Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT00OP43)

• DOT Name: Carboxylesterase 3 (CES3)
• Synonyms: EC 3.1.1.1; Liver carboxylesterase 31 homolog
• Gene Name: CES3
• UniProt ID: EST3_HUMAN
• EC Number: 3.1.1.1
• Pfam ID: PF00135
• Sequence:
  MERAVRVESGVLVGVVCLLLACPATATGPEVAQPEVDTTLGRVRGRQVGVKGTDRLVNVF
  LGIPFAQPPLGPDRFSAPHPAQPWEGVRDASTAPPMCLQDVESMNSSRFVLNGKQQIFSV
  SEDCLVLNVYSPAEVPAGSGRPVMVWVHGGALITGAATSYDGSALAAYGDVVVVTVQYRL
  GVLGFFSTGDEHAPGNQGFLDVVAALRWVQENIAPFGGDLNCVTVFGGSAGGSIISGLVL
  SPVAAGLFHRAITQSGVITTPGIIDSHPWPLAQKIANTLACSSSSPAEMVQCLQQKEGEE
  LVLSKKLKNTIYPLTVDGTVFPKSPKELLKEKPFHSVPFLMGVNNHEFSWLIPRGWGLLD
  TMEQMSREDMLAISTPVLTSLDVPPEMMPTVIDEYLGSNSDAQAKCQAFQEFMGDVFINV
  PTVSFSRYLRDSGSPVFFYEFQHRPSSFAKIKPAWVKADHGAEGAFVFGGPFLMDESSRL
  AFPEATEEEKQLSLTMMAQWTHFARTGDPNSKALPPWPQFNQAEQYLEINPVPRAGQKFR
  EAWMQFWSETLPSKIQQWHQKQKNRKAQEDL
• Function: Involved in the detoxification of xenobiotics and in the activation of ester and amide prodrugs. Shows low catalytic efficiency for hydrolysis of CPT-11 (7-ethyl-10-[4-(1-piperidino)-1-piperidino]-carbonyloxycamptothecin), a prodrug for camptothecin used in cancer therapeutics.
• Tissue Specificity: Expressed in liver, colon and small intestine.
• Reactome Pathway:
  LDL clearance (R-HSA-8964038)
  Phase I - Functionalization of compounds (R-HSA-211945)
• BioCyc Pathway: MetaCyc:HS10576-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Biotransformations of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Irinotecan	DMP6SC2	Approved	Carboxylesterase 3 (CES3) increases the hydrolysis of Irinotecan.	[4]
Nitrophenyl acetate	DMHSD8A	Investigative	Carboxylesterase 3 (CES3) increases the hydrolysis of Nitrophenyl acetate.	[5]

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 increases the methylation of Carboxylesterase 3 (CES3).	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Carboxylesterase 3 (CES3).	[2]
Paraoxon	DMN4ZKC	Investigative	Paraoxon decreases the activity of Carboxylesterase 3 (CES3).	[3]
S 3025	DMZN0RW	Investigative	S 3025 decreases the activity of Carboxylesterase 3 (CES3).	[3]

References

• [1] 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.
• [2] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.
• [3] Human and rodent carboxylesterases: immunorelatedness, overlapping substrate specificity, differential sensitivity to serine enzyme inhibitors, and tumor-related expression. Drug Metab Dispos. 2002 May;30(5):541-7.
• [4] Hydrolysis of irinotecan and its oxidative metabolites, 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino] carbonyloxycamptothecin and 7-ethyl-10-[4-(1-piperidino)-1-amino]-carbonyloxycamptothecin, by human carboxylesterases CES1A1, CES2, and a newly expressed carboxylesterase isoenzyme, CES3. Drug Metab Dispos. 2004 May;32(5):505-11.
• [5] cDNA cloning, characterization and stable expression of novel human brain carboxylesterase. FEBS Lett. 1999 Sep 10;458(1):17-22.