Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTNBE033)

• DOT Name: Mitochondrial amidoxime-reducing component 1 (MTARC1)
• Synonyms: mARC1; EC 1.7.-.-; Molybdenum cofactor sulfurase C-terminal domain-containing protein 1; MOSC domain-containing protein 1; Moco sulfurase C-terminal domain-containing protein 1
• Gene Name: MTARC1
• UniProt ID: MARC1_HUMAN
• PDB ID: 6FW2
• EC Number: 1.7.-.-
• Pfam ID: PF03473 ; PF03476
• Sequence:
  MGAAGSSALARFVLLAQSRPGWLGVAALGLTAVALGAVAWRRAWPTRRRRLLQQVGTVAQ
  LWIYPVKSCKGVPVSEAECTAMGLRSGNLRDRFWLVINQEGNMVTARQEPRLVLISLTCD
  GDTLTLSAAYTKDLLLPIKTPTTNAVHKCRVHGLEIEGRDCGEATAQWITSFLKSQPYRL
  VHFEPHMRPRRPHQIADLFRPKDQIAYSDTSPFLILSEASLADLNSRLEKKVKATNFRPN
  IVISGCDVYAEDSWDELLIGDVELKRVMACSRCILTTVDPDTGVMSRKEPLETLKSYRQC
  DPSERKLYGKSPLFGQYFVLENPGTIKVGDPVYLLGQ
• Function: Catalyzes the reduction of N-oxygenated molecules, acting as a counterpart of cytochrome P450 and flavin-containing monooxygenases in metabolic cycles. As a component of prodrug-converting system, reduces a multitude of N-hydroxylated prodrugs particularly amidoximes, leading to increased drug bioavailability. May be involved in mitochondrial N(omega)-hydroxy-L-arginine (NOHA) reduction, regulating endogenous nitric oxide levels and biosynthesis. Postulated to cleave the N-OH bond of N-hydroxylated substrates in concert with electron transfer from NADH to cytochrome b5 reductase then to cytochrome b5, the ultimate electron donor that primes the active site for substrate reduction.
• Reactome Pathway: Phase I - Functionalization of compounds (R-HSA-211945)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Methamphetamine	DMPM4SK	Approved	Mitochondrial amidoxime-reducing component 1 (MTARC1) affects the response to substance of Methamphetamine.	[16]

This DOT Affected the Biotransformations of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
trimethylamine	DM8LJ3C	Investigative	Mitochondrial amidoxime-reducing component 1 (MTARC1) increases the chemical synthesis of trimethylamine.	[17]

16 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 Mitochondrial amidoxime-reducing component 1 (MTARC1).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Mitochondrial amidoxime-reducing component 1 (MTARC1).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Mitochondrial amidoxime-reducing component 1 (MTARC1).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Mitochondrial amidoxime-reducing component 1 (MTARC1).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Mitochondrial amidoxime-reducing component 1 (MTARC1).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Mitochondrial amidoxime-reducing component 1 (MTARC1).	[6]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Mitochondrial amidoxime-reducing component 1 (MTARC1).	[7]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Mitochondrial amidoxime-reducing component 1 (MTARC1).	[8]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of Mitochondrial amidoxime-reducing component 1 (MTARC1).	[9]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Mitochondrial amidoxime-reducing component 1 (MTARC1).	[8]
Azathioprine	DMMZSXQ	Approved	Azathioprine decreases the expression of Mitochondrial amidoxime-reducing component 1 (MTARC1).	[10]
Pioglitazone	DMKJ485	Approved	Pioglitazone increases the expression of Mitochondrial amidoxime-reducing component 1 (MTARC1).	[11]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Mitochondrial amidoxime-reducing component 1 (MTARC1).	[12]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Mitochondrial amidoxime-reducing component 1 (MTARC1).	[13]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Mitochondrial amidoxime-reducing component 1 (MTARC1).	[14]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Mitochondrial amidoxime-reducing component 1 (MTARC1).	[15]

References

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• [2] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [3] 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.
• [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] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] 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.
• [8] Time series analysis of oxidative stress response patterns in HepG2: a toxicogenomics approach. Toxicology. 2013 Apr 5;306:24-34.
• [9] Endometrial receptivity is affected in women with high circulating progesterone levels at the end of the follicular phase: a functional genomics analysis. Hum Reprod. 2011 Jul;26(7):1813-25.
• [10] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.
• [11] Peroxisome proliferator activated receptor gamma (PPAR-gama) ligand pioglitazone regulated gene networks in term human primary trophoblast cells. Reprod Toxicol. 2018 Oct;81:99-107.
• [12] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [13] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.
• [14] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [15] Chemical stresses fail to mimic the unfolded protein response resulting from luminal load with unfolded polypeptides. J Biol Chem. 2018 Apr 13;293(15):5600-5612.
• [16] Genome-wide association for methamphetamine dependence: convergent results from 2 samples. Arch Gen Psychiatry. 2008 Mar;65(3):345-55. doi: 10.1001/archpsyc.65.3.345.
• [17] Detoxification of Trimethylamine N-Oxide by the Mitochondrial Amidoxime Reducing Component mARC. Chem Res Toxicol. 2018 Jun 18;31(6):447-453. doi: 10.1021/acs.chemrestox.7b00329. Epub 2018 Jun 1.