Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTEPHG0S)

• DOT Name: ATP-dependent Clp protease proteolytic subunit, mitochondrial (CLPP)
• Synonyms: EC 3.4.21.92; Endopeptidase Clp
• Gene Name: CLPP
• Related Disease:
  Perrault syndrome 3
  Pendred syndrome
  Perrault syndrome
  Mitochondrial disease
  Perrault syndrome 1
  Perrault syndrome 2
  Perrault syndrome 4
• UniProt ID: CLPP_HUMAN
• PDB ID: 1TG6; 6BBA; 6DL7; 6H23; 7UVM; 7UVN; 7UVR; 7UVU; 7UW0; 7VP9; 7WH5; 8HGK; 8I7X
• EC Number: 3.4.21.92
• Pfam ID: PF00574
• Sequence:
  MWPGILVGGARVASCRYPALGPRLAAHFPAQRPPQRTLQNGLALQRCLHATATRALPLIP
  IVVEQTGRGERAYDIYSRLLRERIVCVMGPIDDSVASLVIAQLLFLQSESNKKPIHMYIN
  SPGGVVTAGLAIYDTMQYILNPICTWCVGQAASMGSLLLAAGTPGMRHSLPNSRIMIHQP
  SGGARGQATDIAIQAEEIMKLKKQLYNIYAKHTKQSLQVIESAMERDRYMSPMEAQEFGI
  LDKVLVHPPQDGEDEPTLVQKEPVEAAPAAEPVPAST
• Function: Protease component of the Clp complex that cleaves peptides and various proteins in an ATP-dependent process. Has low peptidase activity in the absence of CLPX. The Clp complex can degrade CSN1S1, CSN2 and CSN3, as well as synthetic peptides (in vitro) and may be responsible for a fairly general and central housekeeping function rather than for the degradation of specific substrates. Cleaves PINK1 in the mitochondrion.
• Tissue Specificity: Detected in liver (at protein level). Predominantly expressed in skeletal muscle. Intermediate levels in heart, liver and pancreas. Low in brain, placenta, lung and kidney.

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Perrault syndrome 3	DIS365S8	Definitive	Autosomal recessive	[1]
Pendred syndrome	DISZ1MU8	Strong	Genetic Variation	[2]
Perrault syndrome	DISG2YOV	Supportive	Autosomal recessive	[3]
Mitochondrial disease	DISKAHA3	Limited	Biomarker	[4]
Perrault syndrome 1	DISP3IK3	Limited	Biomarker	[5]
Perrault syndrome 2	DIS5PQ0K	Limited	Biomarker	[5]
Perrault syndrome 4	DISCAHXP	Limited	Biomarker	[5]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Josamycin	DMKJ8LB	Approved	ATP-dependent Clp protease proteolytic subunit, mitochondrial (CLPP) affects the response to substance of Josamycin.	[14]
Afimoxifene	DMFORDT	Phase 2	ATP-dependent Clp protease proteolytic subunit, mitochondrial (CLPP) affects the response to substance of Afimoxifene.	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of ATP-dependent Clp protease proteolytic subunit, mitochondrial (CLPP).	[6]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of ATP-dependent Clp protease proteolytic subunit, mitochondrial (CLPP).	[10]

6 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 ATP-dependent Clp protease proteolytic subunit, mitochondrial (CLPP).	[7]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of ATP-dependent Clp protease proteolytic subunit, mitochondrial (CLPP).	[8]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of ATP-dependent Clp protease proteolytic subunit, mitochondrial (CLPP).	[9]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of ATP-dependent Clp protease proteolytic subunit, mitochondrial (CLPP).	[11]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of ATP-dependent Clp protease proteolytic subunit, mitochondrial (CLPP).	[12]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of ATP-dependent Clp protease proteolytic subunit, mitochondrial (CLPP).	[13]

References

• [1] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [2] Unresolved questions regarding human hereditary deafness.Oral Dis. 2017 Jul;23(5):551-558. doi: 10.1111/odi.12516. Epub 2016 Jul 11.
• [3] Perrault syndrome is caused by recessive mutations in CLPP, encoding a mitochondrial ATP-dependent chambered protease. Am J Hum Genet. 2013 Apr 4;92(4):605-13. doi: 10.1016/j.ajhg.2013.02.013. Epub 2013 Mar 28.
• [4] CLPP deficiency protects against metabolic syndrome but hinders adaptive thermogenesis.EMBO Rep. 2018 May;19(5):e45126. doi: 10.15252/embr.201745126. Epub 2018 Mar 27.
• [5] Loss of mitochondrial peptidase Clpp leads to infertility, hearing loss plus growth retardation via accumulation of CLPX, mtDNA and inflammatory factors.Hum Mol Genet. 2013 Dec 15;22(24):4871-87. doi: 10.1093/hmg/ddt338. Epub 2013 Jul 12.
• [6] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [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] 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.
• [9] 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.
• [10] 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.
• [11] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [12] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [13] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [14] A genome-wide analysis of targets of macrolide antibiotics in mammalian cells. J Biol Chem. 2020 Feb 14;295(7):2057-2067. doi: 10.1074/jbc.RA119.010770. Epub 2020 Jan 8.
• [15] Genome-wide functional screen identifies a compendium of genes affecting sensitivity to tamoxifen. Proc Natl Acad Sci U S A. 2012 Feb 21;109(8):2730-5. doi: 10.1073/pnas.1018872108. Epub 2011 Apr 11.