Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT7DMHSA)

• DOT Name: Presenilin-associated rhomboid-like protein, mitochondrial (PARL)
• Synonyms: EC 3.4.21.105; Mitochondrial intramembrane cleaving protease PARL
• Gene Name: PARL
• Related Disease:
  Advanced cancer
  Angle-closure glaucoma
  Leigh syndrome
  Leprosy
  Multibacillary leprosy
  Parkinson disease
  Primary angle-closure glaucoma
  Coronary atherosclerosis
  Coronary heart disease
• UniProt ID: PARL_HUMAN
• EC Number: 3.4.21.105
• Pfam ID: PF01694
• Sequence:
  MAWRGWAQRGWGCGQAWGASVGGRSCEELTAVLTPPQLLGRRFNFFIQQKCGFRKAPRKV
  EPRRSDPGTSGEAYKRSALIPPVEETVFYPSPYPIRSLIKPLFFTVGFTGCAFGSAAIWQ
  YESLKSRVQSYFDGIKADWLDSIRPQKEGDFRKEINKWWNNLSDGQRTVTGIIAANVLVF
  CLWRVPSLQRTMIRYFTSNPASKVLCSPMLLSTFSHFSLFHMAANMYVLWSFSSSIVNIL
  GQEQFMAVYLSAGVISNFVSYVGKVATGRYGPSLGASGAIMTVLAAVCTKIPEGRLAIIF
  LPMFTFTAGNALKAIIAMDTAGMILGWKFFDHAAHLGGALFGIWYVTYGHELIWKNREPL
  VKIWHEIRTNGPKKGGGSK
• Function: Required for the control of apoptosis during postnatal growth. Essential for proteolytic processing of an antiapoptotic form of OPA1 which prevents the release of mitochondrial cytochrome c in response to intrinsic apoptotic signals. Required for the maturation of PINK1 into its 52kDa mature form after its cleavage by mitochondrial-processing peptidase (MPP). Promotes cleavage of serine/threonine-protein phosphatase PGAM5 in damaged mitochondria in response to loss of mitochondrial membrane potential. Mediates differential cleavage of PINK1 and PGAM5 depending on the health status of mitochondria, disassociating from PINK1 and associating with PGAM5 in response to mitochondrial membrane potential loss. Required for processing of CLPB into a form with higher protein disaggregase activity by removing an autoinhibitory N-terminal peptide. Promotes processing of DIABLO/SMAC in the mitochondrion which is required for DIABLO apoptotic activity. Also required for cleavage of STARD7 and TTC19. Promotes changes in mitochondria morphology regulated by phosphorylation of P-beta domain.
• Reactome Pathway: Processing of SMDT1 (R-HSA-8949664)

Molecular Interaction Atlas (MIA) of This DOT

9 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Angle-closure glaucoma	DISZ95KY	Strong	Genetic Variation	[2]
Leigh syndrome	DISWQU45	Strong	Biomarker	[3]
Leprosy	DISAA4UI	Strong	Biomarker	[4]
Multibacillary leprosy	DIS90T7X	Strong	Genetic Variation	[4]
Parkinson disease	DISQVHKL	Strong	Genetic Variation	[5]
Primary angle-closure glaucoma	DISX8UKZ	Strong	Genetic Variation	[2]
Coronary atherosclerosis	DISKNDYU	moderate	Genetic Variation	[6]
Coronary heart disease	DIS5OIP1	moderate	Genetic Variation	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Presenilin-associated rhomboid-like protein, mitochondrial (PARL).	[7]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Presenilin-associated rhomboid-like protein, mitochondrial (PARL).	[8]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Presenilin-associated rhomboid-like protein, mitochondrial (PARL).	[10]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Presenilin-associated rhomboid-like protein, mitochondrial (PARL).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Presenilin-associated rhomboid-like protein, mitochondrial (PARL).	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Presenilin-associated rhomboid-like protein, mitochondrial (PARL).	[9]

References

• [1] PHB2 (prohibitin 2) promotes PINK1-PRKN/Parkin-dependent mitophagy by the PARL-PGAM5-PINK1 axis.Autophagy. 2020 Mar;16(3):419-434. doi: 10.1080/15548627.2019.1628520. Epub 2019 Jun 16.
• [2] Genetic Association of the PARL-ABCC5-HTR3D-HTR3C Locus With Primary Angle-Closure Glaucoma in Chinese.Invest Ophthalmol Vis Sci. 2017 Aug 1;58(10):4384?389. doi: 10.1167/iovs.17-22304.
• [3] PARL deficiency in mouse causes Complex III defects, coenzyme Q depletion, and Leigh-like syndrome.Proc Natl Acad Sci U S A. 2019 Jan 2;116(1):277-286. doi: 10.1073/pnas.1811938116. Epub 2018 Dec 21.
• [4] Common variants in the PARL and PINK1 genes increase the risk to leprosy in Han Chinese from South China.Sci Rep. 2016 Nov 23;6:37086. doi: 10.1038/srep37086.
• [5] Mutation analyses and association studies to assess the role of the presenilin-associated rhomboid-like gene in Parkinson's disease.Neurobiol Aging. 2016 Mar;39:217.e13-5. doi: 10.1016/j.neurobiolaging.2015.11.025. Epub 2015 Dec 8.
• [6] Association of PARL rs3732581 genetic variant with insulin levels, metabolic syndrome and coronary artery disease.Hum Genet. 2008 Oct;124(3):263-70. doi: 10.1007/s00439-008-0552-2. Epub 2008 Aug 30.
• [7] 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.
• [8] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [9] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [10] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [11] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [12] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.