Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTRDWN2V)

• DOT Name: Platelet-activating factor acetylhydrolase IB subunit alpha2 (PAFAH1B2)
• Synonyms: EC 3.1.1.47; PAF acetylhydrolase 30 kDa subunit; PAF-AH 30 kDa subunit; PAF-AH subunit beta; PAFAH subunit beta
• Gene Name: PAFAH1B2
• Related Disease:
  Alzheimer disease
  Advanced cancer
  Matthew-Wood syndrome
  Neoplasm
  Pancreatic cancer
  Pancreatic ductal carcinoma
• UniProt ID: PA1B2_HUMAN
• PDB ID: 1VYH
• EC Number: 3.1.1.47
• Pfam ID: PF13472
• Sequence:
  MSQGDSNPAAIPHAAEDIQGDDRWMSQHNRFVLDCKDKEPDVLFVGDSMVQLMQQYEIWR
  ELFSPLHALNFGIGGDTTRHVLWRLKNGELENIKPKVIVVWVGTNNHENTAEEVAGGIEA
  IVQLINTRQPQAKIIVLGLLPRGEKPNPLRQKNAKVNQLLKVSLPKLANVQLLDTDGGFV
  HSDGAISCHDMFDFLHLTGGGYAKICKPLHELIMQLLEETPEEKQTTIA
• Function: Alpha2 catalytic subunit of the cytosolic type I platelet-activating factor (PAF) acetylhydrolase (PAF-AH (I)) heterotetrameric enzyme that catalyzes the hydrolyze of the acetyl group at the sn-2 position of PAF and its analogs and modulates the action of PAF. The activity and substrate specificity of PAF-AH (I) are affected by its subunit composition. The alpha2/alpha2 homodimer (PAFAH1B2/PAFAH1B2 homodimer) hydrolyzes PAF and 1-O-alkyl-2-acetyl-sn-glycero-3-phosphorylethanolamine (AAGPE) more efficiently than 1-O-alkyl-2-acetyl-sn-glycero-3-phosphoric acid (AAGPA). In contrast, the alpha1/alpha2 heterodimer(PAFAH1B3/PAFAH1B3 heterodimer) hydrolyzes AAGPA more efficiently than PAF, but has little hydrolytic activity towards AAGPE. May play a role in male germ cell meiosis during the late pachytenestage and meiotic divisions as well as early spermiogenesis.
• Tissue Specificity: Ubiquitous.
• KEGG Pathway:
  Ether lipid metabolism (hsa00565)
  Metabolic pathways (hsa01100)
• Reactome Pathway:
  COPI-independent Golgi-to-ER retrograde traffic (R-HSA-6811436)
  Neutrophil degranulation (R-HSA-6798695)

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[1]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[2]
Matthew-Wood syndrome	DISA7HR7	Limited	Biomarker	[3]
Neoplasm	DISZKGEW	Limited	Biomarker	[2]
Pancreatic cancer	DISJC981	Limited	Biomarker	[3]
Pancreatic ductal carcinoma	DIS26F9Q	Limited	Altered Expression	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Platelet-activating factor acetylhydrolase IB subunit alpha2 (PAFAH1B2).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Platelet-activating factor acetylhydrolase IB subunit alpha2 (PAFAH1B2).	[5]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Platelet-activating factor acetylhydrolase IB subunit alpha2 (PAFAH1B2).	[6]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Platelet-activating factor acetylhydrolase IB subunit alpha2 (PAFAH1B2).	[7]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Platelet-activating factor acetylhydrolase IB subunit alpha2 (PAFAH1B2).	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Platelet-activating factor acetylhydrolase IB subunit alpha2 (PAFAH1B2).	[9]

References

• [1] RNA editing alterations in a multi-ethnic Alzheimer disease cohort converge on immune and endocytic molecular pathways.Hum Mol Genet. 2019 Sep 15;28(18):3053-3061. doi: 10.1093/hmg/ddz110.
• [2] Selective inhibitor of platelet-activating factor acetylhydrolases 1b2 and 1b3 that impairs cancer cell survival.ACS Chem Biol. 2015 Apr 17;10(4):925-32. doi: 10.1021/cb500893q. Epub 2015 Jan 20.
• [3] PAFAH1B2 is a HIF1a target gene and promotes metastasis in pancreatic cancer.Biochem Biophys Res Commun. 2018 Jun 27;501(3):654-660. doi: 10.1016/j.bbrc.2018.05.039. Epub 2018 May 16.
• [4] 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.
• [5] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [6] 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.
• [7] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.
• [8] Cellular reactions to long-term volatile organic compound (VOC) exposures. Sci Rep. 2016 Dec 1;6:37842. doi: 10.1038/srep37842.
• [9] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.