Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTF2K2TA)

• DOT Name: Methionine synthase (MTR)
• Synonyms: MS; EC 2.1.1.13; 5-methyltetrahydrofolate--homocysteine methyltransferase; Cobalamin-dependent methionine synthase; Vitamin-B12 dependent methionine synthase
• Gene Name: MTR
• Related Disease: Methylcobalamin deficiency type cblG
• UniProt ID: METH_HUMAN
• PDB ID: 2O2K; 4CCZ
• EC Number: 2.1.1.13
• Pfam ID: PF02310 ; PF02607 ; PF02965 ; PF00809 ; PF02574
• Sequence:
  MSPALQDLSQPEGLKKTLRDEINAILQKRIMVLDGGMGTMIQREKLNEEHFRGQEFKDHA
  RPLKGNNDILSITQPDVIYQIHKEYLLAGADIIETNTFSSTSIAQADYGLEHLAYRMNMC
  SAGVARKAAEEVTLQTGIKRFVAGALGPTNKTLSVSPSVERPDYRNITFDELVEAYQEQA
  KGLLDGGVDILLIETIFDTANAKAALFALQNLFEEKYAPRPIFISGTIVDKSGRTLSGQT
  GEGFVISVSHGEPLCIGLNCALGAAEMRPFIEIIGKCTTAYVLCYPNAGLPNTFGDYDET
  PSMMAKHLKDFAMDGLVNIVGGCCGSTPDHIREIAEAVKNCKPRVPPATAFEGHMLLSGL
  EPFRIGPYTNFVNIGERCNVAGSRKFAKLIMAGNYEEALCVAKVQVEMGAQVLDVNMDDG
  MLDGPSAMTRFCNLIASEPDIAKVPLCIDSSNFAVIEAGLKCCQGKCIVNSISLKEGEDD
  FLEKARKIKKYGAAMVVMAFDEEGQATETDTKIRVCTRAYHLLVKKLGFNPNDIIFDPNI
  LTIGTGMEEHNLYAINFIHATKVIKETLPGARISGGLSNLSFSFRGMEAIREAMHGVFLY
  HAIKSGMDMGIVNAGNLPVYDDIHKELLQLCEDLIWNKDPEATEKLLRYAQTQGTGGKKV
  IQTDEWRNGPVEERLEYALVKGIEKHIIEDTEEARLNQKKYPRPLNIIEGPLMNGMKIVG
  DLFGAGKMFLPQVIKSARVMKKAVGHLIPFMEKEREETRVLNGTVEEEDPYQGTIVLATV
  KGDVHDIGKNIVGVVLGCNNFRVIDLGVMTPCDKILKAALDHKADIIGLSGLITPSLDEM
  IFVAKEMERLAIRIPLLIGGATTSKTHTAVKIAPRYSAPVIHVLDASKSVVVCSQLLDEN
  LKDEYFEEIMEEYEDIRQDHYESLKERRYLPLSQARKSGFQMDWLSEPHPVKPTFIGTQV
  FEDYDLQKLVDYIDWKPFFDVWQLRGKYPNRGFPKIFNDKTVGGEARKVYDDAHNMLNTL
  ISQKKLRARGVVGFWPAQSIQDDIHLYAEAAVPQAAEPIATFYGLRQQAEKDSASTEPYY
  CLSDFIAPLHSGIRDYLGLFAVACFGVEELSKAYEDDGDDYSSIMVKALGDRLAEAFAEE
  LHERVRRELWAYCGSEQLDVADLRRLRYKGIRPAPGYPSQPDHTEKLTMWRLADIEQSTG
  IRLTESLAMAPASAVSGLYFSNLKSKYFAVGKISKDQVEDYALRKNISVAEVEKWLGPIL
  GYDTD
• 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.
• 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 .
• KEGG Pathway:
  Cysteine and methionine metabolism (hsa00270)
  Selenocompound metabolism (hsa00450)
  One carbon pool by folate (hsa00670)
  Metabolic pathways (hsa01100)
  Biosynthesis of amino acids (hsa01230)
  Cobalamin transport and metabolism (hsa04980)
• Reactome Pathway:
  Sulfur amino acid metabolism (R-HSA-1614635)
  Defective MTRR causes HMAE (R-HSA-3359467)
  Defective MTR causes HMAG (R-HSA-3359469)
  RHOH GTPase cycle (R-HSA-9013407)
  Cobalamin (Cbl) metabolism (R-HSA-9759218)
  Methylation (R-HSA-156581)
• BioCyc Pathway: MetaCyc:HS04076-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Methylcobalamin deficiency type cblG	DISZQIZM	Definitive	Autosomal recessive	[1]

This DOT Affected the Drug Response of 4 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Methionine synthase (MTR) decreases the response to substance of Doxorubicin.	[20]
Arsenic	DMTL2Y1	Approved	Methionine synthase (MTR) affects the response to substance of Arsenic.	[21]
Methotrexate	DM2TEOL	Approved	Methionine synthase (MTR) decreases the response to substance of Methotrexate.	[22]
Benazepril	DMH1M9B	Approved	Methionine synthase (MTR) affects the response to substance of Benazepril.	[23]

18 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Methionine synthase (MTR).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Methionine synthase (MTR).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Methionine synthase (MTR).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Methionine synthase (MTR).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Methionine synthase (MTR).	[6]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Methionine synthase (MTR).	[7]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Methionine synthase (MTR).	[8]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Methionine synthase (MTR).	[9]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Methionine synthase (MTR).	[10]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Methionine synthase (MTR).	[11]
Folic acid	DMEMBJC	Approved	Folic acid affects the expression of Methionine synthase (MTR).	[12]
Dopamine	DMPGUCF	Approved	Dopamine increases the activity of Methionine synthase (MTR).	[13]
Nitrous oxide	DMTHWBI	Approved	Nitrous oxide decreases the activity of Methionine synthase (MTR).	[15]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Methionine synthase (MTR).	[16]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the mutagenesis of Methionine synthase (MTR).	[17]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Methionine synthase (MTR).	[18]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Methionine synthase (MTR).	[2]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Methionine synthase (MTR).	[19]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Ademetionine	DMYQDBO	Approved	Ademetionine affects the binding of Methionine synthase (MTR).	[14]

References

• [1] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [2] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [3] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [4] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [5] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [8] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [9] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [10] Systems analysis of transcriptome and proteome in retinoic acid/arsenic trioxide-induced cell differentiation/apoptosis of promyelocytic leukemia. Proc Natl Acad Sci U S A. 2005 May 24;102(21):7653-8.
• [11] Unique transcriptome, pathways, and networks in the human endometrial fibroblast response to progesterone in endometriosis. Biol Reprod. 2011 Apr;84(4):801-15.
• [12] Folate deficiency induces cell-specific changes in the steady-state transcript levels of genes involved in folate metabolism and 1-carbon transfer reactions in human colonic epithelial cells. J Nutr. 2007 Mar;137(3):607-13. doi: 10.1093/jn/137.3.607.
• [13] Activation of methionine synthase by insulin-like growth factor-1 and dopamine: a target for neurodevelopmental toxins and thimerosal. Mol Psychiatry. 2004 Apr;9(4):358-70.
• [14] Protein interactions in the human methionine synthase-methionine synthase reductase complex and implications for the mechanism of enzyme reactivation. Biochemistry. 2007 Jun 12;46(23):6696-709. doi: 10.1021/bi700339v. Epub 2007 May 4.
• [15] Copper deficiency myelopathy and subacute combined degeneration of the cord - why is the phenotype so similar? Med Hypotheses. 2008 Aug;71(2):229-36.
• [16] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [17] Exome-wide mutation profile in benzo[a]pyrene-derived post-stasis and immortal human mammary epithelial cells. Mutat Res Genet Toxicol Environ Mutagen. 2014 Dec;775-776:48-54. doi: 10.1016/j.mrgentox.2014.10.011. Epub 2014 Nov 4.
• [18] Isobaric tags for relative and absolute quantitation-based proteomics analysis of the effect of ginger oil on bisphenol A-induced breast cancer cell proliferation. Oncol Lett. 2021 Feb;21(2):101. doi: 10.3892/ol.2020.12362. Epub 2020 Dec 8.
• [19] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [20] cDNA microarray analysis of isogenic paclitaxel- and doxorubicin-resistant breast tumor cell lines reveals distinct drug-specific genetic signatures of resistance. Breast Cancer Res Treat. 2006 Mar;96(1):17-39. doi: 10.1007/s10549-005-9026-6. Epub 2005 Dec 2.
• [21] Genetic susceptibility to breast cancer risk associated with inorganic arsenic exposure. Environ Toxicol Pharmacol. 2017 Dec;56:106-113. doi: 10.1016/j.etap.2017.08.032. Epub 2017 Sep 8.
• [22] Gene expression profiling of leukemia T-cells resistant to methotrexate and 7-hydroxymethotrexate reveals alterations that preserve intracellular levels of folate and nucleotide biosynthesis. Biochem Pharmacol. 2009 Apr 15;77(8):1410-7.
• [23] Effects of MTHFR and MS gene polymorphisms on baseline blood pressure and Benazepril effectiveness in Chinese hypertensive patients. J Hum Hypertens. 2011 Mar;25(3):172-7.