Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTJPJ8N6)

• DOT Name: Rhomboid-related protein 2 (RHBDL2)
• Synonyms: RRP2; EC 3.4.21.105; Rhomboid-like protein 2
• Gene Name: RHBDL2
• Related Disease:
  Lyme disease
  Alcohol dependence
  Alcohol-induced disorders
  Alcohol-related disorders
  Major depressive disorder
  Tuberculosis
• UniProt ID: RHBL2_HUMAN
• EC Number: 3.4.21.105
• Pfam ID: PF01694
• Sequence:
  MAAVHDLEMESMNLNMGREMKEELEEEEKMREDGGGKDRAKSKKVHRIVSKWMLPEKSRG
  TYLERANCFPPPVFIISISLAELAVFIYYAVWKPQKQWITLDTGILESPFIYSPEKREEA
  WRFISYMLVHAGVQHILGNLCMQLVLGIPLEMVHKGLRVGLVYLAGVIAGSLASSIFDPL
  RYLVGASGGVYALMGGYFMNVLVNFQEMIPAFGIFRLLIIILIIVLDMGFALYRRFFVPE
  DGSPVSFAAHIAGGFAGMSIGYTVFSCFDKALLKDPRFWIAIAAYLACVLFAVFFNIFLS
  PAN
• Function: Involved in regulated intramembrane proteolysis and the subsequent release of functional polypeptides from their membrane anchors. Known substrate: EFNB3.

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Lyme disease	DISO70G5	Strong	Biomarker	[1]
Alcohol dependence	DIS4ZSCO	moderate	Genetic Variation	[2]
Alcohol-induced disorders	DIS3SFYT	moderate	Genetic Variation	[2]
Alcohol-related disorders	DIS3K4KK	moderate	Genetic Variation	[2]
Major depressive disorder	DIS4CL3X	moderate	Genetic Variation	[2]
Tuberculosis	DIS2YIMD	Limited	Biomarker	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Fluorouracil	DMUM7HZ	Approved	Rhomboid-related protein 2 (RHBDL2) affects the response to substance of Fluorouracil.	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Rhomboid-related protein 2 (RHBDL2).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Rhomboid-related protein 2 (RHBDL2).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Rhomboid-related protein 2 (RHBDL2).	[6]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Rhomboid-related protein 2 (RHBDL2).	[7]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Rhomboid-related protein 2 (RHBDL2).	[8]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Rhomboid-related protein 2 (RHBDL2).	[9]
Sodium lauryl sulfate	DMLJ634	Approved	Sodium lauryl sulfate decreases the expression of Rhomboid-related protein 2 (RHBDL2).	[10]
Permethrin	DMZ0Q1G	Approved	Permethrin increases the expression of Rhomboid-related protein 2 (RHBDL2).	[11]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Rhomboid-related protein 2 (RHBDL2).	[12]
OTX-015	DMI8RG1	Phase 1/2	OTX-015 decreases the expression of Rhomboid-related protein 2 (RHBDL2).	[13]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Rhomboid-related protein 2 (RHBDL2).	[13]
Mivebresib	DMCPF90	Phase 1	Mivebresib decreases the expression of Rhomboid-related protein 2 (RHBDL2).	[13]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Rhomboid-related protein 2 (RHBDL2).	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Rhomboid-related protein 2 (RHBDL2).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Rhomboid-related protein 2 (RHBDL2).	[15]

References

• [1] The RpoS Gatekeeper in Borrelia burgdorferi: An Invariant Regulatory Scheme That Promotes Spirochete Persistence in Reservoir Hosts and Niche Diversity.Front Microbiol. 2019 Aug 21;10:1923. doi: 10.3389/fmicb.2019.01923. eCollection 2019.
• [2] Genetic Risk Variants Associated With Comorbid Alcohol Dependence and Major Depression.JAMA Psychiatry. 2017 Dec 1;74(12):1234-1241. doi: 10.1001/jamapsychiatry.2017.3275.
• [3] Rhomboid homologs in mycobacteria: insights from phylogeny and genomic analysis.BMC Microbiol. 2010 Oct 29;10:272. doi: 10.1186/1471-2180-10-272.
• [4] 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.
• [5] Retinoic acid receptor alpha amplifications and retinoic acid sensitivity in breast cancers. Clin Breast Cancer. 2013 Oct;13(5):401-8.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] High-throughput ectopic expression screen for tamoxifen resistance identifies an atypical kinase that blocks autophagy. Proc Natl Acad Sci U S A. 2011 Feb 1;108(5):2058-63.
• [8] 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.
• [9] Minimal peroxide exposure of neuronal cells induces multifaceted adaptive responses. PLoS One. 2010 Dec 17;5(12):e14352. doi: 10.1371/journal.pone.0014352.
• [10] CXCL14 downregulation in human keratinocytes is a potential biomarker for a novel in vitro skin sensitization test. Toxicol Appl Pharmacol. 2020 Jan 1;386:114828. doi: 10.1016/j.taap.2019.114828. Epub 2019 Nov 14.
• [11] Exposure to Insecticides Modifies Gene Expression and DNA Methylation in Hematopoietic Tissues In Vitro. Int J Mol Sci. 2023 Mar 26;24(7):6259. doi: 10.3390/ijms24076259.
• [12] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [13] Comprehensive transcriptome profiling of BET inhibitor-treated HepG2 cells. PLoS One. 2022 Apr 29;17(4):e0266966. doi: 10.1371/journal.pone.0266966. eCollection 2022.
• [14] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [15] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [16] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [17] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.