MTR

Summary

MTR (5-methyltetrahydrofolate-homocysteine methyltransferase, HGNC:7468) is a protein-coding gene on chromosome 1q43, encoding Methionine synthase (Q99707). Catalyzes the transfer of a methyl group from methylcob(III)alamin (MeCbl) to homocysteine, yielding enzyme-bound cob(I)alamin and methionine in the cytosol.

This gene encodes the 5-methyltetrahydrofolate-homocysteine methyltransferase. This enzyme, also known as cobalamin-dependent methionine synthase, catalyzes the final step in methionine biosynthesis. Mutations in MTR have been identified as the underlying cause of methylcobalamin deficiency complementation group G. Alternatively spliced transcript variants encoding distinct isoforms have been found for this gene.

Source: NCBI Gene 4548 — RefSeq curated summary.

At a glance

• Gene–disease (curated): methylcobalamin deficiency type cblG (Definitive, ClinGen)
• GWAS associations: 2
• Clinical variants (ClinVar): 1,439 total — 63 pathogenic, 37 likely-pathogenic
• Phenotypes (HPO): 41
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_000254

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7468
Approved symbol	MTR
Name	5-methyltetrahydrofolate-homocysteine methyltransferase
Location	1q43
Locus type	gene with protein product
Status	Approved
Aliases	cblG
Ensembl gene	ENSG00000116984
Ensembl biotype	protein_coding
OMIM	156570
Entrez	4548

Gene structure

Transcript identifiers

Ensembl transcripts: 19 — 9 protein_coding, 4 nonsense_mediated_decay, 4 retained_intron, 2 protein_coding_CDS_not_defined

ENST00000366576, ENST00000366577, ENST00000463959, ENST00000470570, ENST00000535889, ENST00000650888, ENST00000651455, ENST00000652435, ENST00000652483, ENST00000674797, ENST00000679569, ENST00000679842, ENST00000680454, ENST00000681102, ENST00000681177, ENST00000681813, ENST00000681937, ENST00000905140, ENST00000961801

RefSeq mRNA: 4 — MANE Select: NM_000254 NM_000254, NM_001291939, NM_001291940, NM_001410942

CCDS: CCDS1614, CCDS73054, CCDS91175

Canonical transcript exons

ENST00000366577 — 33 exons

Exon	Start	End
ENSE00000793568	236880755	236880836
ENSE00000908104	236861125	236861277
ENSE00000908106	236863454	236863554
ENSE00000961552	236885121	236885219
ENSE00000961554	236886292	236886367
ENSE00000961556	236889181	236889336
ENSE00000961558	236891133	236891329
ENSE00001069115	236894357	236894557
ENSE00001069631	236859833	236859922
ENSE00001166366	236895358	236895550
ENSE00001166403	236874726	236874846
ENSE00001166408	236873773	236873840
ENSE00001166419	236862236	236862343
ENSE00001166501	236808704	236808773
ENSE00001442090	236897558	236903981
ENSE00002230148	236795292	236795737
ENSE00003465483	236835547	236835687
ENSE00003499808	236831966	236832078
ENSE00003508071	236806144	236806233
ENSE00003543860	236825338	236825399
ENSE00003544646	236812738	236812844
ENSE00003548759	236850344	236850523
ENSE00003570655	236826829	236826896
ENSE00003584442	236824119	236824219
ENSE00003596150	236838414	236838599
ENSE00003601386	236803428	236803642
ENSE00003621485	236852521	236852637
ENSE00003627998	236815604	236815663
ENSE00003643307	236816449	236816543
ENSE00003660391	236829189	236829268
ENSE00003661804	236852948	236853088
ENSE00003670237	236810503	236810595
ENSE00003688474	236897006	236897118

Expression profiles

Bgee: expression breadth ubiquitous, 294 present calls, max score 94.72.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 27.1988 / max 215.9876, expressed in 1819 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
9266	16.2007	1792
9267	9.9979	1757
9268	0.9328	571
9269	0.0673	25

Top tissues by expression

295 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
caput epididymis	UBERON:0004358	94.72	gold quality
corpus epididymis	UBERON:0004359	94.28	gold quality
decidua	UBERON:0002450	94.16	gold quality
calcaneal tendon	UBERON:0003701	93.69	gold quality
cauda epididymis	UBERON:0004360	93.27	gold quality
superficial temporal artery	UBERON:0001614	92.66	gold quality
parietal pleura	UBERON:0002400	92.59	gold quality
adrenal tissue	UBERON:0018303	92.48	gold quality
renal medulla	UBERON:0000362	92.17	gold quality
heart right ventricle	UBERON:0002080	92.17	gold quality
pleura	UBERON:0000977	91.98	gold quality
endometrium	UBERON:0001295	91.98	gold quality
sural nerve	UBERON:0015488	91.89	gold quality
seminal vesicle	UBERON:0000998	91.70	gold quality
visceral pleura	UBERON:0002401	91.65	gold quality
left ventricle myocardium	UBERON:0006566	91.60	gold quality
secondary oocyte	CL:0000655	90.97	gold quality
tibia	UBERON:0000979	90.96	gold quality
epithelial cell of pancreas	CL:0000083	90.82	gold quality
mucosa of paranasal sinus	UBERON:0005030	90.75	gold quality
cartilage tissue	UBERON:0002418	90.39	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	90.33	gold quality
blood vessel layer	UBERON:0004797	90.32	gold quality
germinal epithelium of ovary	UBERON:0001304	90.26	gold quality
biceps brachii	UBERON:0001507	90.22	gold quality
tendon	UBERON:0000043	89.88	gold quality
deltoid	UBERON:0001476	89.86	gold quality
myocardium	UBERON:0002349	89.64	gold quality
mucosa of stomach	UBERON:0001199	89.45	gold quality
placenta	UBERON:0001987	88.90	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	7.24

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): HNF1A, JUNB, PITX2, RELA

miRNA regulators (miRDB)

176 targeting MTR, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-3120-5P	100.00	65.56	965
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-6888-3P	99.97	65.95	1170
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-146A-5P	99.96	68.93	988
HSA-MIR-146B-5P	99.96	69.13	977
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-96-5P	99.95	72.80	2140
HSA-MIR-7153-5P	99.94	68.89	1006
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AQ-3P	99.93	72.66	4867

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• polymorphisms are not risk factors for venous thromboembolism [methionine synthase and methylenetrahydrofolate reductase] (PMID:11920232)
• Hyperhomocysteinemia due to methionine synthase deficiency, cblG: structure of the MTR gene, genotype diversity, and recognition of a common mutation, P1173L. (PMID:12068375)
• polymorphisms in methionine synthase is associated with increased risk for neural tube defects (PMID:12111380)
• Variants influence the risk of spina bifida via the maternal rather than the embryonic genotype. (PMID:12375236)
• results indicate that MTRR and MTR genes may interact to increase the infants’ Neural tube defects risks (PMID:12649067)
• B12 supplementation does not alter mRNA or protein turnover rates but induces translational up-regulation of MTR by shifting the mRNA from the ribonucleoprotein to the polysome pool. (PMID:12670934)
• Results of screening mutations 2756A–>G and 66A–>G in MTR and MTRR genes respectively show that are might have an effect on NTDs incidence (neural tube defects). (PMID:12810988)
• Despite absence of association with plasma homocysteine, the GG genotype represented a four-fold increased risk of coronary disease when compared to AA genotype. (PMID:12893022)
• polymorphisms in methionine synthase is associated with increased risk for Down syndrome (PMID:12923861)
• Polymorphisms of methionine Synthase is associated wtih bladder cancer (PMID:15117811)
• D919G polymorphism of methionine synthase gene has a role in blood pressure response to antihypertensive agents (PMID:15148588)
• Methionine synthase gene variation in parents is associated with occurrence of congenital heart defects in offspring (PMID:15202865)
• The effect of C677T methylenetetrahydrofolate reductase and A2756G methionine synthase polymorphisms could affect the relative risk for MI is reported. (PMID:15820491)
• Finds that MTR variant AG and AG/GG genotypes associated with a significantly increased squamous cell head and neck cancer risk. (PMID:15894670)
• analysis of the B12-responsive internal ribosome entry site (IRES) element in human methionine synthase (PMID:16051610)
• The methionine synthase G-allele was significantly higher in the older than in the younger individuals and the influence of the genotype on male subjects became relevant at a younger age as opposed to female subjects suggesting a gender-dependent effect. (PMID:16142417)
• Mothers with c.2756AG or GG genotype displayed a 2.195-fold increased risk of having a child with non-syndromic cleft lip with or without cleft palate. (PMID:16712703)
• the methionine synthase polymorphism c.2756A>G alters susceptibility to glioblastoma multiforme (PMID:17119065)
• a significant association of the MTR polymorphism c.2756A>G (D919G) with diastolic blood pressure was found which might explain the beneficial effects of its G-allele on vascular disease and disease-free longevity (PMID:17287836)
• MTR genotype is not associated with cognitive functioning, cognitive decline, or survival among nonagenarians (PMID:17339646)
• Serum folate and MTHFR C677T and MTR A2576G gene polymorphisms were the determinants for tHcy levels. (PMID:17522601)
• study of whether C677T & A1298C MTHFR, A2756G MTR & -786 C/T eNOS polymorphisms are associated with NonValvular Atrial Fibrillation; data show the polymorphisms were not associated with an increased risk of NVAF per se or in combination (PMID:17551576)
• Results suggest that the alterations of folate metabolism related to MTHFR, MTR and MTRR polymorphisms are not involved in clefting in South Brazil. (PMID:17581676)
• These results suggest, for the first time, a role for the MTR A2756G polymorphism in MM risk in our country. (PMID:17655928)
• study found that MTR 2756AG (919DG) or GG (919GG) genotype exhibited 2.005-fold increased risk of systemic lupus erythematosus (95% CI = 1.177-3.416, P = 0.0146) (PMID:17664238)
• The results indicate that of the enzymes studied the polymorphisms of MTR no significant differences in intensity of turnover of circulating thiols between AD and PD patients. (PMID:17691219)
• no association between methionine synthase A2756G polymorphism insertion polymorphism and cancer of the upper gastrointestinal tract. (PMID:17726616)
• The risk of having a child with congenital malformation or FACS was three to four times higher for mothers who were MTHFR 677TT homozygotes compared with MTHFR 677CC homozygotes (PMID:17853476)
• Homozygosis for the MTR 2756CC genotype was not related to prostatic carginogenesis (PMID:17967524)
• These findings suggest that in obese subjects, homocysteine cycle efficiency is impaired by MTHFR, MTR, and MTRR inability to supply methyl-group donors, providing evidence that MTHFR, MTR, and MTRR gene polymorphisms are genetic risk factors for obesity. (PMID:17993766)
• Hcy concentrations were significantly increased in the MTR 2756AG heterozygous genotype compared to the MTR 2756AA wild-type genotype. (PMID:18060320)
• A 2756 A - G polymorhpism in the MTR gene seems to be associated with homocysteine. (PMID:18222012)
• The presence of the genetic polymorphism of MTR is a maternal risk factor for Down syndrome in Brazil. (PMID:18273817)
• The SNP 2756 A>G in the methionine synthase gene does not appear to influence the plasma Hcy levels. (PMID:18281142)
• Our data did not reveal significant association between the methionine synthase polymorphism and Alzheimer disease development (PMID:18329006)
• Methylenetetrahydrofolate reductase and Methionine synthase polymorphisms might have protective effect on the risk of cervical cancer in the North Indian women. (PMID:18351371)
• The results of this study suggest that genetic variants of methionine metabolism are associated with meningioma formation. (PMID:18447718)
• The MTR A2756G genotype showed a non-significant association between homozygosity and decreased risk of glioblastoma. (PMID:18483342)
• Methionine synthase is associated with risk and extent of ulcerative colitis, at least in Central China (PMID:18700049)
• This study suggests the maternal and fetal MTR2756G allele is an important risk factor in the development of uteroplacental insufficiency. (PMID:18771981)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	mtr	ENSDARG00000104906
mus_musculus	Mtr	ENSMUSG00000021311
rattus_norvegicus	Mtr	ENSRNOG00000017593
caenorhabditis_elegans		WBGENE00010988

Paralogs (4): UROD (ENSG00000126088), BHMT2 (ENSG00000132840), BHMT (ENSG00000145692), MTHFR (ENSG00000177000)

Protein

Protein identifiers

Methionine synthase — Q99707 (reviewed: Q99707)

Alternative names: 5-methyltetrahydrofolate–homocysteine methyltransferase, Cobalamin-dependent methionine synthase, Vitamin-B12 dependent methionine synthase

All UniProt accessions (10): A0A494C064, A0A494C1A2, A0A6Q8PGK3, A0A7P0T956, A0A7P0T9G7, A0A7P0TA06, A0A7P0TAJ0, A0A7P0TAV2, B1ANE3, Q99707

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the transfer of a methyl group from methylcob(III)alamin (MeCbl) to homocysteine, yielding enzyme-bound cob(I)alamin and methionine in the cytosol. MeCbl is an active form of cobalamin (vitamin B12) used as a cofactor for methionine biosynthesis. Cob(I)alamin form is regenerated to MeCbl by a transfer of a methyl group from 5-methyltetrahydrofolate. The processing of cobalamin in the cytosol occurs in a multiprotein complex composed of at least MMACHC, MMADHC, MTRR (methionine synthase reductase) and MTR which may contribute to shuttle safely and efficiently cobalamin towards MTR in order to produce methionine.

Subunit / interactions. Monomer. Dimer. Forms a multiprotein complex with MMACHC, MMADHC and MTRR.

Subcellular location. Cytoplasm.

Tissue specificity. Widely expressed. Expressed at the highest levels in pancreas, heart, brain, skeletal muscle and placenta. Expressed at lower levels in lung, liver and kidney.

Disease relevance. Homocystinuria-megaloblastic anemia, cblG type (HMAG) [MIM:250940] An 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. The disease is caused by variants affecting the gene represented in this entry. Neural tube defects, folate-sensitive (NTDFS) [MIM:601634] The most common NTDs are open spina bifida (myelomeningocele) and anencephaly. Disease susceptibility is associated with variants affecting the gene represented in this entry.

Cofactor. Binds 1 zinc ion per subunit.

Domain organisation. Modular enzyme with four functionally distinct domains. The isolated Hcy-binding domain catalyzes methyl transfer from free methylcobalamin to homocysteine. The Hcy-binding domain in association with the pterin-binding domain catalyzes the methylation of cob(I)alamin by methyltetrahydrofolate and the methylation of homocysteine. The B12-binding domain binds the cofactor. The AdoMet activation domain binds S-adenosyl-L-methionine. Under aerobic conditions cob(I)alamin can be converted to inactive cob(II)alamin. Reductive methylation by S-adenosyl-L-methionine and flavodoxin regenerates methylcobalamin.

Pathway. Amino-acid biosynthesis; L-methionine biosynthesis via de novo pathway; L-methionine from L-homocysteine (MetH route): step 1/1.

Similarity. Belongs to the vitamin-B12 dependent methionine synthase family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q99707-1	1	yes
Q99707-2	2

RefSeq proteins (4): NP_000245, NP_001278868, NP_001278869, NP_001397871 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000489	Pterin-binding_dom	Domain
IPR003726	HCY_dom	Domain
IPR003759	Cbl-bd_cap	Domain
IPR004223	VitB12-dep_Met_synth_activ_dom	Domain
IPR006158	Cobalamin-bd	Domain
IPR011005	Dihydropteroate_synth-like_sf	Homologous_superfamily
IPR011822	MetH	Family
IPR033706	Met_synthase_B12-bd	Domain
IPR036589	HCY_dom_sf	Homologous_superfamily
IPR036594	Meth_synthase_dom	Homologous_superfamily
IPR036724	Cobalamin-bd_sf	Homologous_superfamily
IPR037010	VitB12-dep_Met_synth_activ_sf	Homologous_superfamily
IPR050554	Met_Synthase/Corrinoid	Family

Pfam: PF00809, PF02310, PF02574, PF02607, PF02965

Enzyme classification (BRENDA):

• EC 2.1.1.13 — methionine synthase (BRENDA: 35 organisms, 26 substrates, 55 inhibitors, 26 Km, 5 kcat entries)

Substrate kinetics (BRENDA)

11 substrates with measured Km, best-characterized 11. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
L-HOMOCYSTEINE	0.001–0.43	8
5-METHYLTETRAHYDROFOLATE	0.03–0.06	3
N5-METHYLTETRAHYDROPTEROYLMONOGLUTAMATE	0.025–2.4	3
5-METHYL-5,6,7,8-TETRAHYDROPTEROYLMONOGLUTAMATE	0.013–0.0731	2
5-METHYL-5,6,7,8-TETRAHYDROPTEROYLPENTAGLUTAMATE	0.004–0.0277	2
S-ADENOSYL-L-METHIONINE	0.0006–0.0016	2
5-METHYL-5,6,7,8-TETRAHYDROPTEROYLHEPTAGLUTAMATE	0.0223	1
5-METHYL-5,6,7,8-TETRAHYDROPTEROYLTRIGLUTAMATE	0.0244	1
L-SELENOHOMOCYSTEINE	0.017	1
METHYLCOB(III)ALAMIN	0.236	1
N5-METHYLTETRAHYDROFOLATE	0.089	1

Catalyzed reactions (Rhea), 1 shown:

• (6S)-5-methyl-5,6,7,8-tetrahydrofolate + L-homocysteine = (6S)-5,6,7,8-tetrahydrofolate + L-methionine (RHEA:11172)

UniProt features (114 total): helix 48, strand 24, binding site 19, sequence variant 8, domain 5, turn 5, mutagenesis site 2, chain 1, modified residue 1, splice variant 1

Structure

Experimental structures (PDB)

9 structures.

PDB	Method	Resolution (Å)
2O2K	X-RAY DIFFRACTION	1.6
9SSU	ELECTRON MICROSCOPY	2.63
4CCZ	X-RAY DIFFRACTION	2.7
9SSQ	ELECTRON MICROSCOPY	2.82
9SST	ELECTRON MICROSCOPY	2.82
9SSR	ELECTRON MICROSCOPY	2.84
9SSS	ELECTRON MICROSCOPY	3.01
9SSV	ELECTRON MICROSCOPY	3.09
9SSP	ELECTRON MICROSCOPY	3.1

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q99707-F1	87.60	0.55

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (19): 449; 470; 537; 579; 585; 591; 709; 782–786; 785 (axial binding residue); 830; 834; 886 …

Post-translational modifications (1): 1264

Mutagenesis-validated functional residues (2):

Position	Phenotype
963	decreases binding to mtrr; when associated with n-1071.
1071	decreases binding to mtrr; when associated with e-963.

Function

Pathways and Gene Ontology

Reactome pathways

21 pathways

ID	Pathway
R-HSA-156581	Methylation
R-HSA-1614635	Sulfur amino acid metabolism
R-HSA-3359467	Defective MTRR causes HMAE
R-HSA-3359469	Defective MTR causes HMAG
R-HSA-9013407	RHOH GTPase cycle
R-HSA-9759218	Cobalamin (Cbl) metabolism
R-HSA-1430728	Metabolism
R-HSA-156580	Phase II - Conjugation of compounds
R-HSA-162582	Signal Transduction
R-HSA-1643685	Disease
R-HSA-194315	Signaling by Rho GTPases
R-HSA-196741	Cobalamin (Cbl, vitamin B12) transport and metabolism
R-HSA-196849	Metabolism of water-soluble vitamins and cofactors
R-HSA-196854	Metabolism of vitamins and cofactors
R-HSA-211859	Biological oxidations
R-HSA-3296469	Defects in cobalamin (B12) metabolism
R-HSA-3296482	Defects in vitamin and cofactor metabolism
R-HSA-5668914	Diseases of metabolism
R-HSA-71291	Metabolism of amino acids and derivatives
R-HSA-9012999	RHO GTPase cycle
R-HSA-9716542	Signaling by Rho GTPases, Miro GTPases and RHOBTB3

MSigDB gene sets: 336 (showing top): GOBP_RESPONSE_TO_NITROGEN_COMPOUND, REACTOME_BIOLOGICAL_OXIDATIONS, GOBP_ALPHA_AMINO_ACID_METABOLIC_PROCESS, KEGG_CYSTEINE_AND_METHIONINE_METABOLISM, MODULE_493, GOBP_REGENERATION, GOBP_NEUROGENESIS, GOBP_AMINO_ACID_BIOSYNTHETIC_PROCESS, GOBP_RESPONSE_TO_AXON_INJURY, GOBP_ASPARTATE_FAMILY_AMINO_ACID_BIOSYNTHETIC_PROCESS, GGAMTNNNNNTCCY_UNKNOWN, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, GOBP_ORGANIC_ACID_BIOSYNTHETIC_PROCESS, RODWELL_AGING_KIDNEY_NO_BLOOD_DN, MONNIER_POSTRADIATION_TUMOR_ESCAPE_UP

GO Biological Process (14): sulfur amino acid metabolic process (GO:0000096), nervous system development (GO:0007399), obsolete methionine biosynthetic process (GO:0009086), cobalamin metabolic process (GO:0009235), axon regeneration (GO:0031103), methylation (GO:0032259), tetrahydrofolate metabolic process (GO:0046653), response to axon injury (GO:0048678), homocysteine metabolic process (GO:0050667), cellular response to nitric oxide (GO:0071732), sulfur compound metabolic process (GO:0006790), amino acid biosynthetic process (GO:0008652), pteridine-containing compound metabolic process (GO:0042558), L-methionine salvage (GO:0071267)

GO Molecular Function (8): zinc ion binding (GO:0008270), methionine synthase activity (GO:0008705), cobalamin binding (GO:0031419), protein binding (GO:0005515), methyltransferase activity (GO:0008168), S-methyltransferase activity (GO:0008172), transferase activity (GO:0016740), metal ion binding (GO:0046872)

GO Cellular Component (2): cytosol (GO:0005829), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-14 pathways:

Category	Pathways
Metabolism	3
Defects in cobalamin (B12) metabolism	2
Phase II - Conjugation of compounds	1
Metabolism of amino acids and derivatives	1
RHO GTPase cycle	1
Cobalamin (Cbl, vitamin B12) transport and metabolism	1
Biological oxidations	1
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1
Metabolism of water-soluble vitamins and cofactors	1
Metabolism of vitamins and cofactors	1
Defects in vitamin and cofactor metabolism	1
Diseases of metabolism	1
Disease	1
Signaling by Rho GTPases	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
metabolic process	3
cellular anatomical structure	2
sulfur compound metabolic process	1
carboxylic acid metabolic process	1
system development	1
tetrapyrrole metabolic process	1
neuron projection regeneration	1
response to axon injury	1
axon development	1
folic acid-containing compound metabolic process	1
response to wounding	1
sulfur amino acid metabolic process	1
non-proteinogenic amino acid metabolic process	1
response to nitric oxide	1
cellular response to oxygen-containing compound	1
cellular response to reactive nitrogen species	1
amino acid metabolic process	1
biosynthetic process	1
amino acid salvage	1
L-methionine biosynthetic process	1
transition metal ion binding	1
S-methyltransferase activity	1
L-methionine salvage	1
vitamin binding	1
tetrapyrrole binding	1
heterocyclic compound binding	1
binding	1
transferase activity, transferring one-carbon groups	1
methyltransferase activity	1
catalytic activity	1
cation binding	1
cytoplasm	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

2348 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MTR	MTRR	Q9UBK8	993
MTR	MTHFR	P42898	978
MTR	MMADHC	Q9H3L0	955
MTR	LMBRD1	Q9NUN5	950
MTR	MMUT	P22033	944
MTR	MTHFD1	P11586	944
MTR	H7C2H4	H7C2H4	938
MTR	P0DN79	P0DN79	933
MTR	SHMT1	P34896	909
MTR	MMACHC	Q9Y4U1	902
MTR	MMAA	Q8IVH4	883
MTR	AHCY	P23526	882
MTR	MMAB	Q96EY8	831
MTR	CD320	Q9NPF0	816
MTR	TYMS	P04818	809

IntAct

106 interactions, top by confidence:

A	B	Type	Score
FAM174A	GAK	psi-mi:“MI:0914”(association)	0.640
SLC16A3	CASK	psi-mi:“MI:0914”(association)	0.590
LPCAT1	SLC27A2	psi-mi:“MI:0914”(association)	0.530
ARRDC4	WWP2	psi-mi:“MI:0914”(association)	0.530
TFDP3	E2F3	psi-mi:“MI:0914”(association)	0.530
INSYN2A	CHUK	psi-mi:“MI:0914”(association)	0.530
EMILIN1	METTL15	psi-mi:“MI:0914”(association)	0.530
LRRC27	HMOX1	psi-mi:“MI:0914”(association)	0.530
CAPN2	MYO9A	psi-mi:“MI:0914”(association)	0.530
CDK18	UBL4A	psi-mi:“MI:0914”(association)	0.530
HSPA8	ARHGEF10	psi-mi:“MI:2364”(proximity)	0.480
NRAS	ESYT2	psi-mi:“MI:2364”(proximity)	0.480
MTR	MMACHC	psi-mi:“MI:0915”(physical association)	0.470
MMACHC	MTR	psi-mi:“MI:2364”(proximity)	0.470
MTR	MTRR	psi-mi:“MI:0407”(direct interaction)	0.440
MTR	PLEC	psi-mi:“MI:0915”(physical association)	0.400
SOX12	MTR	psi-mi:“MI:0915”(physical association)	0.400
XRCC3	DERL1	psi-mi:“MI:0914”(association)	0.350
CDKN2A	ACTN4	psi-mi:“MI:0914”(association)	0.350
SPATA5L1	HSPA8	psi-mi:“MI:0914”(association)	0.350
INSYN2A	NOP56	psi-mi:“MI:0914”(association)	0.350
DOCK5	DPYSL4	psi-mi:“MI:0914”(association)	0.350
IQCF1	TBC1D4	psi-mi:“MI:0914”(association)	0.350
AKAP13	UBB	psi-mi:“MI:0914”(association)	0.350
M		psi-mi:“MI:0914”(association)	0.350
SLC16A11	ESYT2	psi-mi:“MI:0914”(association)	0.350
MAP2K7	ILVBL	psi-mi:“MI:0914”(association)	0.350
RAF1	MYO9A	psi-mi:“MI:0914”(association)	0.350
GRK6	ILVBL	psi-mi:“MI:0914”(association)	0.350

BioGRID (153): MTR (Affinity Capture-RNA), MTR (Affinity Capture-RNA), MTR (Affinity Capture-MS), MTR (Affinity Capture-MS), MTR (Proximity Label-MS), MTR (Proximity Label-MS), MTR (Proximity Label-MS), MTR (Proximity Label-MS), MTR (Proximity Label-MS), MTR (Affinity Capture-MS), MTR (Affinity Capture-MS), MTR (Affinity Capture-MS), MTR (Affinity Capture-MS), MTR (Affinity Capture-MS), MTR (Affinity Capture-MS)

ESM2 similar proteins: A0A3A6NE59, A5FHX8, A6GY30, A6H5Y3, A7GYI5, A8EYY8, A8F1K7, A8GNF5, A8GS29, B0B7Q0, B0BXJ5, B0RDZ5, B3E7B3, B4U901, C3PNF9, C4K0K1, E5Y8P8, O05966, O52682, P0CE21, P26752, P39475, P53589, P56097, Q1RH78, Q1RJU4, Q255N7, Q2GEF1, Q4JIJ3, Q4UKR1, Q4ULQ7, Q54P92, Q5E814, Q5GSB6, Q5LCW4, Q64U25, Q68WU5, Q68XA5, Q6FYD1, Q8A9M7

Diamond homologs: A6H5Y3, A8XY95, O30641, O33259, O33465, O93657, P0DX07, P13009, P37586, P58620, P58867, P58868, P58977, P58978, P58979, P58980, P58981, P58982, P80078, Q09582, Q24SP8, Q32IJ3, Q46EH4, Q49775, Q4JIJ3, Q54P92, Q55786, Q57195, Q5E814, Q7MHB1, Q87L95, Q890S0, Q8DCJ7, Q8TN69, Q8TS71, Q8TS74, Q8TTA8, Q8TTB0, Q99707, Q9AJQ8

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
MTR	“down-regulates quantity”	homocysteine	“chemical modification”
MTR	“up-regulates quantity”	methionine	“chemical modification”
MTR	“down-regulates quantity”	(6S)-5-methyltetrahydrofolate(2-)	“chemical modification”

Disease & clinical

Clinical variants and AI predictions

ClinVar

1439 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	63
Likely pathogenic	37
Uncertain significance	398
Likely benign	667
Benign	169

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1048517	NM_000254.3(MTR):c.609+1088G>A	Pathogenic
1048518	NM_000254.3(MTR):c.2788_2791del (p.Leu930fs)	Pathogenic
1331535	NM_000254.3(MTR):c.1771C>T (p.Arg591Ter)	Pathogenic
14278	NM_000254.3(MTR):c.3518C>T (p.Pro1173Leu)	Pathogenic
14280	NM_000254.3(MTR):c.2758C>G (p.His920Asp)	Pathogenic
14282	NM_000254.3(MTR):c.2114_2115del (p.Leu705fs)	Pathogenic
14283	MTR, IVS6AS, G-A, LYS203	Pathogenic
14284	NM_000254.3(MTR):c.3380dup (p.Ala1128fs)	Pathogenic
14287	NM_000254.3(MTR):c.3613G>T (p.Glu1205Ter)	Pathogenic
1447405	NM_000254.3(MTR):c.2101del (p.Tyr701fs)	Pathogenic
1685963	NM_000254.3(MTR):c.2059_2060del (p.Ile687fs)	Pathogenic
1905103	NM_000254.3(MTR):c.1200dup (p.Val401fs)	Pathogenic
195849	NM_000254.3(MTR):c.2669_2670del (p.Val890fs)	Pathogenic
2025555	NM_000254.3(MTR):c.2472dup (p.Asp825fs)	Pathogenic
2093880	NM_000254.3(MTR):c.1330-2A>T	Pathogenic
2570756	NM_000254.3(MTR):c.1941dup (p.Arg648fs)	Pathogenic
2582874	NM_000254.3(MTR):c.920dup (p.His307fs)	Pathogenic
2636752	NM_000254.3(MTR):c.2799_2803del (p.Ala935fs)	Pathogenic
2693476	NM_000254.3(MTR):c.3570G>A (p.Trp1190Ter)	Pathogenic
2694577	NM_000254.3(MTR):c.610-1_613dup	Pathogenic
2696262	NM_000254.3(MTR):c.313C>T (p.Gln105Ter)	Pathogenic
2697612	NM_000254.3(MTR):c.1636G>T (p.Gly546Ter)	Pathogenic
2709023	NM_000254.3(MTR):c.2730_2731delinsCT (p.Met910_Glu911delinsIleTer)	Pathogenic
2714103	NM_000254.3(MTR):c.899dup (p.Pro301fs)	Pathogenic
2734111	NM_000254.3(MTR):c.381del (p.Ala128fs)	Pathogenic
2746182	NM_000254.3(MTR):c.3247_3248del (p.Ser1083fs)	Pathogenic
2753126	NM_000254.3(MTR):c.2087T>G (p.Leu696Ter)	Pathogenic
2761905	NM_000254.3(MTR):c.1512del (p.Gln505fs)	Pathogenic
2764273	NM_000254.3(MTR):c.1475dup (p.Ala493fs)	Pathogenic
2765543	NM_000254.3(MTR):c.648_652del (p.Lys216fs)	Pathogenic

SpliceAI

5893 predictions. Top by Δscore:

Variant	Effect	Δscore
1:236803601:T:G	donor_gain	1.0000
1:236812736:A:AG	acceptor_gain	1.0000
1:236812737:G:GG	acceptor_gain	1.0000
1:236812737:GC:G	acceptor_gain	1.0000
1:236812737:GCA:G	acceptor_gain	1.0000
1:236812737:GCAT:G	acceptor_gain	1.0000
1:236812737:GCATT:G	acceptor_gain	1.0000
1:236812844:GGT:G	donor_loss	1.0000
1:236812846:T:G	donor_loss	1.0000
1:236814010:T:TA	donor_gain	1.0000
1:236814011:A:AA	donor_gain	1.0000
1:236815664:G:GG	donor_gain	1.0000
1:236816442:A:AG	acceptor_gain	1.0000
1:236816447:A:AG	acceptor_gain	1.0000
1:236816448:G:GG	acceptor_gain	1.0000
1:236816448:GA:G	acceptor_gain	1.0000
1:236816448:GAT:G	acceptor_gain	1.0000
1:236816448:GATT:G	acceptor_gain	1.0000
1:236816448:GATTT:G	acceptor_gain	1.0000
1:236816539:CTCTG:C	donor_gain	1.0000
1:236816540:TCTG:T	donor_gain	1.0000
1:236816541:CTG:C	donor_gain	1.0000
1:236816542:TG:T	donor_gain	1.0000
1:236816543:GG:G	donor_gain	1.0000
1:236816544:G:GG	donor_gain	1.0000
1:236816544:GTGA:G	donor_loss	1.0000
1:236824117:A:AG	acceptor_gain	1.0000
1:236824118:G:GG	acceptor_gain	1.0000
1:236826824:TGCAG:T	acceptor_loss	1.0000
1:236826825:GCAGG:G	acceptor_loss	1.0000

AlphaMissense

8353 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:236862249:C:A	A737D	1.000
1:236863512:G:A	G788D	1.000
1:236874747:T:C	L832P	1.000
1:236838501:A:C	S473R	0.999
1:236838503:T:A	S473R	0.999
1:236838503:T:G	S473R	0.999
1:236852569:T:C	F582L	0.999
1:236852571:C:A	F582L	0.999
1:236852571:C:G	F582L	0.999
1:236861248:T:C	F723L	0.999
1:236861250:T:A	F723L	0.999
1:236861250:T:G	F723L	0.999
1:236862266:G:C	A743P	0.999
1:236862279:T:C	L747P	0.999
1:236863496:G:C	D783H	0.999
1:236863497:A:G	D783G	0.999
1:236863506:A:T	D786V	0.999
1:236863511:G:C	G788R	0.999
1:236863512:G:T	G788V	0.999
1:236863521:T:A	I791K	0.999
1:236863533:T:A	V795D	0.999
1:236863536:T:C	L796P	0.999
1:236863541:T:C	C798R	0.999
1:236863543:C:G	C798W	0.999
1:236874735:G:A	G828D	0.999
1:236874738:T:C	L829P	0.999
1:236874743:G:A	G831R	0.999
1:236874743:G:C	G831R	0.999
1:236874744:G:A	G831E	0.999
1:236874747:T:A	L832H	0.999

dbSNP variants (sampled 300 via entrez): RS1000012548 (1:236889019 C>T), RS1000039645 (1:236809029 A>G), RS1000070785 (1:236809280 AGT>A), RS1000091988 (1:236840476 T>C), RS1000117404 (1:236865925 A>G), RS1000145901 (1:236852723 G>A), RS1000217435 (1:236817814 A>G), RS1000256828 (1:236888670 A>G), RS1000277079 (1:236856570 C>T), RS1000292614 (1:236802588 G>A,T), RS1000310450 (1:236833461 C>T), RS1000340263 (1:236900349 A>G), RS1000445521 (1:236868523 T>C), RS1000499662 (1:236861011 G>A), RS1000528736 (1:236821828 A>G)

Disease associations

OMIM: gene MIM:156570 | disease phenotypes: MIM:250940, MIM:601634, MIM:606764

GenCC curated gene-disease

Disease	Classification	Inheritance
methylcobalamin deficiency type cblG	Definitive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
methylcobalamin deficiency type cblG	Definitive	AR

Mondo (6): methylcobalamin deficiency type cblG (MONDO:0009609), neural tube defects, folate-sensitive (MONDO:0011120), gastrointestinal stromal tumor (MONDO:0011719), homocystinuria (MONDO:0004737), epilepsy (MONDO:0005027), intellectual disability (MONDO:0001071)

Orphanet (5): Methylcobalamin deficiency type cblG (Orphanet:2170), Homocystinuria without methylmalonic aciduria (Orphanet:622), Spina bifida and other spinal dysraphisms (Orphanet:823), Gastrointestinal stromal tumor (Orphanet:44890), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

41 total (30 of 41 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000252	Microcephaly
HP:0000618	Blindness
HP:0000639	Nystagmus
HP:0000952	Jaundice
HP:0001238	Slender finger
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001254	Lethargy
HP:0001257	Spasticity
HP:0001263	Global developmental delay
HP:0001288	Gait disturbance
HP:0001508	Failure to thrive
HP:0001510	Growth delay
HP:0001583	Rotary nystagmus
HP:0001763	Pes planus
HP:0001875	Decreased total neutrophil count
HP:0001889	Megaloblastic anemia
HP:0001939	Abnormality of metabolism/homeostasis
HP:0002013	Vomiting
HP:0002014	Diarrhea
HP:0002059	Cerebral atrophy
HP:0002098	Respiratory distress
HP:0002156	Homocystinuria
HP:0002160	Hyperhomocystinemia
HP:0002197	Generalized-onset seizure
HP:0002311	Incoordination
HP:0002878	Respiratory failure
HP:0003223	Decreased circulating methylcobalamin concentration

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST002087_2	Homocysteine levels	2.000000e-10
GCST009846_14	Hallux valgus	2.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004578	homocysteine measurement

MeSH disease descriptors (5)

Descriptor	Name	Tree numbers
D004827	Epilepsy	C10.228.140.490
D046152	Gastrointestinal Stromal Tumors	C04.557.450.565.370; C06.301.371.308; C06.405.249.308
D006712	Homocystinuria	C10.228.140.163.100.365; C16.320.565.100.480.500; C16.320.565.189.365; C17.300.428; C18.452.132.100.365; C18.452.648.100.480.500; C18.452.648.189.365
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
C536409	Neural tube defect, folate-sensitive (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2150844 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 1,163 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL354541	LOMITAPIDE	4	1,163

PharmGKB: 1 entry (VIP=true, CPIC=false)

PharmGKB clinical annotations

7 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs1805087	Efficacy	3	benazepril	Essential hypertension
rs1805087	Efficacy,Toxicity	3	carboplatin;cisplatin	Neoplasms
rs1805087	Efficacy	3	folic acid;hydroxychloroquine;methotrexate;sulfasalazine	Rheumatoid arthritis
rs1805087	Efficacy	3	methotrexate	Rheumatoid arthritis
rs1805087	Toxicity	3	methotrexate	Rheumatoid arthritis
rs1805087	Toxicity	4	methotrexate	Acute lymphoblastic leukemia;Brain Diseases;Drug Toxicity;Osteosarcoma
rs3768142	Toxicity	3	methotrexate	Agranulocytosis

PharmGKB variants

2 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs1805087	MTR	3	3.25	6	carboplatin;cisplatin;methotrexate;benazepril;folic acid;hydroxychloroquine;methotrexate;sulfasalazine
rs3768142	MTR	3	2.75	1	methotrexate

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — Methionine turnover

ChEMBL bioactivities

9 potent at pChembl≥5 of 22 total, top 9 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.30	IC50	0.5	nM	LOMITAPIDE
8.66	IC50	2.2	nM	CHEMBL27364
5.84	IC50	1430	nM	CHEMBL2153714
5.76	IC50	1730	nM	CHEMBL2153712
5.35	IC50	4460	nM	CHEMBL4778495
5.30	IC50	4990	nM	CHEMBL4789573
5.25	IC50	5660	nM	CHEMBL4787377
5.12	IC50	7640	nM	CHEMBL4778495
5.09	IC50	8110	nM	CHEMBL2153711

PubChem BioAssay actives

9 with measured affinity, of 40 total; 8 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
Lomitapide	1979280: Inhibition of MTR (unknown origin)	ic50	0.0005	uM
2-[1-(3,3-diphenylpropyl)piperidin-4-yl]-3H-isoindol-1-one	1979280: Inhibition of MTR (unknown origin)	ic50	0.0022	uM
(2S)-2-[[3-bromo-4-[[2,4-diamino-5-(2,3-dibromopropyl)-7,8-dihydro-6H-pyrido[3,2-d]pyrimidin-6-yl]methylamino]benzoyl]amino]pentanedioic acid	693367: Inhibition of methionine synthase in human HL60 cells using L-homocysteine as substrate incubated for 3 hrs prior to substrate addition measured after 10 mins spectrophotometric analysis	ic50	1.4300	uM
(2S)-2-[[4-[acetyl-[(2,4-diamino-5-formyl-7,8-dihydro-6H-pyrido[3,2-d]pyrimidin-6-yl)methyl]amino]benzoyl]amino]pentanedioic acid	693367: Inhibition of methionine synthase in human HL60 cells using L-homocysteine as substrate incubated for 3 hrs prior to substrate addition measured after 10 mins spectrophotometric analysis	ic50	1.7300	uM
2-chloro-1-[2,4-diamino-6-[2-(4-ethylphenyl)ethyl]-7,8-dihydro-6H-pyrido[3,2-d]pyrimidin-5-yl]ethanone	1736629: Inhibition of human Cobalamin-dependent methionine synthase isolated from HL-60 cells using 63 uM of methyltetrahydrofolate as substrate incubated for 10 mins and measured by spectrophotometer based microplate reader assay	ic50	4.4600	uM
2-chloro-1-[2,4-diamino-6-[2-(4-fluorophenyl)ethyl]-7,8-dihydro-6H-pyrido[3,2-d]pyrimidin-5-yl]ethanone	1736627: Inhibition of human Cobalamin-dependent methionine synthase isolated from HL-60 cells using methyltetrahydrofolate as substrate incubated for 10 mins and measured by spectrophotometer based microplate reader assay	ic50	4.9900	uM
2-chloro-1-[2,4-diamino-6-[2-(4-methylphenyl)ethyl]-7,8-dihydro-6H-pyrido[3,2-d]pyrimidin-5-yl]ethanone	1736627: Inhibition of human Cobalamin-dependent methionine synthase isolated from HL-60 cells using methyltetrahydrofolate as substrate incubated for 10 mins and measured by spectrophotometer based microplate reader assay	ic50	5.6600	uM
(2S)-2-[[4-[(2,4-diamino-5-formyl-7,8-dihydro-6H-pyrido[3,2-d]pyrimidin-6-yl)methyl-methylamino]benzoyl]amino]pentanedioic acid	693367: Inhibition of methionine synthase in human HL60 cells using L-homocysteine as substrate incubated for 3 hrs prior to substrate addition measured after 10 mins spectrophotometric analysis	ic50	8.1100	uM

CTD chemical–gene interactions

71 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Methotrexate	decreases expression, decreases reaction, affects localization, affects metabolic processing, decreases response to substance (+1 more)	4
Arsenic	increases activity, affects response to substance, affects abundance, affects cotreatment, decreases reaction	3
Benzo(a)pyrene	increases mutagenesis, decreases expression, increases methylation	3
Thimerosal	affects cotreatment, decreases reaction, increases activity, affects reaction, decreases expression	3
benazepril	affects response to substance	2
Aluminum	affects cotreatment, decreases reaction, increases activity	2
Estradiol	affects cotreatment, decreases expression, increases expression	2
Homocysteine	affects binding, affects metabolic processing	2
Lead	increases activity, affects cotreatment, decreases reaction	2
Mercury	affects cotreatment, decreases reaction, increases activity	2
S-Adenosylmethionine	decreases reaction, increases activity, increases reaction, affects binding, affects cotreatment	2
Tobacco Smoke Pollution	decreases expression	2
Valproic Acid	affects expression, increases expression	2
Vitamin B 12	affects binding, increases activity	2
aristolochic acid I	decreases expression	1
bismuth tripotassium dicitrate	decreases expression	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
5-methyltetrahydrofolate	affects binding	1
pirinixic acid	increases activity, increases expression, affects binding	1
bisphenol A	decreases expression	1
trichostatin A	increases expression	1
arsenite	affects binding, decreases reaction	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
sodium arsenite	increases expression	1
cobaltous chloride	decreases expression	1
butyraldehyde	decreases expression	1
mecobalamin	affects cotreatment, decreases reaction, increases activity	1
5,6,7,8-tetrahydrofolic acid	decreases expression, decreases reaction, affects cotreatment	1
glutathionylcobalamin	affects cotreatment, increases activity	1

ChEMBL screening assays

8 unique, capped per target: 8 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL2153942	Binding	Inhibition of methionine synthase in human HL60 cells using L-homocysteine as substrate incubated for 3 hrs prior to substrate addition measured after 10 mins spectrophotometric analysis	Mechanism-based design, synthesis and biological studies of N⁵-substituted tetrahydrofolate analogs as inhibitors of cobalamin-dependent methionine synthase and potential anticancer agents. — Eur J Med Chem

Cellosaurus cell lines

8 cell lines: 4 finite cell line, 2 transformed cell line, 2 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B3BI	Abcam HEK293T MTR KO	Transformed cell line	Female
CVCL_D6Y7	GM28741	Transformed cell line	Male
CVCL_QZ29	WG1505	Finite cell line	Male
CVCL_QZ34	WG1671	Finite cell line
CVCL_QZ35	WG1892	Finite cell line	Male
CVCL_QZ36	WG2290	Finite cell line	Male
CVCL_SZ35	HAP1 MTR (-) 1	Cancer cell line	Male
CVCL_SZ36	HAP1 MTR (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

300 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00171977	PHASE4	COMPLETED	Post-Marketing Clinical Study of Postoperative Adjuvant Therapy With Imatinib Mesylate in Patients With Gastrointestinal Stromal Tumors (GIST)
NCT00510354	PHASE4	COMPLETED	Treatment of Patients With Everolimus and Imatinib Mesylate Who Have Progressive Gastro Intestinal Stromal Tumors (GIST) and Are Resistant to Imatinib Mesylate
NCT00756509	PHASE4	COMPLETED	Treatment of Patients With Metastatic or Unresectable Gastrointestinal Stromal Tumors in First Line With Nilotinib
NCT00777504	PHASE4	UNKNOWN	Study to the Optimal Duration of Therapy With Oral Angiogenesis Inhibitors
NCT02800330	PHASE4	COMPLETED	The Effects of the Proton Pump Inhibitor Esomeprazole on the Bioavailability of Regorafenib
NCT04825574	PHASE4	COMPLETED	Study for Patients Previously Treated in Avapritinib Clinical Trials
NCT00009906	PHASE3	TERMINATED	Comparison of Two Different Doses of STI571 in Treating Patients With Metastatic or Unresectable Gastrointestinal Stromal Tumor
NCT00041197	PHASE3	COMPLETED	Imatinib Mesylate in Treating Patients With Primary Gastrointestinal Stromal Tumor That Has Been Completely Removed By Surgery
NCT00075218	PHASE3	COMPLETED	A Study To Assess The Safety And Efficacy Of SU11248 In Patients With Gastrointestinal Stromal Tumor(GIST)
NCT00103168	PHASE3	COMPLETED	Imatinib Mesylate or Observation Only in Treating Patients Who Have Undergone Surgery for Localized Gastrointestinal Stromal Tumor
NCT00293124	PHASE3	COMPLETED	Open-label Trial of GlivecWith Unresectable or Metastatic Malignant Gastrointestinal Stromal Tumors
NCT00324987	PHASE3	TERMINATED	Imatinib Mesylate With or Without Bevacizumab in Treating Patients With Metastatic or Unresectable Gastrointestinal Stromal Tumor
NCT00372567	PHASE3	TERMINATED	Safety And Effectiveness Of Daily Dosing With Sunitinib Or Imatinib In Patients With Gastrointestinal Stromal Tumors
NCT00471328	PHASE3	COMPLETED	Efficacy and Safety of Nilotinib (AMN107) Compared With Current Treatment Options in Patients With GIST Who Have Failed Both Imatinib and Sunitinib
NCT00685828	PHASE3	UNKNOWN	Imatinib Mesylate in Treating Patients With Unresectable or Metastatic Gastrointestinal Stromal Tumor
NCT00688766	PHASE3	TERMINATED	Study Evaluating IPI-504 in Patients With Gastrointestinal Stromal Tumors (GIST) Following Failure of at Least Imatinib and Sunitinib
NCT00751036	PHASE3	TERMINATED	Nilotinib 800 Mg And Imatinib 800 Mg For The Treatment Of Patients With Gastrointestinal Stromal Tumors (Gist) Refractory To Imatinib 400 Mg
NCT00785785	PHASE3	COMPLETED	A Study of Nilotinib Versus Imatinib in GIST Patients
NCT00812240	PHASE3	TERMINATED	Masitinib in First Line Treatment of Gastro-Intestinal Stromal Tumor (GIST)
NCT00956072	PHASE3	TERMINATED	Imatinib Mesylate With or Without Surgery in Treating Patients With Metastatic Gastrointestinal Stromal Tumor That is Responding to Imatinib Mesylate
NCT01031628	PHASE3	TERMINATED	Study of Dose Escalation Versus no Dose Escalation of Imatinib in Metastatic Gastrointestinal Stromal Tumors (GIST) Patients
NCT01151852	PHASE3	COMPLETED	Rechallenge of Imatinib in GIST Having no Effective Treatment: RIGHT
NCT01265810	PHASE3	COMPLETED	Caphosol in Oral Mucositis Due to Targeted Therapy
NCT01271712	PHASE3	COMPLETED	Study of Regorafenib as a 3rd-line or Beyond Treatment for Gastrointestinal Stromal Tumors (GIST)
NCT01289028	PHASE3	COMPLETED	Efficacy of Nilotinib in Adult Patients With Gastrointestinal Stromal Tumors Resistant to Imatinib and Sunitinib.
NCT01462994	PHASE3	COMPLETED	Detection of CF-DNA in Patients With Gastrointestinal Stromal Tumors (GIST)
NCT01694277	PHASE3	COMPLETED	Masitinib in Patients With Gastrointestinal Stromal Tumour After Progression With Imatinib
NCT02260505	PHASE3	COMPLETED	Efficiency of Imatinib Treatment Maintenance or Interruption After 3 Years of Adjuvant Treatment in Patients With Gastrointestinal Stromal Tumours (GIST)
NCT02576080	PHASE3	UNKNOWN	Efficacy of Imatinib in Patients With Intermediate-risk Gastrointestinal Stromal Tumor With a High-risk Genomic Grade Index
NCT02866045	PHASE3	UNKNOWN	EUS-FNB vs. Single-incision Needle-knife (SINK) Biopsy for Gastrointestinal SELs
NCT03353753	PHASE3	COMPLETED	Phase 3 Study of DCC-2618 vs Placebo in Advanced GIST Patients Who Have Been Treated With Prior Anticancer Therapies
NCT03426722	PHASE3	COMPLETED	L-carnitine vs Placebo for the Treatment of Muscle Cramps After Imatinib in Gastrointestinal Stromal Tumors
NCT03465722	PHASE3	COMPLETED	(VOYAGER) Study of Avapritinib vs Regorafenib in Patients With Locally Advanced Unresectable or Metastatic GIST
NCT03673501	PHASE3	ACTIVE_NOT_RECRUITING	A Study of Ripretinib vs Sunitinib in Advanced GIST Patients After Treatment With Imatinib
NCT04409223	PHASE3	TERMINATED	Efficacy and Safety of Famitinib Versus Sunitinib in the Treatment of Advanced Gastrointestinal Stromal Tumour Patients After Failure of Imatinib
NCT05208047	PHASE3	ACTIVE_NOT_RECRUITING	(Peak) A Phase 3 Randomized Trial of CGT9486+Sunitinib vs. Sunitinib in Subjects With Gastrointestinal Stromal Tumors
NCT05734105	PHASE3	ACTIVE_NOT_RECRUITING	A Study of Ripretinib vs Sunitinib in Patients With Advanced GIST With Specific KIT Exon Mutations Who Were Previously Treated With Imatinib
NCT06640361	PHASE3	RECRUITING	A Study of Olverembatinib in SDH-deficient GIST.
NCT07585266	PHASE3	NOT_YET_RECRUITING	A Study to Investigate Velzatinib Compared With Imatinib in Adult Participants With Previously Untreated Metastatic and/or Unresectable Gastrointestinal Stromal Tumors (StrateGIST Frontline)
NCT00003939	PHASE2	COMPLETED	Ecteinascidin 743 in Treating Patients With Advanced Soft Tissue Sarcoma