Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT0F2THD)

• DOT Name: Caspase-5 (CASP5)
• Synonyms: CASP-5; EC 3.4.22.58; ICE(rel)-III; Protease ICH-3; Protease TY
• Gene Name: CASP5
• UniProt ID: CASP5_HUMAN
• EC Number: 3.4.22.58
• Pfam ID: PF00619 ; PF00656
• Sequence:
  MAEDSGKKKRRKNFEAMFKGILQSGLDNFVINHMLKNNVAGQTSIQTLVPNTDQKSTSVK
  KDNHKKKTVKMLEYLGKDVLHGVFNYLAKHDVLTLKEEEKKKYYDTKIEDKALILVDSLR
  KNRVAHQMFTQTLLNMDQKITSVKPLLQIEAGPPESAESTNILKLCPREEFLRLCKKNHD
  EIYPIKKREDRRRLALIICNTKFDHLPARNGAHYDIVGMKRLLQGLGYTVVDEKNLTARD
  MESVLRAFAARPEHKSSDSTFLVLMSHGILEGICGTAHKKKKPDVLLYDTIFQIFNNRNC
  LSLKDKPKVIIVQACRGEKHGELWVRDSPASLALISSQSSENLEADSVCKIHEEKDFIAF
  CSSTPHNVSWRDRTRGSIFITELITCFQKYSCCCHLMEIFRKVQKSFEVPQAKAQMPTIE
  RATLTRDFYLFPGN
• Function: Thiol protease that acts as a mediator of programmed cell death. Initiates pyroptosis, a programmed lytic cell death pathway through cleavage of Gasdermin-D (GSDMD): cleavage releases the N-terminal gasdermin moiety (Gasdermin-D, N-terminal) that binds to membranes and forms pores, triggering pyroptosis. Also mediates cleavage and maturation of IL18. Cleavage of GSDMD and IL18 is not strictly dependent on the consensus cleavage site but depends on an exosite interface on CASP4. During non-canonical inflammasome activation, cuts CGAS and may play a role in the regulation of antiviral innate immune activation.
• Tissue Specificity: Expressed in barely detectable amounts in most tissues except brain, highest levels being found in lung, liver and skeletal muscle.
• KEGG Pathway:
  NOD-like receptor sig.ling pathway (hsa04621)
  Salmonella infection (hsa05132)
• Reactome Pathway: Pyroptosis (R-HSA-5620971)
• BioCyc Pathway: MetaCyc:HS06389-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Caspase-5 (CASP5).	[1]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of Caspase-5 (CASP5).	[2]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Caspase-5 (CASP5).	[3]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Caspase-5 (CASP5).	[4]
Paclitaxel	DMLB81S	Approved	Paclitaxel increases the expression of Caspase-5 (CASP5).	[5]
Menthol	DMG2KW7	Approved	Menthol decreases the expression of Caspase-5 (CASP5).	[6]
Sanguinarine	DMDINFS	Approved	Sanguinarine increases the expression of Caspase-5 (CASP5).	[3]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Caspase-5 (CASP5).	[2]
Paraquat	DMR8O3X	Investigative	Paraquat decreases the expression of Caspase-5 (CASP5).	[8]
Lithium chloride	DMHYLQ2	Investigative	Lithium chloride increases the expression of Caspase-5 (CASP5).	[9]
9-hydroxyoctadecadienoic acid	DM0FWNJ	Investigative	9-hydroxyoctadecadienoic acid increases the expression of Caspase-5 (CASP5).	[11]

1 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 affects the methylation of Caspase-5 (CASP5).	[7]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
CHLORANIL	DMCHGF1	Investigative	CHLORANIL increases the cleavage of Caspase-5 (CASP5).	[10]

References

• [1] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [2] Gene alterations of ovarian cancer cells expressing estrogen receptors by estrogen and bisphenol a using microarray analysis. Lab Anim Res. 2011 Jun;27(2):99-107. doi: 10.5625/lar.2011.27.2.99. Epub 2011 Jun 22.
• [3] Improved apoptotic cell death in drug-resistant non-small-cell lung cancer cells by tumor necrosis factor-related apoptosis-inducing ligand-based treatment. J Pharmacol Exp Ther. 2014 Mar;348(3):360-71. doi: 10.1124/jpet.113.210054. Epub 2013 Dec 17.
• [4] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [5] Marked regression of liver metastasis by combined therapy of ultrasound-mediated NF kappaB-decoy transfer and transportal injection of paclitaxel, in mouse. Int J Cancer. 2008 Apr 1;122(7):1645-56. doi: 10.1002/ijc.23280.
• [6] Repurposing L-menthol for systems medicine and cancer therapeutics? L-menthol induces apoptosis through caspase 10 and by suppressing HSP90. OMICS. 2016 Jan;20(1):53-64.
• [7] 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.
• [8] Identification of genes associated with paraquat-induced toxicity in SH-SY5Y cells by PCR array focused on apoptotic pathways. J Toxicol Environ Health A. 2008;71(22):1457-67. doi: 10.1080/15287390802329364.
• [9] Effects of lithium and valproic acid on gene expression and phenotypic markers in an NT2 neurosphere model of neural development. PLoS One. 2013;8(3):e58822.
• [10] Atypical Gasdermin D and Mixed Lineage Kinase Domain-like Protein Leakage Aggravates Tetrachlorobenzoquinone-Induced Nod-like Receptor Protein 3 Inflammasome Activation. Chem Res Toxicol. 2018 Dec 17;31(12):1418-1425. doi: 10.1021/acs.chemrestox.8b00306. Epub 2018 Nov 9.
• [11] A proteomic analysis of acute leukemia cells treated with 9-hydroxyoctadecadienoic acid. Lipids Health Dis. 2016 Nov 10;15(1):192. doi: 10.1186/s12944-016-0359-4.