Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT167UBM)

• DOT Name: Lysosomal protective protein (CTSA)
• Synonyms: EC 3.4.16.5; Carboxypeptidase C; Carboxypeptidase L; Cathepsin A; Protective protein cathepsin A; PPCA; Protective protein for beta-galactosidase
• Gene Name: CTSA
• Related Disease: Galactosialidosis
• UniProt ID: PPGB_HUMAN
• PDB ID: 1IVY; 3BP4; 3BP7; 3BXN; 4AZ0; 4AZ3; 4CI9; 4CIA; 4CIB; 4MWS; 4MWT; 6WIA
• EC Number: 3.4.16.5
• Pfam ID: PF00450
• Sequence:
  MIRAAPPPLFLLLLLLLLLVSWASRGEAAPDQDEIQRLPGLAKQPSFRQYSGYLKGSGSK
  HLHYWFVESQKDPENSPVVLWLNGGPGCSSLDGLLTEHGPFLVQPDGVTLEYNPYSWNLI
  ANVLYLESPAGVGFSYSDDKFYATNDTEVAQSNFEALQDFFRLFPEYKNNKLFLTGESYA
  GIYIPTLAVLVMQDPSMNLQGLAVGNGLSSYEQNDNSLVYFAYYHGLLGNRLWSSLQTHC
  CSQNKCNFYDNKDLECVTNLQEVARIVGNSGLNIYNLYAPCAGGVPSHFRYEKDTVVVQD
  LGNIFTRLPLKRMWHQALLRSGDKVRMDPPCTNTTAASTYLNNPYVRKALNIPEQLPQWD
  MCNFLVNLQYRRLYRSMNSQYLKLLSSQKYQILLYNGDVDMACNFMGDEWFVDSLNQKME
  VQRRPWLVKYGDSGEQIAGFVKEFSHIAFLTIKGAGHMVPTDKPLAAFTMFSRFLNKQPY
• Function: Protective protein appears to be essential for both the activity of beta-galactosidase and neuraminidase, it associates with these enzymes and exerts a protective function necessary for their stability and activity. This protein is also a carboxypeptidase and can deamidate tachykinins.
• KEGG Pathway:
  Lysosome (hsa04142)
  Renin-angiotensin system (hsa04614)
• Reactome Pathway:
  Sialic acid metabolism (R-HSA-4085001)
  Defective NEU1 causes sialidosis (R-HSA-4341670)
  Neutrophil degranulation (R-HSA-6798695)
  Glycosphingolipid catabolism (R-HSA-9840310)
  MHC class II antigen presentation (R-HSA-2132295)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Galactosialidosis	DIS0XSEE	Definitive	Autosomal recessive	[1]

This DOT Affected the Biotransformations of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Remdesivir	DMBFZ6L	Phase 3 Trial	Lysosomal protective protein (CTSA) increases the hydrolysis of Remdesivir.	[15]

12 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 Lysosomal protective protein (CTSA).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Lysosomal protective protein (CTSA).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Lysosomal protective protein (CTSA).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Lysosomal protective protein (CTSA).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin affects the expression of Lysosomal protective protein (CTSA).	[6]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Lysosomal protective protein (CTSA).	[7]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Lysosomal protective protein (CTSA).	[8]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Lysosomal protective protein (CTSA).	[9]
Marinol	DM70IK5	Approved	Marinol increases the expression of Lysosomal protective protein (CTSA).	[10]
Selenium	DM25CGV	Approved	Selenium increases the expression of Lysosomal protective protein (CTSA).	[11]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene increases the expression of Lysosomal protective protein (CTSA).	[12]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Lysosomal protective protein (CTSA).	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Lysosomal protective protein (CTSA).	[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] 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] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [5] 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.
• [6] 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.
• [7] 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.
• [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] Changes in gene expression profiles of multiple myeloma cells induced by arsenic trioxide (ATO): possible mechanisms to explain ATO resistance in vivo. Br J Haematol. 2005 Mar;128(5):636-44.
• [10] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [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] Induction of class II major histocompatibility complex expression in human multiple myeloma cells by retinoid. Haematologica. 2007 Jan;92(1):115-20.
• [13] 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.
• [14] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [15] Human carboxylesterase 1A plays a predominant role in the hydrolytic activation of remdesivir in humans. Chem Biol Interact. 2022 Jan 5;351:109744. doi: 10.1016/j.cbi.2021.109744. Epub 2021 Nov 11.