Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTRLMLK0)

• DOT Name: Phosphatidylcholine-sterol acyltransferase (LCAT)
• Synonyms: EC 2.3.1.43; 1-alkyl-2-acetylglycerophosphocholine esterase; EC 3.1.1.47; Lecithin-cholesterol acyltransferase; Phospholipid-cholesterol acyltransferase; Platelet-activating factor acetylhydrolase; PAF acetylhydrolase
• Gene Name: LCAT
• Related Disease:
  Fish eye disease
  LCAT deficiency
  Norum disease
• UniProt ID: LCAT_HUMAN
• PDB ID: 4X96; 4XWG; 4XX1; 5BV7; 5TXF; 6MVD
• EC Number: 2.3.1.43; 3.1.1.47
• Pfam ID: PF02450
• Sequence:
  MGPPGSPWQWVTLLLGLLLPPAAPFWLLNVLFPPHTTPKAELSNHTRPVILVPGCLGNQL
  EAKLDKPDVVNWMCYRKTEDFFTIWLDLNMFLPLGVDCWIDNTRVVYNRSSGLVSNAPGV
  QIRVPGFGKTYSVEYLDSSKLAGYLHTLVQNLVNNGYVRDETVRAAPYDWRLEPGQQEEY
  YRKLAGLVEEMHAAYGKPVFLIGHSLGCLHLLYFLLRQPQAWKDRFIDGFISLGAPWGGS
  IKPMLVLASGDNQGIPIMSSIKLKEEQRITTTSPWMFPSRMAWPEDHVFISTPSFNYTGR
  DFQRFFADLHFEEGWYMWLQSRDLLAGLPAPGVEVYCLYGVGLPTPRTYIYDHGFPYTDP
  VGVLYEDGDDTVATRSTELCGLWQGRQPQPVHLLPLHGIQHLNMVFSNLTLEHINAILLG
  AYRQGPPASPTASPEPPPPE
• Function: Central enzyme in the extracellular metabolism of plasma lipoproteins. Synthesized mainly in the liver and secreted into plasma where it converts cholesterol and phosphatidylcholines (lecithins) to cholesteryl esters and lysophosphatidylcholines on the surface of high and low density lipoproteins (HDLs and LDLs). The cholesterol ester is then transported back to the liver. Has a preference for plasma 16:0-18:2 or 18:O-18:2 phosphatidylcholines. Also produced in the brain by primary astrocytes, and esterifies free cholesterol on nascent APOE-containing lipoproteins secreted from glia and influences cerebral spinal fluid (CSF) APOE- and APOA1 levels. Together with APOE and the cholesterol transporter ABCA1, plays a key role in the maturation of glial-derived, nascent lipoproteins. Required for remodeling high-density lipoprotein particles into their spherical forms. Catalyzes the hydrolysis of 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine (platelet-activating factor or PAF) to 1-O-alkyl-sn-glycero-3-phosphocholine (lyso-PAF). Also catalyzes the transfer of the acetate group from PAF to 1-hexadecanoyl-sn-glycero-3-phosphocholine forming lyso-PAF. Catalyzes the esterification of (24S)-hydroxycholesterol (24(S)OH-C), also known as cerebrosterol to produce 24(S)OH-C monoesters.
• Tissue Specificity: Detected in blood plasma . Detected in cerebral spinal fluid (at protein level) . Detected in liver . Expressed mainly in brain, liver and testes.
• KEGG Pathway:
  Glycerophospholipid metabolism (hsa00564)
  Cholesterol metabolism (hsa04979)
• Reactome Pathway: HDL remodeling (R-HSA-8964058)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Fish eye disease	DISYTZNQ	Definitive	Autosomal recessive	[1]
LCAT deficiency	DISV6DVF	Definitive	Autosomal recessive	[2]
Norum disease	DISSJE3M	Supportive	Autosomal recessive	[3]

This DOT Affected the Biotransformations of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
ANW-32821	DMMJOZD	Phase 2	Phosphatidylcholine-sterol acyltransferase (LCAT) increases the acylation of ANW-32821.	[19]

This DOT Affected the Regulation of Drug Effects of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
27-hydroxycholesterol	DM2L6OZ	Investigative	Phosphatidylcholine-sterol acyltransferase (LCAT) increases the metabolism of 27-hydroxycholesterol.	[20]

1 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 Phosphatidylcholine-sterol acyltransferase (LCAT).	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Phosphatidylcholine-sterol acyltransferase (LCAT).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Phosphatidylcholine-sterol acyltransferase (LCAT).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Phosphatidylcholine-sterol acyltransferase (LCAT).	[7]
Cisplatin	DMRHGI9	Approved	Cisplatin affects the expression of Phosphatidylcholine-sterol acyltransferase (LCAT).	[8]
Quercetin	DM3NC4M	Approved	Quercetin affects the expression of Phosphatidylcholine-sterol acyltransferase (LCAT).	[9]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide decreases the expression of Phosphatidylcholine-sterol acyltransferase (LCAT).	[10]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Phosphatidylcholine-sterol acyltransferase (LCAT).	[8]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of Phosphatidylcholine-sterol acyltransferase (LCAT).	[11]
Obeticholic acid	DM3Q1SM	Approved	Obeticholic acid decreases the expression of Phosphatidylcholine-sterol acyltransferase (LCAT).	[12]
Nevirapine	DM6HX9B	Approved	Nevirapine increases the expression of Phosphatidylcholine-sterol acyltransferase (LCAT).	[13]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Phosphatidylcholine-sterol acyltransferase (LCAT).	[14]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Phosphatidylcholine-sterol acyltransferase (LCAT).	[15]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Phosphatidylcholine-sterol acyltransferase (LCAT).	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Phosphatidylcholine-sterol acyltransferase (LCAT).	[17]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Phosphatidylcholine-sterol acyltransferase (LCAT).	[18]
4-hydroxy-2-nonenal	DM2LJFZ	Investigative	4-hydroxy-2-nonenal decreases the expression of Phosphatidylcholine-sterol acyltransferase (LCAT).	[10]

References

• [1] Flexible and scalable diagnostic filtering of genomic variants using G2P with Ensembl VEP. Nat Commun. 2019 May 30;10(1):2373. doi: 10.1038/s41467-019-10016-3.
• [2] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [3] The molecular pathology of lecithin:cholesterol acyltransferase (LCAT) deficiency syndromes. J Lipid Res. 1997 Feb;38(2):191-205.
• [4] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [5] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [6] 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.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [9] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [10] Microarray analysis of H2O2-, HNE-, or tBH-treated ARPE-19 cells. Free Radic Biol Med. 2002 Nov 15;33(10):1419-32.
• [11] Computational discovery of niclosamide ethanolamine, a repurposed drug candidate that reduces growth of hepatocellular carcinoma cells initro and in mice by inhibiting cell division cycle 37 signaling. Gastroenterology. 2017 Jun;152(8):2022-2036.
• [12] Pharmacotoxicology of clinically-relevant concentrations of obeticholic acid in an organotypic human hepatocyte system. Toxicol In Vitro. 2017 Mar;39:93-103.
• [13] Nevirapine increases high-density lipoprotein cholesterol concentration by stimulation of apolipoprotein A-I production. Arterioscler Thromb Vasc Biol. 2009 Sep;29(9):1336-41. doi: 10.1161/ATVBAHA.109.192088. Epub 2009 Aug 10.
• [14] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [15] New insights into BaP-induced toxicity: role of major metabolites in transcriptomics and contribution to hepatocarcinogenesis. Arch Toxicol. 2016 Jun;90(6):1449-58.
• [16] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [17] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.
• [18] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [19] Effect of organophosphate pesticides on lecithin-cholesterol acyltransferase in human plasma. Biochem Pharmacol. 1974 May 1;23(11):1641-5. doi: 10.1016/0006-2952(74)90376-1.
• [20] Esterification of oxysterols by human plasma lecithin-cholesterol acyltransferase. J Biol Chem. 1995 May 19;270(20):11812-9. doi: 10.1074/jbc.270.20.11812.