Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTIT4JL0)

• DOT Name: ATP-dependent Clp protease ATP-binding subunit clpX-like, mitochondrial (CLPX)
• Gene Name: CLPX
• Related Disease:
  Erythropoietic protoporphyria
  Protoporphyria, erythropoietic, 2
• UniProt ID: CLPX_HUMAN
• Pfam ID: PF07724 ; PF10431
• Sequence:
  MPSCGACTCGAAAVRLITSSLASAQRGISGGRIHMSVLGRLGTFETQILQRAPLRSFTET
  PAYFASKDGISKDGSGDGNKKSASEGSSKKSGSGNSGKGGNQLRCPKCGDLCTHVETFVS
  STRFVKCEKCHHFFVVLSEADSKKSIIKEPESAAEAVKLAFQQKPPPPPKKIYNYLDKYV
  VGQSFAKKVLSVAVYNHYKRIYNNIPANLRQQAEVEKQTSLTPRELEIRRREDEYRFTKL
  LQIAGISPHGNALGASMQQQVNQQIPQEKRGGEVLDSSHDDIKLEKSNILLLGPTGSGKT
  LLAQTLAKCLDVPFAICDCTTLTQAGYVGEDIESVIAKLLQDANYNVEKAQQGIVFLDEV
  DKIGSVPGIHQLRDVGGEGVQQGLLKLLEGTIVNVPEKNSRKLRGETVQVDTTNILFVAS
  GAFNGLDRIISRRKNEKYLGFGTPSNLGKGRRAAAAADLANRSGESNTHQDIEEKDRLLR
  HVEARDLIEFGMIPEFVGRLPVVVPLHSLDEKTLVQILTEPRNAVIPQYQALFSMDKCEL
  NVTEDALKAIARLALERKTGARGLRSIMEKLLLEPMFEVPNSDIVCVEVDKEVVEGKKEP
  GYIRAPTKESSEEEYDSGVEEEGWPRQADAANS
• Function: ATP-dependent specificity component of the Clp protease complex. Hydrolyzes ATP. Targets specific substrates for degradation by the Clp complex. Can perform chaperone functions in the absence of CLPP. Enhances the DNA-binding activity of TFAM and is required for maintaining a normal mitochondrial nucleoid structure. ATP-dependent unfoldase that stimulates the incorporation of the pyridoxal phosphate cofactor into 5-aminolevulinate synthase, thereby activating 5-aminolevulinate (ALA) synthesis, the first step in heme biosynthesis. Important for efficient erythropoiesis through up-regulation of heme biosynthesis.
• Tissue Specificity: Higher expression in skeletal muscle and heart and to a lesser extent in liver, brain, placenta, lung, kidney and pancreas.

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Erythropoietic protoporphyria	DISH4BY0	Strong	Biomarker	[1]
Protoporphyria, erythropoietic, 2	DIS3EYYJ	Strong	Autosomal dominant	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Josamycin	DMKJ8LB	Approved	ATP-dependent Clp protease ATP-binding subunit clpX-like, mitochondrial (CLPX) affects the response to substance of Josamycin.	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of ATP-dependent Clp protease ATP-binding subunit clpX-like, mitochondrial (CLPX).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of ATP-dependent Clp protease ATP-binding subunit clpX-like, mitochondrial (CLPX).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of ATP-dependent Clp protease ATP-binding subunit clpX-like, mitochondrial (CLPX).	[4]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of ATP-dependent Clp protease ATP-binding subunit clpX-like, mitochondrial (CLPX).	[5]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of ATP-dependent Clp protease ATP-binding subunit clpX-like, mitochondrial (CLPX).	[6]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of ATP-dependent Clp protease ATP-binding subunit clpX-like, mitochondrial (CLPX).	[7]
Paclitaxel	DMLB81S	Approved	Paclitaxel increases the expression of ATP-dependent Clp protease ATP-binding subunit clpX-like, mitochondrial (CLPX).	[8]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of ATP-dependent Clp protease ATP-binding subunit clpX-like, mitochondrial (CLPX).	[9]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of ATP-dependent Clp protease ATP-binding subunit clpX-like, mitochondrial (CLPX).	[10]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of ATP-dependent Clp protease ATP-binding subunit clpX-like, mitochondrial (CLPX).	[11]
Deguelin	DMXT7WG	Investigative	Deguelin increases the expression of ATP-dependent Clp protease ATP-binding subunit clpX-like, mitochondrial (CLPX).	[12]

References

• [1] Mutation in human CLPX elevates levels of -aminolevulinate synthase and protoporphyrin IX to promote erythropoietic protoporphyria. Proc Natl Acad Sci U S A. 2017 Sep 19;114(38):E8045-E8052. doi: 10.1073/pnas.1700632114. Epub 2017 Sep 5.
• [2] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [3] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [4] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [5] 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.
• [6] 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.
• [7] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [8] Proteomic analysis of anti-cancer effects by paclitaxel treatment in cervical cancer cells. Gynecol Oncol. 2005 Jul;98(1):45-53. doi: 10.1016/j.ygyno.2005.04.010.
• [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] 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.
• [11] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [12] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.
• [13] 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.