200
YDTGHADDCV GLELVVEPWI AGLWPALRKH FRSSRGQEEI SGALPVASPA
210 220 230 240 250
SSRTDLVKSE LLHIESQVEL LRFDDSGRKD SEVLKQNAVN SNQSNVVIED
260 270 280 290 300
FESSLTRSVP PLSQASLNIP GLPPEYLQVH LQESLGQEES QVSVTSADPV
310 320 330 340 350
FQVPISKAVQ LTTNDAIKTT LLVELDISNT DFSYQPGDAF SVICPNSDSE
360 370 380 390 400
VQSLLQRLQL EDKREHCVLL KIKADTKKKG ATLPQHIPAG CSLQFIFTWC
410 420 430 440 450
LEIRAIPKKA FLRALVDYTS DSAEKRRLQE LCSKQGAADY SRFVRDACAC
460 470 480 490 500
LLDLLLAFPS CQPPLSLLLE HLPKLQPRPY SCASSSLFHP GKLHFVFNIV
510 520 530 540 550
EFLSTATTEV LRKGVCTGWL ALLVASVLQP NIHASHEDSG KALAPKISIS
560 570 580 590 600
PRTTNSFHLP DDPSIPIIMV GPGTGIAPFI GFLQHREKLQ EQHPDGNFGA
610 620 630 640 650
MWLFFGCRHK DRDYLFRKEL RHFLKHGILT HLKVSFSRDA PVGEEEAPAK
660 670 680 690 700
YVQDNIQLHG QQVARILLQE NGHIYVCGDA KNMAKDVHDA LVQIISKEVG
710 720
VEKLEAMKTL ATLKEEKRYL QDIWS
Natural variant
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Natural variantiVAR_012836 | 49 | I → M Polymorphism; may increase risk for spina bifida. 3 PublicationsCorresponds to variant dbSNP:rs1801394Ensembl. | 1 | |
Natural variantiVAR_012837 | 81 | Missing in HMAE. 1 Publication | 1 | |
Natural variantiVAR_012838 | 83 | V → M in HMAE. 1 PublicationCorresponds to variant dbSNP:rs761061866Ensembl. | 1 | |
Natural variantiVAR_012839 | 156 | A → T in HMAE. 1 Publication | 1 | |
Natural variantiVAR_034595 | 202 | S → LCombined sources3 PublicationsCorresponds to variant dbSNP:rs1532268Ensembl. | 1 | |
Natural variantiVAR_034596 | 284 | S → T. Corresponds to variant dbSNP:rs2303080Ensembl. | 1 | |
Natural variantiVAR_012840 | 360 | L → V1 PublicationCorresponds to variant dbSNP:rs10064631Ensembl. | 1 | |
Natural variantiVAR_034597 | 377 | K → R1 PublicationCorresponds to variant dbSNP:rs162036Ensembl. | 1 | |
Natural variantiVAR_012841 | 432 | C → R in HMAE. 1 Publication | 1 | |
Natural variantiVAR_034598 | 442 | R → C. Corresponds to variant dbSNP:rs2287780Ensembl. | 1 | |
Natural variantiVAR_034599 | 477 | P → R. Corresponds to variant dbSNP:rs16879334Ensembl. | 1 | |
Natural variantiVAR_012842 | 514 | G → R in HMAE. 1 PublicationCorresponds to variant dbSNP:rs137853061Ensembl. | 1 | |
Natural variantiVAR_056947 | 542 | A → V. Corresponds to variant dbSNP:rs16879355Ensembl. | 1 | |
Natural variantiVAR_015731 | 581 | G → R in HMAE. 1 Publication | 1 | |
Natural variantiVAR_012843 | 603 | Missing in HMAE. 1 Publication | 1 | |
Natural variantiVAR_014944 | 622 | H → Y. Corresponds to variant dbSNP:rs10380Ensembl. | 1 |
Alternative sequence
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Alternative sequenceiVSP_003910 | 1 – 27 | Missing in isoform B and isoform C. 3 PublicationsAdd BLAST | 27 | |
Alternative sequenceiVSP_003911 | 71 – 85 | YDLKT…VVVVS → VSVIQNTPTFAMGGR in isoform C. 2 PublicationsAdd BLAST | 15 | |
Alternative sequenceiVSP_003912 | 86 – 725 | Missing in isoform C. 2 PublicationsAdd BLAST | 640 |
Sequence databases
Select the link destinations: EMBLi GenBanki DDBJi Links Updated | AF121213 AF121212 Genomic DNA. Translation: AAF17303.1. AF121214 mRNA. Translation: AAF16876.1. AF121213 AF121212 Genomic DNA. Translation: AAF17304.1. AF025794 mRNA. Translation: AAC39667.1. AC010346 Genomic DNA. No translation available. AC025174 Genomic DNA. No translation available. BC054816 mRNA. Translation: AAH54816.2. BC109216 mRNA. Translation: AAI09217.1. |
CCDSi | CCDS3874.1. [Q9UBK8-1] CCDS47190.1. [Q9UBK8-2] |
RefSeqi | NP_002445.2. NM_002454.2. [Q9UBK8-2] NP_076915.2. NM_024010.2. [Q9UBK8-1] |
UniGenei | Hs.481551. |
Genome annotation databases
Ensembli | ENST00000264668; ENSP00000264668; ENSG00000124275. [Q9UBK8-1] ENST00000440940; ENSP00000402510; ENSG00000124275. [Q9UBK8-2] ENST00000510279; ENSP00000427200; ENSG00000124275. [Q9UBK8-3] ENST00000514369; ENSP00000426132; ENSG00000124275. [Q9UBK8-3] |
GeneIDi | 4552. |
KEGGi | hsa:4552. |
UCSCi | uc003jed.4. human. [Q9UBK8-1] |
Keywords - Coding sequence diversityi
Alternative splicing, PolymorphismSimilar proteinsi
Entry informationi
Entry namei | MTRR_HUMAN | |
Accessioni | Q9UBK8Primary (citable) accession number: Q9UBK8 Secondary accession number(s): O60471, Q32MA9, Q7Z4M8 | |
Entry historyi | Integrated into UniProtKB/Swiss-Prot: | March 27, 2002 |
Last sequence update: | May 18, 2010 | |
Last modified: | February 28, 2018 | |
This is version 175 of the entry and version 3 of the sequence. See complete history. | ||
Entry statusi | Reviewed (UniProtKB/Swiss-Prot) | |
Annotation program | Chordata Protein Annotation Program | |
Disclaimer | Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care. |