Target Information
| Target General Information | Top | |||||
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| Target ID |
T21661
(Former ID: TTDR00247)
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| Target Name |
Methionine synthase (MTR)
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| Synonyms |
Methionine synthase, vitamin-B12dependent; MTR; MS; Cobalamin-dependent methionine synthase; B12 dependent methionine synthetase; 5-methyltetrahydrofolate:homocysteine methyltransferase; 5-methyltetrahydrofolate-homocysteine methyltransferase; 5-methyltetrahydrofolate homocysteine methyltransferase
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| Gene Name |
MTR
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| Target Type |
Literature-reported target
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[1] | ||||
| Function |
Catalyzes the transfer of a methyl group from methyl- cobalamin to homocysteine, yielding enzyme-bound cob(I)alamin and methionine. Subsequently, remethylates the cofactor using methyltetrahydrofolate.
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| BioChemical Class |
Methyltransferase
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| UniProt ID | ||||||
| EC Number |
EC 2.1.1.13
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| Sequence |
MSPALQDLSQPEGLKKTLRDEINAILQKRIMVLDGGMGTMIQREKLNEEHFRGQEFKDHA
RPLKGNNDILSITQPDVIYQIHKEYLLAGADIIETNTFSSTSIAQADYGLEHLAYRMNMC SAGVARKAAEEVTLQTGIKRFVAGALGPTNKTLSVSPSVERPDYRNITFDELVEAYQEQA KGLLDGGVDILLIETIFDTANAKAALFALQNLFEEKYAPRPIFISGTIVDKSGRTLSGQT GEGFVISVSHGEPLCIGLNCALGAAEMRPFIEIIGKCTTAYVLCYPNAGLPNTFGDYDET PSMMAKHLKDFAMDGLVNIVGGCCGSTPDHIREIAEAVKNCKPRVPPATAFEGHMLLSGL EPFRIGPYTNFVNIGERCNVAGSRKFAKLIMAGNYEEALCVAKVQVEMGAQVLDVNMDDG MLDGPSAMTRFCNLIASEPDIAKVPLCIDSSNFAVIEAGLKCCQGKCIVNSISLKEGEDD FLEKARKIKKYGAAMVVMAFDEEGQATETDTKIRVCTRAYHLLVKKLGFNPNDIIFDPNI LTIGTGMEEHNLYAINFIHATKVIKETLPGARISGGLSNLSFSFRGMEAIREAMHGVFLY HAIKSGMDMGIVNAGNLPVYDDIHKELLQLCEDLIWNKDPEATEKLLRYAQTQGTGGKKV IQTDEWRNGPVEERLEYALVKGIEKHIIEDTEEARLNQKKYPRPLNIIEGPLMNGMKIVG DLFGAGKMFLPQVIKSARVMKKAVGHLIPFMEKEREETRVLNGTVEEEDPYQGTIVLATV KGDVHDIGKNIVGVVLGCNNFRVIDLGVMTPCDKILKAALDHKADIIGLSGLITPSLDEM IFVAKEMERLAIRIPLLIGGATTSKTHTAVKIAPRYSAPVIHVLDASKSVVVCSQLLDEN LKDEYFEEIMEEYEDIRQDHYESLKERRYLPLSQARKSGFQMDWLSEPHPVKPTFIGTQV FEDYDLQKLVDYIDWKPFFDVWQLRGKYPNRGFPKIFNDKTVGGEARKVYDDAHNMLNTL ISQKKLRARGVVGFWPAQSIQDDIHLYAEAAVPQAAEPIATFYGLRQQAEKDSASTEPYY CLSDFIAPLHSGIRDYLGLFAVACFGVEELSKAYEDDGDDYSSIMVKALGDRLAEAFAEE LHERVRRELWAYCGSEQLDVADLRRLRYKGIRPAPGYPSQPDHTEKLTMWRLADIEQSTG IRLTESLAMAPASAVSGLYFSNLKSKYFAVGKISKDQVEDYALRKNISVAEVEKWLGPIL GYDTD Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | AlphaFold | ||||
| HIT2.0 ID | T99NM4 | |||||
| Cell-based Target Expression Variations | Top | |||||
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| Cell-based Target Expression Variations | ||||||
| Drug Binding Sites of Target | Top | |||||
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| Ligand Name: (6s)-5,6,7,8-Tetrahydrofolate | Ligand Info | |||||
| Structure Description | Crystal structure of human 5-methyltetrahydrofolate-homocysteine methyltransferase, the homocysteine and folate binding domains | PDB:4CCZ | ||||
| Method | X-ray diffraction | Resolution | 2.70 Å | Mutation | No | [2] |
| PDB Sequence |
TLRDEINAIL
26 QKRIMVLDGG36 MGTMIQREKL46 EEHFRGQEFK57 DHARPLKGNN67 DILSITQPDV 77 IYQIHKEYLL87 ADIIETNTFS99 STSIAQADYG109 LEHLAYRMNM119 CSAGVARKAA 129 EEVTLQTGIK139 RFVAGALGPT149 NKTLSVSPSV159 ERPDYRNITF169 DELVEAYQEQ 179 AKGLLDGGVD189 ILLIETIFDT199 ANAKAALFAL209 QNLFEEKYAP219 RPIFISGTIV 229 DKSGRTLSGQ239 TGEGFVISVS249 HGEPLCIGLN259 CALGAAEMRP269 FIEIIGKCTT 279 AYVLCYPNAG289 FAMDGLVNIV320 GGCCGSTPDH330 IREIAEAVKN340 CKPRVPPATA 350 FEGHMLLSGL360 EPFRIGPYTN370 FVNIGERCNV380 AGSRKFAKLI390 MAGNYEEALC 400 VAKVQVEMGA410 QVLDVNMDDG420 MLDGPSAMTR430 FCNLIASEPD440 IAKVPLCIDS 450 SNFAVIEAGL460 KCCQGKCIVN470 SISLKEGEDD480 FLEKARKIKK490 YGAAMVVMAF 500 DEEGQATETD510 TKIRVCTRAY520 HLLVKKLGFN530 PNDIIFDPNI540 LTIGTGMEEH 550 NLYAINFIHA560 TKVIKETLPG570 ARISGGLSNL580 SFSFRGMEAI590 REAMHGVFLY 600 HAIKSGMDMG610 IVNAGNLPVY620 DDIHKELLQL630 CEDLIWNKDP640 EATEKLLRYA 650 Q
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GLU376
3.522
ARG377
3.745
ASN379
3.678
GLY382
2.968
SER383
3.880
ARG384
3.108
ASP414
4.706
ASN416
4.794
ASP449
3.102
ASN470
3.136
VAL496
4.087
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| Click to View More Binding Site Information of This Target with Different Ligands | ||||||
| Different Human System Profiles of Target | Top |
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Human Similarity Proteins
of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target.
A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs
(Brief Bioinform, 21: 649-662, 2020).
Human Tissue Distribution
of target is determined from a proteomics study that quantified more than 12,000 genes across 32 normal human tissues. Tissue Specificity (TS) score was used to define the enrichment of target across tissues.
The distribution of targets among different tissues or organs need to be taken into consideration when assessing the target druggability, as it is generally accepted that the wider the target distribution, the greater the concern over potential adverse effects
(Nat Rev Drug Discov, 20: 64-81, 2021).
Human Pathway Affiliation
of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function.
Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes
(Pharmacol Rev, 58: 259-279, 2006).
Biological Network Descriptors
of target is determined based on a human protein-protein interactions (PPI) network consisting of 9,309 proteins and 52,713 PPIs, which were with a high confidence score of ≥ 0.95 collected from STRING database.
The network properties of targets based on protein-protein interactions (PPIs) have been widely adopted for the assessment of target’s druggability. Proteins with high node degree tend to have a high impact on network function through multiple interactions, while proteins with high betweenness centrality are regarded to be central for communication in interaction networks and regulate the flow of signaling information
(Front Pharmacol, 9, 1245, 2018;
Curr Opin Struct Biol. 44:134-142, 2017).
Human Similarity Proteins
Human Tissue Distribution
Human Pathway Affiliation
Biological Network Descriptors
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There is no similarity protein (E value < 0.005) for this target
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Note:
If a protein has TS (tissue specficity) scores at least in one tissue >= 2.5, this protein is called tissue-enriched (including tissue-enriched-but-not-specific and tissue-specific). In the plots, the vertical lines are at thresholds 2.5 and 4.
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| KEGG Pathway | Pathway ID | Affiliated Target | Pathway Map |
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| Cysteine and methionine metabolism | hsa00270 | Affiliated Target |
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| Class: Metabolism => Amino acid metabolism | Pathway Hierarchy | ||
| Selenocompound metabolism | hsa00450 | Affiliated Target |
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| Class: Metabolism => Metabolism of other amino acids | Pathway Hierarchy | ||
| One carbon pool by folate | hsa00670 | Affiliated Target |
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| Class: Metabolism => Metabolism of cofactors and vitamins | Pathway Hierarchy | ||
| Degree | 16 | Degree centrality | 1.72E-03 | Betweenness centrality | 1.35E-03 |
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| Closeness centrality | 1.80E-01 | Radiality | 1.30E+01 | Clustering coefficient | 2.67E-01 |
| Neighborhood connectivity | 1.19E+01 | Topological coefficient | 1.70E-01 | Eccentricity | 11 |
| Download | Click to Download the Full PPI Network of This Target | ||||
| Chemical Structure based Activity Landscape of Target | Top |
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| Target Poor or Non Binders | Top | |||||
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| Target Poor or Non Binders | ||||||
| References | Top | |||||
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| REF 1 | Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. | |||||
| REF 2 | Crystal Structure of Human 5-Methyltetrahydrofolate-Homocysteine Methyltransferase, the Homocysteine and Folate Binding Domains | |||||
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