Potent and Selective Fluoroketone Inhibitors of Group VIA Calcium-Independent Phospholipase A<sub>2</sub>

Kokotos, George; Hsu, Yuan-Hao; Burke, John E.; Baskakis, Constantinos; Kokotos, Christoforos G.; Magrioti, Victoria; Dennis, Edward A.

doi:10.1021/jm901872v

Cited by 84 publications

(111 citation statements)

References 47 publications

Supporting

Mentioning

108

Contrasting

Unclassified

Order By: Relevance

“…We have also shown that, at the concentration used in this study (1 mM), the inhibitor blocks essentially all measurable Ca 2+ -dependent PLA 2 activity of cell homogenates, leaving the Ca 2+ -independent activity unchanged (47,67,69). FKGK18, a member of a family of polyfluoroketone-containing compounds, is the most potent iPLA 2 b inhibitor reported, completely blocking iPLA 2 b activity at concentrations $200 times lower than those required for inhibition of other PLA 2 activities, which makes it a valuable tool to explore the role of iPLA 2 b in cells and in in vivo models (11,41). In keeping with this observation, very recent data in pancreatic b cells show that FKGK18 blocks iPLA 2 b-mediated responses in these cells while leaving the cPLA 2 a-dependent ones unchanged (70).…”

Section: Discussionmentioning

confidence: 99%

“…In parallel studies, we also determined the effect of inhibiting iPLA 2 b with the novel selective inhibitor FKGK18 (41). In stark contrast with the experiments using pyrrophenone, the zymosanstimulated decreases in PC and PI molecular species were the same whether or not FKGK18 was present in the incubations (Fig.…”

Section: Aa-containing Species In Macrophagesmentioning

confidence: 97%

“…The cPLA 2 a inhibitor pyrrophenone (40) was synthesized and provided by Dr. A. Llebaria (Institute for Chemical and Environmental Research, Barcelona, Spain). The iPLA 2 b inhibitor FKGK18 (1,1,1-trifluoro-6-(naphthalen-2-yl)hexan-2-1) was synthesized as previously described (41). The CoA-independent transacylase inhibitor SK&F98625 (diethyl 7-(3,4,5-triphenyl-2-oxo-2,3-dihydroimidazol-1-yl)heptane phosphonate) (42-44) was synthesized and provided by Dr. A. Pérez (Department of Organic Chemistry, University of Valladolid).…”

Section: Reagentsmentioning

confidence: 99%

See 2 more Smart Citations

Cytosolic Group IVA and Calcium-Independent Group VIA Phospholipase A2s Act on Distinct Phospholipid Pools in Zymosan-Stimulated Mouse Peritoneal Macrophages

Gil-de-Gómez

Astudillo

Guijas

et al. 2014

The Journal of Immunology

Self Cite

View full text Add to dashboard Cite

Phospholipase A2s generate lipid mediators that constitute an important component of the integrated response of macrophages to stimuli of the innate immune response. Because these cells contain multiple phospholipase A2 forms, the challenge is to elucidate the roles that each of these forms plays in regulating normal cellular processes and in disease pathogenesis. A major issue is to precisely determine the phospholipid substrates that these enzymes use for generating lipid mediators. There is compelling evidence that group IVA cytosolic phospholipase A2 (cPLA2α) targets arachidonic acid–containing phospholipids but the role of the other cytosolic enzyme present in macrophages, the Ca2+-independent group VIA phospholipase A2 (iPLA2β) has not been clearly defined. We applied mass spectrometry–based lipid profiling to study the substrate specificities of these two enzymes during inflammatory activation of macrophages with zymosan. Using selective inhibitors, we find that, contrary to cPLA2α, iPLA2β spares arachidonate-containing phospholipids and hydrolyzes only those that do not contain arachidonate. Analyses of the lysophospholipids generated during activation reveal that one of the major species produced, palmitoyl-glycerophosphocholine, is generated by iPLA2β, with minimal or no involvement of cPLA2α. The other major species produced, stearoyl-glycerophosphocholine, is generated primarily by cPLA2α. Collectively, these findings suggest that cPLA2α and iPLA2β act on different phospholipids during zymosan stimulation of macrophages and that iPLA2β shows a hitherto unrecognized preference for choline phospholipids containing palmitic acid at the sn-1 position that could be exploited for the design of selective inhibitors of this enzyme with therapeutic potential.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Aa-containing Species In Macrophagesmentioning

confidence: 97%

Section: Reagentsmentioning

confidence: 99%

See 1 more Smart Citation

Cytosolic Group IVA and Calcium-Independent Group VIA Phospholipase A2s Act on Distinct Phospholipid Pools in Zymosan-Stimulated Mouse Peritoneal Macrophages

Gil-de-Gómez

Astudillo

Guijas

et al. 2014

The Journal of Immunology

Self Cite

View full text Add to dashboard Cite

show abstract

“…Because FK inhibitors target serine active sites, they could potentially also inhibit cPLA 2 s. However, modifi cation of the FK group along with addition of a hydrophobic terminus, connected by a medium-length carbon chain to mimic the fatty acid chain, conferred selectivity of the FK compounds for iPLA 2 versus sPLA 2 or cPLA 2 ( 157 ), and earlier generation FK compounds (FKGK11 and FKGK2) were found to be benefi cial in an experimental autoimmune encephalomyelitis animal model of multiple sclerosis ( 158 ). Subsequently, the FK-based inhibitor of iPLA 2 ␤ (FKGK18) was found to be 7-fold more potent than FKGK11 toward iPLA 2 ␤ ; 195 and >455 times more potent for iPLA 2 ␤ than for group IVA cPLA 2 and group V sPLA 2 , respectively ( 159 ); and effective in cell-based studies ( 160 ) and in countering T1D ( 161 ).…”

Section: Modulation Of Ipla 2 ␤mentioning

confidence: 99%

Calcium-independent phospholipases A2 and their roles in biological processes and diseases

Ramanadham

Ali

Ashley

et al. 2015

Journal of Lipid Research

169

190

View full text Add to dashboard Cite

The Ca 2+ -independent phospholipases A 2 (iPLA 2 s) are part of a diverse family of PLA 2 s that hydrolyze the sn -2 substituent from membrane phospholipids to release a free fatty acid and a lysolipid ( 1, 2 ). These enzymes are ubiquitously expressed, and in contrast to secretory PLA 2 s (sPLA 2 s) and cytosolic PLA 2 s (cPLA 2 s), do not require Ca 2+ for either translocation or activity. Some of the fi rst descriptions of iPLA 2 activity were in the mid-to late-1980s with the identifi cation of a plasmalogen-selective PLA 2 in Abstract Among the family of phospholipases A 2 (PLA 2 s) are the Ca 2+ -independent PLA 2 s (iPLA 2 s) and they are designated group VI iPLA 2 s. In relation to secretory and cytosolic PLA 2 s, the iPLA 2 s are more recently described and details of their expression and roles in biological functions are rapidly emerging. The iPLA 2 s or patatin-like phospholipases (PNPLAs) are intracellular enzymes that do not require Ca 2+ for activity, and contain lipase (GXSXG) and nucleotide-binding (GXGXXG) consensus sequences. Though nine PNPLAs have been recognized, PNPLA8 (membraneassociated iPLA 2 ␥ ) and PNPLA9 (cytosol-associated iPLA 2 ␤ ) are the most widely studied and understood. The iPLA 2 s manifest a variety of activities in addition to phospholipase, are ubiquitously expressed, and participate in a multitude of biological processes, including fat catabolism, cell differentiation, maintenance of mitochondrial integrity, phospholipid remodeling, cell proliferation, signal transduction, and cell death. As might be expected, increased or decreased expression of iPLA 2 s can have profound effects on the metabolic state, CNS function, cardiovascular performance, and cell survival; therefore, dysregulation of iPLA 2 s can be a critical factor in the development of many diseases. This review is aimed at providing a general framework of the current understanding of the iPLA 2 s and discussion of the potential mechanisms of action of the iPLA 2 s and related involved lipid mediators. -Ramanadham, S

show abstract

“…We thus expanded our initial inhibitor discovery work first to mammalian sPLA 2 s (112), including the use of antisense technology (113), and then to other PLA 2 groups-especially the intracellular cPLA 2 and iPLA 2 -by activated ketones (114,115), fluorophosphonates (116), and other traditional inhibitors (98). In the last decade, this has expanded into a long collaboration with Professor George Kokotos from the University of Athens (9), in which we are designing and testing novel inhibitors including oxoamides (117-120), polyfluoroketones (121,122), and thiazolyl ketones (123). Specifically, we've leaned on insights from molecular dynamics and simulations to inform rational drug design and medicinal chemistry efforts capped off with extensive biochemical characterization.…”

Section: A Turning Point For Lipid Signalingmentioning

confidence: 99%

Liberating Chiral Lipid Mediators, Inflammatory Enzymes, and LIPID MAPS from Biological Grease

Dennis

2016

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

In 1970, it was well accepted that the central role of lipids was in energy storage and metabolism, and it was assumed that amphipathic lipids simply served a passive structural role as the backbone of biological membranes. As a result, the scientific community was focused on nucleic acids, proteins, and carbohydrates as information-containing molecules. It took considerable effort until scientists accepted that lipids also "encode" specific and unique biological information and play a central role in cell signaling. Along with this realization came the recognition that the enzymes that act on lipid substrates residing in or on membranes and micelles must also have important signaling roles, spurring curiosity into their potentially unique modes of action differing from those acting on water-soluble substrates. This led to the creation of the concept of "surface dilution kinetics" for describing the mechanism of enzymes acting on lipid substrates, as well as the demonstration that lipid enzymes such as phospholipase A 2 (PLA 2 ) contain allosteric activator sites for specific phospholipids as well as for membranes. As our understanding of phospholipases advanced, so did the understanding that many of the lipids released by these enzymes are chiral informationcontaining signaling molecules; for example, PLA 2 regulates the generation of precursors for the biosynthesis of eicosanoids and other bioactive lipid mediators of inflammation and resolution underlying disease progression. The creation of the LIPID MAPS initiative in 2003 and the ensuing development of the lipidomics field have revealed that lipid metabolites are central to human metabolism. Today lipids are recognized as key mediators of health and disease as we enter a new era of biomarkers and personalized medicine. This article is my personal "reflection" on these scientific advances.

show abstract

Potent and Selective Fluoroketone Inhibitors of Group VIA Calcium-Independent Phospholipase A₂

Cited by 84 publications

References 47 publications

Cytosolic Group IVA and Calcium-Independent Group VIA Phospholipase A2s Act on Distinct Phospholipid Pools in Zymosan-Stimulated Mouse Peritoneal Macrophages

Cytosolic Group IVA and Calcium-Independent Group VIA Phospholipase A2s Act on Distinct Phospholipid Pools in Zymosan-Stimulated Mouse Peritoneal Macrophages

Calcium-independent phospholipases A2 and their roles in biological processes and diseases

Liberating Chiral Lipid Mediators, Inflammatory Enzymes, and LIPID MAPS from Biological Grease

Contact Info

Product

Resources

About

Potent and Selective Fluoroketone Inhibitors of Group VIA Calcium-Independent Phospholipase A2

Cited by 84 publications

References 47 publications

Cytosolic Group IVA and Calcium-Independent Group VIA Phospholipase A2s Act on Distinct Phospholipid Pools in Zymosan-Stimulated Mouse Peritoneal Macrophages

Cytosolic Group IVA and Calcium-Independent Group VIA Phospholipase A2s Act on Distinct Phospholipid Pools in Zymosan-Stimulated Mouse Peritoneal Macrophages

Calcium-independent phospholipases A2 and their roles in biological processes and diseases

Liberating Chiral Lipid Mediators, Inflammatory Enzymes, and LIPID MAPS from Biological Grease

Contact Info

Product

Resources

About

Potent and Selective Fluoroketone Inhibitors of Group VIA Calcium-Independent Phospholipase A₂