Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTSHD5M5)

• DOT Name: Platelet-activating factor acetylhydrolase 2, cytoplasmic (PAFAH2)
• Synonyms: EC 3.1.1.47; PAF:lysophospholipid transacetylase; PAF:sphingosine transacetylase; Platelet-activating factor acetyltransferase PAFAH2; EC 2.3.1.149; Serine-dependent phospholipase A2; SD-PLA2; hSD-PLA2
• Gene Name: PAFAH2
• Related Disease: Coronary heart disease
• UniProt ID: PAFA2_HUMAN
• EC Number: 2.3.1.149; 3.1.1.47
• Pfam ID: PF03403
• Sequence:
  MGVNQSVGFPPVTGPHLVGCGDVMEGQNLQGSFFRLFYPCQKAEETMEQPLWIPRYEYCT
  GLAEYLQFNKRCGGLLFNLAVGSCRLPVSWNGPFKTKDSGYPLIIFSHGLGAFRTLYSAF
  CMELASRGFVVAVPEHRDRSAATTYFCKQAPEENQPTNESLQEEWIPFRRVEEGEKEFHV
  RNPQVHQRVSECLRVLKILQEVTAGQTVFNILPGGLDLMTLKGNIDMSRVAVMGHSFGGA
  TAILALAKETQFRCAVALDAWMFPLERDFYPKARGPVFFINTEKFQTMESVNLMKKICAQ
  HEQSRIITVLGSVHRSQTDFAFVTGNLIGKFFSTETRGSLDPYEGQEVMVRAMLAFLQKH
  LDLKEDYNQWNNLIEGIGPSLTPGAPHHLSSL
• Function: Catalyzes the hydrolyze of the acetyl group at the sn-2 position of platelet-activating factor (PAF) and its analogs, leading to their inactivation. Hydrolyzes propionyl and butyroyl moieties approximately half as effectively as PAF. Also catalyzes transacetylation of the acetyl group from platelet-activating factor (PAF) to lysoplasmalogen and to sphingosine, producing plasmalogen analogs of PAF and N-acetylsphingosine (C2-ceramide) respectively. Has a marked selectivity for phospholipids with short acyl chains at the sn-2 position.
• Tissue Specificity: Broadly expressed in different tissues, but high in B- and T-lymphocytes. In brain, expression is restricted to amygdala and frontal cortex.
• KEGG Pathway:
  Ether lipid metabolism (hsa00565)
  Metabolic pathways (hsa01100)
• Reactome Pathway: Platelet homeostasis (R-HSA-418346)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Coronary heart disease	DIS5OIP1	Limited	Biomarker	[1]

6 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 Platelet-activating factor acetylhydrolase 2, cytoplasmic (PAFAH2).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Platelet-activating factor acetylhydrolase 2, cytoplasmic (PAFAH2).	[3]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Platelet-activating factor acetylhydrolase 2, cytoplasmic (PAFAH2).	[4]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Platelet-activating factor acetylhydrolase 2, cytoplasmic (PAFAH2).	[5]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Platelet-activating factor acetylhydrolase 2, cytoplasmic (PAFAH2).	[6]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Platelet-activating factor acetylhydrolase 2, cytoplasmic (PAFAH2).	[7]

References

• [1] Lipoprotein-associated phospholipase A2 concentrations in plasma are associated with the extent of coronary artery disease and correlate to adipose tissue levels of marine n-3 fatty acids.Atherosclerosis. 2008 Jan;196(1):420-424. doi: 10.1016/j.atherosclerosis.2006.11.027. Epub 2006 Dec 8.
• [2] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [3] 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.
• [4] Arsenic suppresses gene expression in promyelocytic leukemia cells partly through Sp1 oxidation. Blood. 2005 Jul 1;106(1):304-10.
• [5] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [6] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [7] 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.