Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTJDHIC0)

• DOT Name: Methionine synthase reductase (MTRR)
• Synonyms: MSR; EC 1.16.1.8; Aquacobalamin reductase; AqCbl reductase
• Gene Name: MTRR
• Related Disease: Methylcobalamin deficiency type cblE
• UniProt ID: MTRR_HUMAN
• PDB ID: 2QTL; 2QTZ
• EC Number: 1.16.1.8
• Pfam ID: PF00667 ; PF00258 ; PF00175
• Sequence:
  MRRFLLLYATQQGQAKAIAEEICEQAVVHGFSADLHCISESDKYDLKTETAPLVVVVSTT
  GTGDPPDTARKFVKEIQNQTLPVDFFAHLRYGLLGLGDSEYTYFCNGGKIIDKRLQELGA
  RHFYDTGHADDCVGLELVVEPWIAGLWPALRKHFRSSRGQEEISGALPVASPASSRTDLV
  KSELLHIESQVELLRFDDSGRKDSEVLKQNAVNSNQSNVVIEDFESSLTRSVPPLSQASL
  NIPGLPPEYLQVHLQESLGQEESQVSVTSADPVFQVPISKAVQLTTNDAIKTTLLVELDI
  SNTDFSYQPGDAFSVICPNSDSEVQSLLQRLQLEDKREHCVLLKIKADTKKKGATLPQHI
  PAGCSLQFIFTWCLEIRAIPKKAFLRALVDYTSDSAEKRRLQELCSKQGAADYSRFVRDA
  CACLLDLLLAFPSCQPPLSLLLEHLPKLQPRPYSCASSSLFHPGKLHFVFNIVEFLSTAT
  TEVLRKGVCTGWLALLVASVLQPNIHASHEDSGKALAPKISISPRTTNSFHLPDDPSIPI
  IMVGPGTGIAPFIGFLQHREKLQEQHPDGNFGAMWLFFGCRHKDRDYLFRKELRHFLKHG
  ILTHLKVSFSRDAPVGEEEAPAKYVQDNIQLHGQQVARILLQENGHIYVCGDAKNMAKDV
  HDALVQIISKEVGVEKLEAMKTLATLKEEKRYLQDIWS
• Function: Key enzyme in methionine and folate homeostasis responsible for the reactivation of methionine synthase (MTR/MS) activity by catalyzing the reductive methylation of MTR-bound cob(II)alamin. Cobalamin (vitamin B12) forms a complex with MTR to serve as an intermediary in methyl transfer reactions that cycles between MTR-bound methylcob(III)alamin and MTR bound-cob(I)alamin forms, and occasional oxidative escape of the cob(I)alamin intermediate during the catalytic cycle leads to the inactive cob(II)alamin species (Probable). The processing of cobalamin in the cytosol occurs in a multiprotein complex composed of at least MMACHC, MMADHC, MTRR and MTR which may contribute to shuttle safely and efficiently cobalamin towards MTR in order to produce methionine. Also necessary for the utilization of methyl groups from the folate cycle, thereby affecting transgenerational epigenetic inheritance. Also acts as a molecular chaperone for methionine synthase by stabilizing apoMTR and incorporating methylcob(III)alamin into apoMTR to form the holoenzyme. Also serves as an aquacob(III)alamin reductase by reducing aquacob(III)alamin to cob(II)alamin; this reduction leads to stimulation of the conversion of apoMTR and aquacob(III)alamin to MTR holoenzyme.
• Tissue Specificity: Found in all tissues tested, particularly abundant in skeletal muscle.
• KEGG Pathway: 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)
  Cobalamin (Cbl) metabolism (R-HSA-9759218)
  Methylation (R-HSA-156581)
• BioCyc Pathway: MetaCyc:HS04756-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 cblE	DISKCD2G	Definitive	Autosomal recessive	[1]

This DOT Affected the Regulation of Drug Effects of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Methionine synthase reductase (MTRR) affects the metabolism of Arsenic.	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Methionine synthase reductase (MTRR).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Methionine synthase reductase (MTRR).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Methionine synthase reductase (MTRR).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Methionine synthase reductase (MTRR).	[5]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Methionine synthase reductase (MTRR).	[6]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Methionine synthase reductase (MTRR).	[7]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Methionine synthase reductase (MTRR).	[8]
Folic acid	DMEMBJC	Approved	Folic acid affects the expression of Methionine synthase reductase (MTRR).	[9]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Methionine synthase reductase (MTRR).	[10]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde decreases the expression of Methionine synthase reductase (MTRR).	[12]

1 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Methionine synthase reductase (MTRR).	[11]

References

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• [2] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [3] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [4] Increased mitochondrial ROS formation by acetaminophen in human hepatic cells is associated with gene expression changes suggesting disruption of the mitochondrial electron transport chain. Toxicol Lett. 2015 Apr 16;234(2):139-50.
• [5] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [6] 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.
• [7] 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.
• [8] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [9] 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.
• [10] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [11] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [12] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.
• [13] Arsenic metabolism is influenced by polymorphisms in genes involved in one-carbon metabolism and reduction reactions. Mutat Res. 2009 Jul 10;667(1-2):4-14. doi: 10.1016/j.mrfmmm.2008.07.003. Epub 2008 Jul 17.