Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT8B6LVD)

• DOT Name: Mitochondrial amidoxime reducing component 2 (MTARC2)
• Synonyms: mARC2; EC 1.7.-.-; Molybdenum cofactor sulfurase C-terminal domain-containing protein 2; MOSC domain-containing protein 2; Moco sulfurase C-terminal domain-containing protein 2
• Gene Name: MTARC2
• UniProt ID: MARC2_HUMAN
• EC Number: 1.7.-.-
• Pfam ID: PF03473 ; PF03476
• Sequence:
  MGASSSSALARLGLPARPWPRWLGVAALGLAAVALGTVAWRRAWPRRRRRLQQVGTVAKL
  WIYPVKSCKGVPVSEAECTAMGLRSGNLRDRFWLVIKEDGHMVTARQEPRLVLISIIYEN
  NCLIFRAPDMDQLVLPSKQPSSNKLHNCRIFGLDIKGRDCGNEAAKWFTNFLKTEAYRLV
  QFETNMKGRTSRKLLPTLDQNFQVAYPDYCPLLIMTDASLVDLNTRMEKKMKMENFRPNI
  VVTGCDAFEEDTWDELLIGSVEVKKVMACPRCILTTVDPDTGVIDRKQPLDTLKSYRLCD
  PSERELYKLSPLFGIYYSVEKIGSLRVGDPVYRMV
• 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 2 (MTARC2) affects the response to substance of Methamphetamine.	[10]

10 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 2 (MTARC2).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Mitochondrial amidoxime reducing component 2 (MTARC2).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Mitochondrial amidoxime reducing component 2 (MTARC2).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Mitochondrial amidoxime reducing component 2 (MTARC2).	[4]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Mitochondrial amidoxime reducing component 2 (MTARC2).	[5]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Mitochondrial amidoxime reducing component 2 (MTARC2).	[6]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Mitochondrial amidoxime reducing component 2 (MTARC2).	[6]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Mitochondrial amidoxime reducing component 2 (MTARC2).	[7]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Mitochondrial amidoxime reducing component 2 (MTARC2).	[8]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Mitochondrial amidoxime reducing component 2 (MTARC2).	[9]

References

• [1] The neuroprotective action of the mood stabilizing drugs lithium chloride and sodium valproate is mediated through the up-regulation of the homeodomain protein Six1. Toxicol Appl Pharmacol. 2009 Feb 15;235(1):124-34.
• [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] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [6] 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.
• [7] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [8] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [9] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.
• [10] 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.