PLA2-G7

Target id: 1432

Nomenclature: PLA2-G7

Family: Phospholipase A2, Hydrolases

Annotation status:  image of an orange circle Annotated and awaiting review. Please contact us if you can help with reviewing.  » Email us

   GtoImmuPdb view: OFF :     PLA2-G7 has curated GtoImmuPdb data

Gene and Protein Information
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 441 6p21.2-p12 PLA2G7 phospholipase A2 group VII
Mouse - 440 17 C Pla2g7 phospholipase A2, group VII (platelet-activating factor acetylhydrolase, plasma)
Rat - 440 9q12 Pla2g7 phospholipase A2 group VII
Previous and Unofficial Names
GVII | platelet-activating factor acetylhydrolase | PAF acetylhydrolase | LDL-associated phospholipase A2 | LDL-PLA2 | PAFAH | phospholipase A2, group VII (platelet-activating factor acetylhydrolase, plasma) | phospholipase A2
Database Links
BRENDA
CATH/Gene3D
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Enzyme
KEGG Gene
OMIM
RefSeq Nucleotide
RefSeq Protein
SynPHARM
UniProtKB
Wikipedia
Selected 3D Structures
Image of receptor 3D structure from RCSB PDB
Description:  Fragment-based inhibitors of Lipoprotein associated Phospholipase A2.
PDB Id:  5LZ9
Ligand:  (S)-23 [PMID: 27933945]
Resolution:  2.06Å
Species:  Human
References:  6
Enzyme Reaction
EC Number: 3.1.1.4

Download all structure-activity data for this target as a CSV file

Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Reference
rilapladib Hs Competitive 9.6 pIC50 5
pIC50 9.6 (IC50 2.3x10-10 M) [5]
darapladib Hs Inhibition 7.5 – 10.3 pIC50 1,6
pIC50 10.3 (IC50 4.9x10-11 M) [6]
Description: In a biochemical assay, measuring fluorescence intensity and using Thio-Paf.
pIC50 10.0 (IC50 1.1x10-10 M) [1]
pIC50 7.5 (IC50 3.5x10-8 M) [6]
Description: In an assay using whole human plasma and recombinant hPLA2-G7, that approximates the physiological environment of the enzyme.
compound 37 [PMID: 29193967] Hs Inhibition 7.8 pIC50 3
pIC50 7.8 (IC50 1.4x10-8 M) [3]
(S)-23 [PMID: 27933945] Hs Inhibition 6.9 – 7.5 pIC50 6
pIC50 7.5 (IC50 3.2x10-8 M) [6]
Description: Recombinant hLp-PLA2 in a whole human plasma Thio-PAF assay.
pIC50 6.9 (IC50 1.2x10-7 M) [6]
Description: Recombinant hLp-PLA2 Thio-PAF biochemical assay.
Immunopharmacology Comments
PLA2-G7 (also referred to as Lp-PLA2) is a pro-inflammatory enzyme. It cleaves oxidatively damaged phospholipid substrates to generate pro-inflammatory mediators including lysophosphatidylcholine and oxidized nonesterified fatty acids [4] and this activity has been linked to atherogenesis and cardiovascular disease. PLA2-G7 has been investigated as a CVD drug target, with one clinical candidate (darapladib) failing in Phase 3 trials. In addition, polymorphisms in the PLA2G7 gene are associated with atopy and asthma [2]. The search for drug-like PLA2-G7 inhibitors with alternative chemotypes to darapladib is continuing [3,6].
Immuno Process Associations
Immuno Process:  Inflammation
GO Annotations:  Associated to 2 GO processes
GO:0050729 positive regulation of inflammatory response TAS
GO:0090026 positive regulation of monocyte chemotaxis IDA
Immuno Process:  Immune regulation
GO Annotations:  Associated to 2 GO processes
GO:0050729 positive regulation of inflammatory response TAS
GO:0090026 positive regulation of monocyte chemotaxis IDA
Immuno Process:  Chemotaxis & migration
GO Annotations:  Associated to 1 GO processes
GO:0090026 positive regulation of monocyte chemotaxis IDA
Clinically-Relevant Mutations and Pathophysiology
Disease:  Asthma, susceptibility to
Disease Ontology: DOID:2841
OMIM: 600807
Disease:  IgE responsiveness, atopic; IGER
OMIM: 147050
Disease:  Platelet-activating factor acetylhydrolase deficiency
OMIM: 614278

References

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1. Blackie JA, Bloomer JC, Brown MJ, Cheng HY, Hammond B, Hickey DM, Ife RJ, Leach CA, Lewis VA, Macphee CH et al.. (2003) The identification of clinical candidate SB-480848: a potent inhibitor of lipoprotein-associated phospholipase A2. Bioorg. Med. Chem. Lett., 13 (6): 1067-70. [PMID:12643913]

2. Kruse S, Mao XQ, Heinzmann A, Blattmann S, Roberts MH, Braun S, Gao PS, Forster J, Kuehr J, Hopkin JM et al.. (2000) The Ile198Thr and Ala379Val variants of plasmatic PAF-acetylhydrolase impair catalytical activities and are associated with atopy and asthma. Am. J. Hum. Genet., 66 (5): 1522-30. [PMID:10733466]

3. Liu Q, Huang F, Yuan X, Wang K, Zou Y, Shen J, Xu Y. (2017) Structure-Guided Discovery of Novel, Potent, and Orally Bioavailable Inhibitors of Lipoprotein-Associated Phospholipase A2. J. Med. Chem., 60 (24): 10231-10244. [PMID:29193967]

4. MacPhee CH, Moores KE, Boyd HF, Dhanak D, Ife RJ, Leach CA, Leake DS, Milliner KJ, Patterson RA, Suckling KE et al.. (1999) Lipoprotein-associated phospholipase A2, platelet-activating factor acetylhydrolase, generates two bioactive products during the oxidation of low-density lipoprotein: use of a novel inhibitor. Biochem. J., 338 ( Pt 2): 479-87. [PMID:10024526]

5. Wilensky RL, Macphee CH. (2009) Lipoprotein-associated phospholipase A(2) and atherosclerosis. Curr. Opin. Lipidol., 20 (5): 415-20. [PMID:19667981]

6. Woolford AJ, Day PJ, Bénéton V, Berdini V, Coyle JE, Dudit Y, Grondin P, Huet P, Lee LY, Manas ES et al.. (2016) Fragment-Based Approach to the Development of an Orally Bioavailable Lactam Inhibitor of Lipoprotein-Associated Phospholipase A2 (Lp-PLA2). J. Med. Chem., 59 (23): 10738-10749. [PMID:27933945]

How to cite this page

Phospholipase A2: PLA2-G7. Last modified on 07/02/2018. Accessed on 17/07/2018. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=1432.