Summary of the probe development effort to identify inhibitors of human group III secreted phospholipase A2 enzyme (HGIII-sPLA2).
Name: Summary of the probe development effort to identify inhibitors of human group III secreted phospholipase A2 enzyme (HGIII-sPLA2). ..more
Depositor Specified Assays
Source (MLPCN Center Name): The Scripps Research Institute Molecular Screening Center
Affiliation: The Scripps Research Institute, TSRI
Assay Provider: Michael H. Gelb, University of Washington
Network: Molecular Library Probe Production Centers Network (MLPCN)
Grant Proposal Number R37HL036235
Grant Proposal PI: Michael H. Gelb, University of Washington
External Assay ID: HGIII-SPLA2_INH_SUMMARY
Name: Summary of the probe development effort to identify inhibitors of human group III secreted phospholipase A2 enzyme (HGIII-sPLA2).
Phospholipases A2 (PLA2s) are a class of enzymes that hydrolyze the sn-2 ester of glycerophospholipids to release a free fatty acid and a lysophospholipid . Secreted PLA2s (sPLA2s) have been implicated in the pathogenesis of inflammatory disease in humans. Inhibitors of many of the sPLA2s in the human and mouse genome have been made, but to date no inhibitor of human group III sPLA2 (hGIII-sPLA2) has been discovered. The amino acid sequence of hGIII-sPLA2 is similar to that of the sPLA2 in honey bee venom. This enzyme was discovered about 10 years ago, cloned, its enzymatic properties studied, and a knockout mouse constructed . Over the past few years it has been shown that this enzyme is highly expressed in mast cells . The enzyme is secreted from human and mouse mast cells and, together with lipocalin-type prostaglandin D2 synthase, leads to PGD2 production. Presumably the sPLA2 liberates arachidonic acid from the sn-2 position of membrane phospholipids to provide the arachidonic acid for PGD2 production. PGD2 then binds to its receptor (DP1) on the surface of mast cells leading to mast cell maturation. Mice lacking mGIII-sPLA2 produce immature mast cells . These mice show a dramatic reduction in anaphylatic responses, a process that is well known to be mediated in part by mast cells. The results provide a strong rational for the development of GIII-sPLA2 inhibitors to treat mast cell-mediate diseases.
Summary of Probe Development Effort:
This probe development effort is focused on the identification of inhibitors of human group III secreted phospholipase A2 enzyme (HGIII-sPLA2). All AIDs that contain results associated with this project can be found in the "Related Bioassays" section of this Summary AID.
1. Lambeau G, Gelb MH. Biochemistry and physiology of mammalian secreted phospholipases A2. Annu Rev Biochem. 2008;77:495-520.
2. Valentin E, Ghomashchi F, Gelb MH, Lazdunski M, Lambeau G. Novel human secreted phospholipase A(2) with homology to the group III bee venom enzyme. J Biol Chem. 2000 Mar 17;275(11):7492-7496.
3. Triggiani M, Giannattasio G, Calabrese C, Loffredo S, Granata F, Fiorello A, Santini M, Gelb MH, Marone G. Lung mast cells are a source of secreted phospholipases A2. J Allergy Clin Immunol. 2009 Sep;124(3):558-565.
4. Taketomi Y, Ueno N, Kojima T, Sato H, Murase R, Yamamoto K, Tanaka S, Sakanaka M, Nakamura M, Nishito Y, Kawana M, Kambe N, Ikeda K, Taguchi R, Nakamizo S, Kabashima K, Gelb MH, Arita M, Yokomizo T, Nakamura M, Watanabe K, Hirai H, Nakamura M, Okayama Y, Ra C, Aritake K, Urade Y, Morimoto K, Sugimoto Y, Shimizu T, Narumiya S, Hara S, Murakami M. Mast cell maturation is driven via a group III phospholipase A2-prostaglandin D2-DP1 receptor paracrine axis. Nat Immunol. 2013 Jun;14(6):554-563.
SUMMARY, Summary AID, human group III secreted phospholipase A2, HGIII-sPLA2, PLA2, Phospholipase A2, HGIII-SPLA2, BODIPY substrate, QFRET, BODIPY PC-A2, FRET, BODIPY FL pentanoic acid, biochemical, fluorescence, inhibition, modulators, HTS, high throughput screen, 1536, Scripps Florida, The Scripps Research Institute Molecular Screening Center, SRIMSC inhibitor, fluorescence, HTS, Molecular Libraries Probe Production Centers Network, MLPCN