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Journal of Neurochemistry May 2020Despite the human brain being made of nearly 60% fat, the vast majority of studies on the mechanisms of neuronal communication which underpin cognition, memory and... (Review)
Review
Despite the human brain being made of nearly 60% fat, the vast majority of studies on the mechanisms of neuronal communication which underpin cognition, memory and learning, primarily focus on proteins and/or (epi)genetic mechanisms. Phospholipids are the main component of all cellular membranes and function as substrates for numerous phospholipid-modifying enzymes, including phospholipases, which release free fatty acids (FFAs) and other lipid metabolites that can alter the intrinsic properties of the membranes, recruit and activate critical proteins, and act as lipid signalling molecules. Here, we will review brain specific phospholipases, their roles in membrane remodelling, neuronal function, learning and memory, as well as their disease implications. In particular, we will highlight key roles of unsaturated FFAs, particularly arachidonic acid, in neurotransmitter release, neuroinflammation and memory. In light of recent findings, we will also discuss the emerging role of phospholipase A and the creation of saturated FFAs in the brain.
Topics: Animals; Brain; Humans; Learning; Memory; Neurons; Phospholipases; Phospholipids
PubMed: 31745996
DOI: 10.1111/jnc.14918 -
International Journal of Medical... Jan 2018Plasmodium parasites, the causative agents of malaria, display a well-regulated lipid metabolism required to ensure their survival in the human host as well as in the... (Review)
Review
Plasmodium parasites, the causative agents of malaria, display a well-regulated lipid metabolism required to ensure their survival in the human host as well as in the mosquito vector. The fine-tuning of lipid metabolic pathways is particularly important for the parasites during the rapid erythrocytic infection cycles, and thus enzymes involved in lipid metabolic processes represent prime targets for malaria chemotherapeutics. While plasmodial enzymes involved in lipid synthesis and acquisition have been studied in the past, to date not much is known about the roles of phospholipases for proliferation and transmission of the malaria parasite. These phospholipid-hydrolyzing esterases are crucial for membrane dynamics during host cell infection and egress by the parasite as well as for replication and cell signaling, and thus they are considered important virulence factors. In this review, we provide a comprehensive bioinformatic analysis of plasmodial phospholipases identified to date. We further summarize previous findings on the lipid metabolism of Plasmodium, highlight the roles of phospholipases during parasite life-cycle progression, and discuss the plasmodial phospholipases as potential targets for malaria therapy.
Topics: Animals; Erythrocytes; Humans; Intracellular Membranes; Lipid Metabolism; Malaria; Phospholipases; Plasmodium; Protozoan Proteins; Virulence Factors
PubMed: 28988696
DOI: 10.1016/j.ijmm.2017.09.015 -
Free Radical Biology & Medicine Aug 2022Studies in the last decade have established the roles of oxidized phospholipids as modulators of various cellular processes, from inflammation and immunity to cell... (Review)
Review
Studies in the last decade have established the roles of oxidized phospholipids as modulators of various cellular processes, from inflammation and immunity to cell death. Oxidized lysophospholipids, formed through the activity of phospholipases and oxidative enzymes and lacking an acyl chain in comparison with parent phospholipids, are now emerging as novel bioactive lipid mediators. Their detection and structural characterization have been limited in the past due to low amounts and the complexity of their biosynthetic and removal pathways, but recent studies have unequivocally demonstrated their formation under inflammatory conditions. The involvement of oxidized lysophospholipids in immune regulation classifies them as damage-associated molecular patterns (DAMPs), which can promote sterile inflammation and contribute to autoimmune and chronic diseases as well as aging-related diseases. Their signaling pathways are just beginning to be revealed. As the first publications indicate that oxidized lysophospholipids use the same receptors as pathogen-associated molecular patterns (PAMPs), it is likely that the inhibition of signaling pathways activated by oxidized lysophospholipids would affect innate immunity per se. On the other hand, inhibition or modulation of their enzymatic formation, which would not interfere with the response to pathogens, might be beneficial and is potentially a promising new field of research.
Topics: Humans; Immunity, Innate; Inflammation; Lysophospholipids; Oxidation-Reduction; Phospholipases
PubMed: 35779690
DOI: 10.1016/j.freeradbiomed.2022.06.228 -
Journal of Lipid Research 2021Phospholipidosis, the excessive accumulation of phospholipids within lysosomes, is a pathological response observed following exposure to many drugs across multiple... (Review)
Review
Phospholipidosis, the excessive accumulation of phospholipids within lysosomes, is a pathological response observed following exposure to many drugs across multiple therapeutic groups. A clear mechanistic understanding of the causes and implications of this form of drug toxicity has remained elusive. We previously reported the discovery and characterization of a lysosome-specific phospholipase A2 (PLA2G15) and later reported that amiodarone, a known cause of drug-induced phospholipidosis, inhibits this enzyme. Here, we assayed a library of 163 drugs for inhibition of PLA2G15 to determine whether this phospholipase was the cellular target for therapeutics other than amiodarone that cause phospholipidosis. We observed that 144 compounds inhibited PLA2G15 activity. Thirty-six compounds not previously reported to cause phospholipidosis inhibited PLA2G15 with IC values less than 1 mM and were confirmed to cause phospholipidosis in an in vitro assay. Within this group, fosinopril was the most potent inhibitor (IC 0.18 μM). Additional characterization of the inhibition of PLA2G15 by fosinopril was consistent with interference of PLA2G15 binding to liposomes. PLA2G15 inhibition was more accurate in predicting phospholipidosis compared with in silico models based on pKa and ClogP, measures of protonation, and transport-independent distribution in the lysosome, respectively. In summary, PLA2G15 is a primary target for cationic amphiphilic drugs that cause phospholipidosis, and PLA2G15 inhibition by cationic amphiphilic compounds provides a potentially robust screening platform for potential toxicity during drug development.
Topics: Animals; Enzyme Inhibitors; Humans; Lysosomes; Phospholipases A2; Phospholipids
PubMed: 34087196
DOI: 10.1016/j.jlr.2021.100089 -
Proceedings of the National Academy of... Jul 2023The outer membrane of Gram-negative bacteria is unique in both structure and function. The surface-exposed outer leaflet is composed of lipopolysaccharide, while the...
The outer membrane of Gram-negative bacteria is unique in both structure and function. The surface-exposed outer leaflet is composed of lipopolysaccharide, while the inner leaflet is composed of glycerophospholipids. This lipid asymmetry creates mechanical strength, lowers membrane permeability, and is necessary for virulence in many pathogens. Glycerophospholipids that mislocalize to the outer leaflet are removed by the Mla pathway, which consists of the outer membrane channel MlaA, the periplasmic lipid carrier MlaC, and the inner membrane transporter MlaBDEF. The opportunistic pathogen has two proteins of the MlaA family: PA2800 and PA3239. Here, we show that PA2800 is part of a canonical Mla pathway, while PA3239 functions with the putative lipase PA3238. While loss of either pathway individually has little to no effect on outer membrane integrity, loss of both pathways weakens the outer membrane permeability barrier and increases production of the secondary metabolite pyocyanin. We propose that mislocalized glycerophospholipids are removed from the outer leaflet by PA3239 (renamed MlaZ), transferred to PA3238 (renamed MlaY), and degraded. This pathway streamlines recycling of glycerophospholipid degradation products by removing glycerophospholipids from the outer leaflet prior to degradation.
Topics: Membrane Lipids; Pseudomonas aeruginosa; Biological Transport; Phospholipases; Bacterial Outer Membrane Proteins; Cell Membrane; Glycerophospholipids
PubMed: 37463202
DOI: 10.1073/pnas.2302546120 -
Molecules (Basel, Switzerland) May 2023One of the most important constituents of the cell membrane is arachidonic acid. Lipids forming part of the cellular membrane can be metabolized in a variety of cellular... (Review)
Review
One of the most important constituents of the cell membrane is arachidonic acid. Lipids forming part of the cellular membrane can be metabolized in a variety of cellular types of the body by a family of enzymes termed phospholipases: phospholipase A2, phospholipase C and phospholipase D. Phospholipase A2 is considered the most important enzyme type for the release of arachidonic acid. The latter is subsequently subjected to metabolization via different enzymes. Three enzymatic pathways, involving the enzymes cyclooxygenase, lipoxygenase and cytochrome P450, transform the lipid derivative into several bioactive compounds. Arachidonic acid itself plays a role as an intracellular signaling molecule. Additionally, its derivatives play critical roles in cell physiology and, moreover, are involved in the development of disease. Its metabolites comprise, predominantly, prostaglandins, thromboxanes, leukotrienes and hydroxyeicosatetraenoic acids. Their involvement in cellular responses leading to inflammation and/or cancer development is subject to intense study. This manuscript reviews the findings on the involvement of the membrane lipid derivative arachidonic acid and its metabolites in the development of pancreatitis, diabetes and/or pancreatic cancer.
Topics: Arachidonic Acid; Membrane Lipids; Leukotrienes; Prostaglandins; Phospholipases A2
PubMed: 37298790
DOI: 10.3390/molecules28114316 -
Biomolecules May 2023Phospholipase C (PLC) plays pivotal roles in regulating various cellular functions by metabolizing phosphatidylinositol 4,5-bisphosphate in the plasma membrane. This... (Review)
Review
Phospholipase C (PLC) plays pivotal roles in regulating various cellular functions by metabolizing phosphatidylinositol 4,5-bisphosphate in the plasma membrane. This process generates two second messengers, inositol 1,4,5-trisphosphate and diacylglycerol, which respectively regulate the intracellular Ca levels and protein kinase C activation. In mammals, six classes of typical PLC have been identified and classified based on their structure and activation mechanisms. They all share X and Y domains, which are responsible for enzymatic activity, as well as subtype-specific domains. Furthermore, in addition to typical PLC, atypical PLC with unique structures solely harboring an X domain has been recently discovered. Collectively, seven classes and 16 isozymes of mammalian PLC are known to date. Dysregulation of PLC activity has been implicated in several pathophysiological conditions, including cancer, cardiovascular diseases, and neurological disorders. Therefore, identification of new drug targets that can selectively modulate PLC activity is important. The present review focuses on the structures, activation mechanisms, and physiological functions of mammalian PLC.
Topics: Animals; Type C Phospholipases; Second Messenger Systems; Signal Transduction; Inositol; Mammals
PubMed: 37371495
DOI: 10.3390/biom13060915 -
Biochimica Et Biophysica Acta.... Jun 2019The group 1B phospholipase A (PLA2G1B) is a secreted phospholipase that catalyzes the hydrolytic removal of the sn-2 fatty acyl moiety from phospholipids. This enzyme is... (Review)
Review
The group 1B phospholipase A (PLA2G1B) is a secreted phospholipase that catalyzes the hydrolytic removal of the sn-2 fatty acyl moiety from phospholipids. This enzyme is synthesized most abundantly in the pancreas and is also expressed in the lung. The first part of this review article focuses on the role of pancreatic-derived PLA2G1B in mediating lipid absorption and discusses how the PLA2G1B-derived metabolic product contributes to cardiometabolic diseases, including obesity, hyperinsulinemia, hyperlipidemia, and atherosclerosis. The anti-helminth properties of PLA2G1B will also be discussed. The second part of this review will focus on PLA2G1B expressed in the lung, and in vitro data suggest that how this enzyme may modulate lung inflammation via both hydrolytic activity-dependent and -dependent mechanisms. Finally, recent studies revealing a relationship between PLA2G1B and cancer will also be discussed. This article is part of a Special Issue entitled Novel functions of phospholipase A2 Guest Editors: Makoto Murakami and Gerard Lambeau.
Topics: Animals; Humans; Lipids; Lung; Metabolic Diseases; Phospholipases A2; Pneumonia
PubMed: 30003964
DOI: 10.1016/j.bbalip.2018.07.001 -
Advances in Biological Regulation Dec 2021Ca is a highly versatile intracellular signal that regulates many biological processes such as cell death and proliferation. Broad Ca-signaling machinery is used to... (Review)
Review
Ca is a highly versatile intracellular signal that regulates many biological processes such as cell death and proliferation. Broad Ca-signaling machinery is used to assemble signaling systems with a precise spatial and temporal resolution to achieve this versatility. Ca-signaling components can be organized in different regions of the cell and local increases in Ca within the nucleus can regulate different cellular functions from the increases in cytosolic Ca. However, the mechanisms and pathways that promote localized increases in Ca levels in the nucleus are still under investigation. This review presents evidence that the nucleus has its own Ca stores and signaling machinery, which modulate processes such as cell proliferation and tumor growth. We focus on what is known about the functions of nuclear Phospholipase C (PLC) in the generation of nuclear Ca transients that are involved in cell proliferation.
Topics: Calcium; Calcium Signaling; Cell Nucleus; Cell Proliferation; Cytosol; Signal Transduction; Type C Phospholipases
PubMed: 34710785
DOI: 10.1016/j.jbior.2021.100834 -
Iranian Journal of Medical Sciences Jul 2022Venomous arthropods such as scorpions and bees form one of the important groups with an essential role in medical entomology. Their venom possesses a mixture of diverse... (Review)
Review
Venomous arthropods such as scorpions and bees form one of the important groups with an essential role in medical entomology. Their venom possesses a mixture of diverse compounds, such as peptides, some of which have toxic effects, and enzymatic peptide Phospholipase A2 (PLA2) with a pharmacological potential in the treatment of a wide range of diseases. Bee and scorpion venom PLA2 group III has been used in immunotherapy, the treatment of neurodegenerative and inflammatory diseases. They were assessed for antinociceptive, wound healing, anti-cancer, anti-viral, anti-bacterial, anti-parasitic, and anti-angiogenesis effects. PLA2 has been identified in different species of scorpions and bees. The anti-leishmania, anti-bacterial, anti-viral, and anti-malarial activities of scorpion PLA2 still need further investigation. Many pieces of research have been stopped in the laboratory stage, and several studies need vast investigation in the clinical phase to show the pharmacological potential of PLA2. In this review, the medical significance of PLA2 from the venom of two arthropods, namely bees and scorpions, is discussed.
Topics: Animals; Bee Venoms; Bees; Peptides; Phospholipases A2; Scorpion Venoms; Scorpions
PubMed: 35919080
DOI: 10.30476/IJMS.2021.88511.1927