Details of Drug Off-Target (DOT)

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

• DOT Name: Lon protease homolog 2, peroxisomal (LONP2)
• Synonyms: EC 3.4.21.53; Lon protease-like protein 2; Lon protease 2; Peroxisomal Lon protease; pLon
• Gene Name: LONP2
• Related Disease:
  Advanced cancer
  Cervical cancer
  Cervical carcinoma
• UniProt ID: LONP2_HUMAN
• EC Number: 3.4.21.53
• Pfam ID: PF00004 ; PF05362 ; PF02190
• Sequence:
  MSSVSPIQIPSRLPLLLTHEGVLLPGSTMRTSVDSARNLQLVRSRLLKGTSLQSTILGVI
  PNTPDPASDAQDLPPLHRIGTAALAVQVVGSNWPKPHYTLLITGLCRFQIVQVLKEKPYP
  IAEVEQLDRLEEFPNTCKMREELGELSEQFYKYAVQLVEMLDMSVPAVAKLRRLLDSLPR
  EALPDILTSIIRTSNKEKLQILDAVSLEERFKMTIPLLVRQIEGLKLLQKTRKPKQDDDK
  RVIAIRPIRRITHISGTLEDEDEDEDNDDIVMLEKKIRTSSMPEQAHKVCVKEIKRLKKM
  PQSMPEYALTRNYLELMVELPWNKSTTDRLDIRAARILLDNDHYAMEKLKKRVLEYLAVR
  QLKNNLKGPILCFVGPPGVGKTSVGRSVAKTLGREFHRIALGGVCDQSDIRGHRRTYVGS
  MPGRIINGLKTVGVNNPVFLLDEVDKLGKSLQGDPAAALLEVLDPEQNHNFTDHYLNVAF
  DLSQVLFIATANTTATIPAALLDRMEIIQVPGYTQEEKIEIAHRHLIPKQLEQHGLTPQQ
  IQIPQVTTLDIITRYTREAGVRSLDRKLGAICRAVAVKVAEGQHKEAKLDRSDVTEREGC
  REHILEDEKPESISDTTDLALPPEMPILIDFHALKDILGPPMYEMEVSQRLSQPGVAIGL
  AWTPLGGEIMFVEASRMDGEGQLTLTGQLGDVMKESAHLAISWLRSNAKKYQLTNAFGSF
  DLLDNTDIHLHFPAGAVTKDGPSAGVTIVTCLASLFSGRLVRSDVAMTGEITLRGLVLPV
  GGIKDKVLAAHRAGLKQVIIPRRNEKDLEGIPGNVRQDLSFVTASCLDEVLNAAFDGGFT
  VKTRPGLLNSKL
• Function: ATP-dependent serine protease that mediates the selective degradation of misfolded and unassembled polypeptides in the peroxisomal matrix. Necessary for type 2 peroxisome targeting signal (PTS2)-containing protein processing and facilitates peroxisome matrix protein import. May indirectly regulate peroxisomal fatty acid beta-oxidation through degradation of the self-processed forms of TYSND1.
• Tissue Specificity: Widely expressed, with high levels in the liver, kidney and pancreas.
• Reactome Pathway:
  Peroxisomal protein import (R-HSA-9033241)
  Association of TriC/CCT with target proteins during biosynthesis (R-HSA-390471)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Cervical cancer	DISFSHPF	Strong	Altered Expression	[1]
Cervical carcinoma	DIST4S00	Strong	Altered Expression	[1]

8 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 Lon protease homolog 2, peroxisomal (LONP2).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Lon protease homolog 2, peroxisomal (LONP2).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Lon protease homolog 2, peroxisomal (LONP2).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Lon protease homolog 2, peroxisomal (LONP2).	[5]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Lon protease homolog 2, peroxisomal (LONP2).	[6]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Lon protease homolog 2, peroxisomal (LONP2).	[8]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Lon protease homolog 2, peroxisomal (LONP2).	[9]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Lon protease homolog 2, peroxisomal (LONP2).	[13]

4 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 Lon protease homolog 2, peroxisomal (LONP2).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Lon protease homolog 2, peroxisomal (LONP2).	[10]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Lon protease homolog 2, peroxisomal (LONP2).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the methylation of Lon protease homolog 2, peroxisomal (LONP2).	[12]

References

• [1] Lon Peptidase 2, Peroxisomal (LONP2) Contributes to Cervical Carcinogenesis via Oxidative Stress.Med Sci Monit. 2018 Mar 4;24:1310-1320. doi: 10.12659/msm.908966.
• [2] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [3] 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.
• [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] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [6] 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.
• [7] 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.
• [8] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [9] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [10] 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.
• [11] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [12] 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.
• [13] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.