Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTJG6BA7)

• DOT Name: Pancreatic lipase-related protein 2 (PNLIPRP2)
• Synonyms: PL-RP2; Cytotoxic T lymphocyte lipase; Galactolipase; EC 3.1.1.26; Triacylglycerol lipase; EC 3.1.1.3
• Gene Name: PNLIPRP2
• Related Disease:
  Chronic pancreatitis
  Pancreatitis
• UniProt ID: LIPR2_HUMAN
• PDB ID: 2OXE; 2PVS
• EC Number: 3.1.1.26; 3.1.1.3
• Pfam ID: PF00151 ; PF01477
• Sequence:
  MLPPWTLGLLLLATVRGKEVCYGQLGCFSDEKPWAGTLQRPVKLLPWSPEDIDTRFLLYT
  NENPNNFQLITGTEPDTIEASNFQLDRKTRFIIHGFLDKAEDSWPSDMCKKMFEVEKVNC
  ICVDWRHGSRAMYTQAVQNIRVVGAETAFLIQALSTQLGYSLEDVHVIGHSLGAHTAAEA
  GRRLGGRVGRITGLDPAGPCFQDEPEEVRLDPSDAVFVDVIHTDSSPIVPSLGFGMSQKV
  GHLDFFPNGGKEMPGCKKNVLSTITDIDGIWEGIGGFVSCNHLRSFEYYSSSVLNPDGFL
  GYPCASYDEFQESKCFPCPAEGCPKMGHYADQFKGKTSAVEQTFFLNTGESGNFTSWRYK
  ISVTLSGKEKVNGYIRIALYGSNENSKQYEIFKGSLKPDASHTCAIDVDFNVGKIQKVKF
  LWNKRGINLSEPKLGASQITVQSGEDGTEYNFCSSDTVEENVLQSLYPC
• Function: Lipase that primarily hydrolyzes triglycerides and galactosylglycerides. In neonates, may play a major role in pancreatic digestion of dietary fats such as milk fat globules enriched in long-chain triglycerides. Hydrolyzes short-, medium- and long-chain fatty acyls in triglycerides without apparent positional specificity. Can completely deacylate triacylglycerols. When the liver matures and bile salt synthesis increases, likely functions mainly as a galactolipase and monoacylglycerol lipase. Hydrolyzes monogalactosyldiglycerols (MGDG) and digalactosyldiacylglycerols (DGDG) present in a plant-based diet, releasing long-chain polyunsaturated fatty acids. Hydrolyzes medium- and long-chain fatty acyls in galactolipids. May act together with LIPF to hydrolyze partially digested triglycerides. Hydrolyzes long-chain monoglycerides with high efficiency. In cytotoxic T cells, contributes to perforin-dependent cell lysis, but is unlikely to mediate direct cytotoxicity. Also has low phospholipase activity. In neurons, required for the localization of the phospholipid 1-oleoyl-2-palmitoyl-PC (OPPC) to neurite tips through acyl chain remodeling of membrane phospholipids. The resulting OPPC-rich lipid membrane domain recruits the t-SNARE protein STX4 by selectively interacting with the STX4 transmembrane domain and this promotes surface expression of the dopamine transporter SLC6A3/DAT at neurite tips by facilitating fusion of SLC6A3-containing transport vesicles with the plasma membrane.
• Tissue Specificity: Pancreas.
• KEGG Pathway:
  Glycerolipid metabolism (hsa00561)
  Metabolic pathways (hsa01100)
  Pancreatic secretion (hsa04972)
  Fat digestion and absorption (hsa04975)
• Reactome Pathway: Digestion of dietary lipid (R-HSA-192456)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Chronic pancreatitis	DISBUOMJ	Limited	Biomarker	[1]
Pancreatitis	DIS0IJEF	Limited	Biomarker	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Pancreatic lipase-related protein 2 (PNLIPRP2).	[3]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Pancreatic lipase-related protein 2 (PNLIPRP2).	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Pancreatic lipase-related protein 2 (PNLIPRP2).	[4]
Orlistat	DMRJSP8	Approved	Orlistat decreases the activity of Pancreatic lipase-related protein 2 (PNLIPRP2).	[5]
Belinostat	DM6OC53	Phase 2	Belinostat decreases the expression of Pancreatic lipase-related protein 2 (PNLIPRP2).	[6]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Pancreatic lipase-related protein 2 (PNLIPRP2).	[8]
Paraoxon	DMN4ZKC	Investigative	Paraoxon decreases the activity of Pancreatic lipase-related protein 2 (PNLIPRP2).	[5]

References

• [1] The common truncation variant in pancreatic lipase related protein 2 (PNLIPRP2) is expressed poorly and does not alter risk for chronic pancreatitis.PLoS One. 2018 Nov 8;13(11):e0206869. doi: 10.1371/journal.pone.0206869. eCollection 2018.
• [2] Carboxyl Ester Lipase May Not Mediate Lipotoxic Injury during Severe Acute Pancreatitis.Am J Pathol. 2019 Jun;189(6):1226-1240. doi: 10.1016/j.ajpath.2019.02.015. Epub 2019 Apr 5.
• [3] Integrated 'omics analysis reveals new drug-induced mitochondrial perturbations in human hepatocytes. Toxicol Lett. 2018 Jun 1;289:1-13.
• [4] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [5] Further biochemical characterization of human pancreatic lipase-related protein 2 expressed in yeast cells. J Lipid Res. 2007 Jul;48(7):1539-49. doi: 10.1194/jlr.M600486-JLR200. Epub 2007 Mar 30.
• [6] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [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] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.