Other search tools

About this data

The publication data currently available has been vetted by Vanderbilt faculty, staff, administrators and trainees. The data itself is retrieved directly from NCBI's PubMed and is automatically updated on a weekly basis to ensure accuracy and completeness.

If you have any questions or comments, please contact us.

Results: 1 to 10 of 67

Publication Record

Connections

Symmetrically substituted dichlorophenes inhibit -acyl-phosphatidylethanolamine phospholipase D.
Aggarwal G, Zarrow JE, Mashhadi Z, Flynn CR, Vinson P, Weaver CD, Davies SS
(2020) J Biol Chem 295: 7289-7300
MeSH Terms: Animals, Bacterial Proteins, Bithionol, Dichlorophen, Enzyme Inhibitors, HEK293 Cells, Hexachlorophene, Humans, Mice, Phospholipase D, Quinazolines, Streptomyces, Sulfonamides
Show Abstract · Added August 18, 2020
-Acyl-phosphatidylethanolamine phospholipase D (NAPE-PLD) (EC 3.1.4.4) catalyzes the final step in the biosynthesis of -acyl-ethanolamides. Reduced NAPE-PLD expression and activity may contribute to obesity and inflammation, but a lack of effective NAPE-PLD inhibitors has been a major obstacle to elucidating the role of NAPE-PLD and -acyl-ethanolamide biosynthesis in these processes. The endogenous bile acid lithocholic acid (LCA) inhibits NAPE-PLD activity (with an IC of 68 μm), but LCA is also a highly potent ligand for TGR5 (EC 0.52 μm). Recently, the first selective small-molecule inhibitor of NAPE-PLD, ARN19874, has been reported (having an IC of 34 μm). To identify more potent inhibitors of NAPE-PLD, here we used a quenched fluorescent NAPE analog, PED-A1, as a substrate for recombinant mouse Nape-pld to screen a panel of bile acids and a library of experimental compounds (the Spectrum Collection). Muricholic acids and several other bile acids inhibited Nape-pld with potency similar to that of LCA. We identified 14 potent Nape-pld inhibitors in the Spectrum Collection, with the two most potent (IC = ∼2 μm) being symmetrically substituted dichlorophenes, hexachlorophene and bithionol. Structure-activity relationship assays using additional substituted dichlorophenes identified key moieties needed for Nape-pld inhibition. Both hexachlorophene and bithionol exhibited significant selectivity for Nape-pld compared with nontarget lipase activities such as PLD or serum lipase. Both also effectively inhibited NAPE-PLD activity in cultured HEK293 cells. We conclude that symmetrically substituted dichlorophenes potently inhibit NAPE-PLD in cultured cells and have significant selectivity for NAPE-PLD other tissue-associated lipases.
© 2020 Aggarwal et al.
0 Communities
1 Members
0 Resources
13 MeSH Terms
Biased M receptor-positive allosteric modulators reveal role of phospholipase D in M-dependent rodent cortical plasticity.
Moran SP, Xiang Z, Doyle CA, Maksymetz J, Lv X, Faltin S, Fisher NM, Niswender CM, Rook JM, Lindsley CW, Conn PJ
(2019) Sci Signal 12:
MeSH Terms: Allosteric Site, Animals, CHO Cells, Calcium, Cerebral Cortex, Cognition, Cricetinae, Cricetulus, Electrophysiology, Female, Humans, Long-Term Synaptic Depression, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Neuronal Plasticity, Phospholipase D, Prefrontal Cortex, Receptor, Muscarinic M1, Signal Transduction, Type C Phospholipases
Show Abstract · Added March 3, 2020
Highly selective, positive allosteric modulators (PAMs) of the M subtype of muscarinic acetylcholine receptor have emerged as an exciting new approach to potentially improve cognitive function in patients suffering from Alzheimer's disease and schizophrenia. Discovery programs have produced a structurally diverse range of M receptor PAMs with distinct pharmacological properties, including different extents of agonist activity and differences in signal bias. This includes biased M receptor PAMs that can potentiate coupling of the receptor to activation of phospholipase C (PLC) but not phospholipase D (PLD). However, little is known about the role of PLD in M receptor signaling in native systems, and it is not clear whether biased M PAMs display differences in modulating M-mediated responses in native tissue. Using PLD inhibitors and PLD knockout mice, we showed that PLD was necessary for the induction of M-dependent long-term depression (LTD) in the prefrontal cortex (PFC). Furthermore, biased M PAMs that did not couple to PLD not only failed to potentiate orthosteric agonist-induced LTD but also blocked M-dependent LTD in the PFC. In contrast, biased and nonbiased M PAMs acted similarly in potentiating M-dependent electrophysiological responses that were PLD independent. These findings demonstrate that PLD plays a critical role in the ability of M PAMs to modulate certain central nervous system (CNS) functions and that biased M PAMs function differently in brain regions implicated in cognition.
Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
0 Communities
2 Members
0 Resources
22 MeSH Terms
Leptogenic effects of NAPE require activity of NAPE-hydrolyzing phospholipase D.
Chen Z, Zhang Y, Guo L, Dosoky N, de Ferra L, Peters S, Niswender KD, Davies SS
(2017) J Lipid Res 58: 1624-1635
MeSH Terms: Animals, Arabidopsis, Hydrolysis, Leptin, Mice, Phosphatidylethanolamines, Phospholipase D
Show Abstract · Added April 10, 2018
Food intake induces synthesis of -acylphosphatidylethanolamines (NAPEs) in the intestinal tract. While NAPEs exert leptin-like (leptogenic) effects, including reduced weight gain and food intake, the mechanisms by which NAPEs induce these leptogenic effects remain unclear. One key question is whether intestinal NAPEs act directly on cognate receptors or first require conversion to -acylethanolamides (NAEs) by NAPE-hydrolyzing phospholipase D (NAPE-PLD). Previous studies using mice were equivocal because intraperitoneal injection of NAPEs led to nonspecific aversive effects. To avoid the aversive effects of injection, we delivered NAPEs and NAEs intestinally using gut bacteria synthesizing these compounds. Unlike in wild-type mice, increasing intestinal levels of NAPE using NAPE-synthesizing bacteria in mice failed to reduce food intake and weight gain or alter gene expression. In contrast, increasing intestinal NAE levels in mice using NAE-synthesizing bacteria induced all of these effects. These NAE-synthesizing bacteria also markedly increased NAE levels and decreased inflammatory gene expression in omental adipose tissue. These results demonstrate that intestinal NAPEs require conversion to NAEs by the action of NAPE-PLD to exert their various leptogenic effects, so that the reduced intestinal NAPE-PLD activity found in obese subjects may directly contribute to excess food intake and obesity.
Copyright © 2017 by the American Society for Biochemistry and Molecular Biology, Inc.
1 Communities
2 Members
0 Resources
MeSH Terms
Human phospholipase D activity transiently regulates pyrimidine biosynthesis in malignant gliomas.
Mathews TP, Hill S, Rose KL, Ivanova PT, Lindsley CW, Brown HA
(2015) ACS Chem Biol 10: 1258-68
MeSH Terms: Amino Acid Sequence, Brain Neoplasms, Cell Line, Tumor, Enzyme Inhibitors, Glioma, Humans, Molecular Sequence Data, Phospholipase D, Pyrimidines, Signal Transduction, Structure-Activity Relationship, TOR Serine-Threonine Kinases
Show Abstract · Added February 12, 2015
Cancer cells reorganize their metabolic pathways to fuel demanding rates of proliferation. Oftentimes, these metabolic phenotypes lie downstream of prominent oncogenes. The lipid signaling molecule phosphatidic acid (PtdOH), which is produced by the hydrolytic enzyme phospholipase D (PLD), has been identified as a critical regulatory molecule for oncogenic signaling in many cancers. In an effort to identify novel regulatory mechanisms for PtdOH, we screened various cancer cell lines, assessing whether treatment of cancer models with PLD inhibitors altered production of intracellular metabolites. Preliminary findings lead us to focus on how deoxyribonucleoside triphosphates (dNTPs) are altered upon PLD inhibitor treatment in gliomas. Using a combination of proteomics and small molecule intracellular metabolomics, we show herein that PtdOH acutely regulates the production of these pyrimidine metabolites through activation of CAD via mTOR signaling pathways independently of Akt. These changes are responsible for decreases in dNTP production after PLD inhibitor treatment. Our data identify a novel regulatory role for PLD activity in specific cancer types.
0 Communities
1 Members
0 Resources
12 MeSH Terms
Biochemical characterization of a Pseudomonas aeruginosa phospholipase D.
Spencer C, Brown HA
(2015) Biochemistry 54: 1208-18
MeSH Terms: Bacterial Proteins, Cell Line, Humans, Phospholipase D, Pseudomonas aeruginosa, Sequence Homology, Amino Acid, Species Specificity, Substrate Specificity
Show Abstract · Added February 12, 2015
Phospholipase D is a ubiquitous protein in eukaryotes that hydrolyzes phospholipids to generate the signaling lipid phosphatidic acid (PtdOH). PldA, a Pseudomonas aeruginosa PLD, is a secreted protein that targets bacterial and eukaryotic cells. Here we have characterized the in vitro factors that modulate enzymatic activity of PldA, including divalent cations and phosphoinositides. We have identified several similarities between the eukaryotic-like PldA and the human PLD isoforms, as well as several properties in which the enzymes diverge. Notable differences include the substrate preference and transphosphatidylation efficiency for PldA. These findings offer new insights into potential regulatory mechanisms of PldA and its role in pathogenesis.
0 Communities
1 Members
0 Resources
8 MeSH Terms
Further evaluation of novel structural modifications to scaffolds that engender PLD isoform selective inhibition.
O'Reilly MC, Scott SA, Brown HA, Lindsley CW
(2014) Bioorg Med Chem Lett 24: 5553-5557
MeSH Terms: Animals, Benzimidazoles, Enzyme Inhibitors, HEK293 Cells, Humans, Kinetics, Microsomes, Phospholipase D, Piperidines, Protein Binding, Rats, Structure-Activity Relationship
Show Abstract · Added February 12, 2015
This Letter describes the on-going SAR efforts based on two scaffolds, a PLD1-biased piperidinyl benzimidazolone and a PLD2-biased piperidinyl triazaspirone, with the goal of enhancing PLD inhibitory potency and isoform selectivity. Here, we found that addition of an α-methyl moiety within the PLD2-biased piperidinyl triazaspirone scaffold abolished PLD2 preference, while the incorporation of substituents onto the piperidine moiety of the PLD1-biased piperidinyl benzimidazolone, or replacement with a bioisosteric [3.3.0] core, generally retained PLD1 preference, but at diminished significance. The SAR uncovered within these two allosteric PLD inhibitor series further highlights the inherent challenges of developing isoform selective PLD inhibitors.
Copyright © 2014 Elsevier Ltd. All rights reserved.
0 Communities
1 Members
0 Resources
12 MeSH Terms
Phospholipase D facilitates efficient entry of influenza virus, allowing escape from innate immune inhibition.
Oguin TH, Sharma S, Stuart AD, Duan S, Scott SA, Jones CK, Daniels JS, Lindsley CW, Thomas PG, Brown HA
(2014) J Biol Chem 289: 25405-17
MeSH Terms: Cell Line, Endocytosis, Gene Expression Regulation, Viral, Humans, Immunity, Innate, Influenza A Virus, H1N1 Subtype, Influenza, Human, Orthomyxoviridae, Phospholipase D, Phospholipids, RNA Interference, Virus Internalization, Virus Replication
Show Abstract · Added March 18, 2020
Lipid metabolism plays a fundamental role during influenza virus replication, although key regulators of lipid-dependent trafficking and virus production remain inadequately defined. This report demonstrates that infection by influenza virus stimulates phospholipase D (PLD) activity and that PLD co-localizes with influenza during infection. Both chemical inhibition and RNA interference of PLD delayed viral entry and reduced viral titers in vitro. Although there may be contributions by both major isoenzymes, the effects on viral infectivity appear to be more dependent on the PLD2 isoenzyme. In vivo, PLD2 inhibition reduced virus titer and correlated with significant increases in transcription of innate antiviral effectors. The reduction in viral titer downstream of PLD2 inhibition was dependent on Rig-I (retinoic acid-inducible gene-1), IRF3, and MxA (myxovirus resistance gene A) but not IRF7. Inhibition of PLD2 accelerated the accumulation of MxA in foci as early as 30 min postinfection. Together these data suggest that PLD facilitates the rapid endocytosis of influenza virus, permitting viral escape from innate immune detection and effectors that are capable of limiting lethal infection.
© 2014 by The American Society for Biochemistry and Molecular Biology, Inc.
0 Communities
1 Members
0 Resources
MeSH Terms
Isolevuglandin-modified phosphatidylethanolamine is metabolized by NAPE-hydrolyzing phospholipase D.
Guo L, Gragg SD, Chen Z, Zhang Y, Amarnath V, Davies SS
(2013) J Lipid Res 54: 3151-7
MeSH Terms: Aldehydes, Animals, Gene Silencing, HEK293 Cells, Humans, Hydrolysis, Mice, Phosphatidylethanolamines, Phospholipase D
Show Abstract · Added January 3, 2014
Lipid aldehydes including isolevuglandins (IsoLGs) and 4-hydroxynonenal modify phosphatidylethanolamine (PE) to form proinflammatory and cytotoxic adducts. Therefore, cells may have evolved mechanisms to degrade and prevent accumulation of these potentially harmful compounds. To test if cells could degrade isolevuglandin-modified phosphatidylethanolamine (IsoLG-PE), we generated IsoLG-PE in human embryonic kidney 293 (HEK293) cells and human umbilical cord endothelial cells and measured its stability over time. We found that IsoLG-PE levels decreased more than 75% after 6 h, suggesting that IsoLG-PE was indeed degraded. Because N-acyl phosphatidylethanolamine-hydrolyzing phospholipase D (NAPE-PLD) has been described as a key enzyme in the hydrolysis of N-acyl phosphatidylethanoamine (NAPE) and both NAPE and IsoLG-PE have large aliphatic headgroups, we considered the possibility that this enzyme might also hydrolyze IsoLG-PE. We found that knockdown of NAPE-PLD expression using small interfering RNA (siRNA) significantly increased the persistence of IsoLG-PE in HEK293 cells. IsoLG-PE competed with NAPE for hydrolysis by recombinant mouse NAPE-PLD, with the catalytic efficiency (V(max)/K(m)) for hydrolysis of IsoLG-PE being 30% of that for hydrolysis of NAPE. LC-MS/MS analysis confirmed that recombinant NAPE-PLD hydrolyzed IsoLG-PE to IsoLG-ethanolamine. These results demonstrate that NAPE-PLD contributes to the degradation of IsoLG-PE and suggest that a major physiological role of NAPE-PLD may be to degrade aldehyde-modified PE, thereby preventing the accumulation of these harmful compounds.
2 Communities
1 Members
0 Resources
9 MeSH Terms
Regulation of phospholipase D activity and phosphatidic acid production after purinergic (P2Y6) receptor stimulation.
Scott SA, Xiang Y, Mathews TP, Cho HP, Myers DS, Armstrong MD, Tallman KA, O'Reilly MC, Lindsley CW, Brown HA
(2013) J Biol Chem 288: 20477-87
MeSH Terms: 1-Butanol, Blotting, Western, Cell Line, Tumor, Diacylglycerol Kinase, Diglycerides, Dose-Response Relationship, Drug, Enzyme Inhibitors, Humans, Hydrolysis, Isoenzymes, Mass Spectrometry, Models, Biological, Phosphatidic Acids, Phosphatidylcholines, Phospholipase C delta, Phospholipase D, Protein Kinase C-alpha, RNA Interference, Receptors, Purinergic P2, Signal Transduction, Uridine Diphosphate
Show Abstract · Added March 7, 2014
Phosphatidic acid (PA) is a lipid second messenger located at the intersection of several lipid metabolism and cell signaling events including membrane trafficking, survival, and proliferation. Generation of signaling PA has long been primarily attributed to the activation of phospholipase D (PLD). PLD catalyzes the hydrolysis of phosphatidylcholine into PA. A variety of both receptor-tyrosine kinase and G-protein-coupled receptor stimulations have been shown to lead to PLD activation and PA generation. This study focuses on profiling the PA pool upon P2Y6 receptor signaling manipulation to determine the major PA producing enzymes. Here we show that PLD, although highly active, is not responsible for the majority of stable PA being produced upon UDP stimulation of the P2Y6 receptor and that PA levels are tightly regulated. By following PA flux in the cell we show that PLD is involved in an initial increase in PA upon receptor stimulation; however, when PLD is blocked, the cell compensates by increasing PA production from other sources. We further delineate the P2Y6 signaling pathway showing that phospholipase Cβ3 (PLCβ3), PLCδ1, DGKζ and PLD are all downstream of receptor activation. We also show that DGKζ is a novel negative regulator of PLD activity in this system that occurs through an inhibitory mechanism with PKCα. These results further define the downstream events resulting in PA production in the P2Y6 receptor signaling pathway.
1 Communities
2 Members
0 Resources
21 MeSH Terms
Development of dual PLD1/2 and PLD2 selective inhibitors from a common 1,3,8-Triazaspiro[4.5]decane Core: discovery of Ml298 and Ml299 that decrease invasive migration in U87-MG glioblastoma cells.
O'Reilly MC, Scott SA, Brown KA, Oguin TH, Thomas PG, Daniels JS, Morrison R, Brown HA, Lindsley CW
(2013) J Med Chem 56: 2695-9
MeSH Terms: Benzamides, Cell Line, Tumor, Cell Movement, Drug Discovery, Enzyme Inhibitors, Glioblastoma, Humans, Neoplasm Invasiveness, Phospholipase D, Spiro Compounds
Show Abstract · Added March 19, 2013
An iterative parallel synthesis effort identified a PLD2 selective inhibitor, ML298 (PLD1 IC50 > 20000 nM, PLD2 IC50 = 355 nM) and a dual PLD1/2 inhibitor, ML299 (PLD1 IC50 = 6 nM, PLD2 IC50 = 20 nM). SAR studies revealed that a small structural change (incorporation of a methyl group) increased PLD1 activity within this classically PLD2-preferring core and that the effect was enantiospecific. Both probes decreased invasive migration in U87-MG glioblastoma cells.
1 Communities
2 Members
0 Resources
10 MeSH Terms