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Biochimica Et Biophysica Acta Nov 2006As saprophytes or disease causing microorganisms, fungi acquire nutrients from dead organic material or living host organisms. Lipids as structural components of cell... (Review)
Review
As saprophytes or disease causing microorganisms, fungi acquire nutrients from dead organic material or living host organisms. Lipids as structural components of cell membranes and storage compartments play an important role as energy-rich food source. In recent years, it also has become clear that lipids have a wide range of bioactive properties including signal transduction and cell to cell communication. Thus, it is not surprising that fungi possess a broad range of hydrolytic enzymes that attack neutral lipids and phospholipids. Especially during infection of a mammalian host, phospholipase A(2) (PLA(2)) enzymes released by fungi could play important roles not only for nutrient acquisition and tissue invasion, but for intricate modulation of the host's immune response. Sequencing of fungal genomes has revealed a wide range of genes encoding PLA(2) activities in fungi. We are just beginning to become aware of the significance these enzymes could have for the fungal cells and their interaction with the host.
Topics: Animals; Fungal Proteins; Fungi; Genome, Fungal; Group IV Phospholipases A2; Humans; Lysophospholipase; Mycoses; Phospholipases A; Phospholipases A2; Phospholipids; Signal Transduction
PubMed: 17081801
DOI: 10.1016/j.bbalip.2006.09.011 -
FEBS Letters Jun 1997The 85-kDa cytosolic PLA2 (cPLA2) is present in many cells and tissues and its unusual functional properties and catalytic mechanism are being elucidated. Notably, cPLA2... (Review)
Review
The 85-kDa cytosolic PLA2 (cPLA2) is present in many cells and tissues and its unusual functional properties and catalytic mechanism are being elucidated. Notably, cPLA2 becomes catalytically active in the presence of free Ca2+ concentrations as present in stimulated cells and preferentially cleaves arachidonic acid-containing phospholipids. A variety of agonists, growth factors and cytokines, as well as stressful stimuli activate cPLA2 to hydrolyze cellular phospholipids thereby liberating fatty acids and lysophospholipids and providing the precursor substrates for the biosynthesis of eicosanoids and platelet-activating factor. These products of cPLA2 contribute to inflammatory and degenerative disease states and cPLA2 is therefore an attractive target for the development of novel therapies.
Topics: Animals; Calcium; Cytosol; Enzyme Activation; Humans; Phospholipases A; Phospholipases A2; Structure-Activity Relationship
PubMed: 9247121
DOI: 10.1016/s0014-5793(97)00322-0 -
Biological & Pharmaceutical Bulletin Aug 2004Cytosolic phospholipase A2alpha (cPLA2alpha) preferentially hydrolyzes phospholipids containing arachidonic acid and plays a key role in the biosynthesis of eicosanoids.... (Review)
Review
Cytosolic phospholipase A2alpha (cPLA2alpha) preferentially hydrolyzes phospholipids containing arachidonic acid and plays a key role in the biosynthesis of eicosanoids. This review discusses the essential features of cPLA2alpha regulation and addresses new insights into the functional properties of this enzyme. Full activation of the enzyme requires Ca2+ binding to an N-terminal C2 domain and phosphorylation on serine residues. Ca2+ binding induces translocation of cPLA2alpha from the cytosol to the perinuclear membranes. Serine phosphorylation is mediated by mitogen-activated protein kinases (MAPKs), Ca2+/calmodulin-dependent protein kinase II, and MAPK-interacting kinase Mnk1. Interaction with proteins and lipids, which include vimentin, annexins, NADPH oxidase, phosphatidylcholine, phosphatidylinositol 4,5-bisphosphate (PIP2), and ceramide-1-phosphate, can also modulate the activity of cPLA2alpha. Recent evidence has established the physiological and pathological roles of cPLA2alpha using cPLA2alpha knockout mice. This enzyme has been implicated in fertility, striated muscle growth, renal concentration, postischemic brain injury, arthritis, inflammatory bone resorption, intestinal polyposis, pulmonary fibrosis, acute respiratory distress syndrome, and autoimmune encephalomyelitis. Now novel three paralogs, cPLA2beta, cPLA2gamma, and cPLA2delta, have been identified in humans. cPLA2gamma is distinct from others in that it is farnesylated and lacks the C2 domain. Biological roles for these new enzymes have not yet been defined.
Topics: Cytosol; Models, Molecular; Phospholipases A; Phospholipases A2; Phosphorylation; Protein Conformation
PubMed: 15305015
DOI: 10.1248/bpb.27.1168 -
Microbiological Research Apr 2018Phospholipases are ubiquitous enzymes that hydrolyze phospholipids. Based on the cleavage site of the ester linkage in the substrate phospholipids, phospholipases are... (Review)
Review
Phospholipases are ubiquitous enzymes that hydrolyze phospholipids. Based on the cleavage site of the ester linkage in the substrate phospholipids, phospholipases are classified into four major types, phospholipase A (PLA), phospholipase B (PLB), phospholipase C (PLC), and phospholipase D (PLD), which are further classified into various subtypes. Phospholipases hydrolyze phospholipids into various signaling products including phosphatidic acid (PA), diacylglycerol (DAG), free fatty acids (FFAs), and lyso-phospholipids (LPLs). These signaling products regulate numerous processes such as cytoskeletal dynamics, growth, homeostasis, membrane remodeling, nutrient acquisition, secretion, signal transduction, stress tolerance, sexual development, and virulence in various organisms including fungi. Due to these key cellular roles, phospholipases are also promising targets in diagnostic and therapeutic applications. In this review, we discuss current knowledge about the cellular roles of different classes of phospholipases in fungi.
Topics: Binding Sites; Calcium Signaling; Catalytic Domain; Fungi; Humans; Lysophospholipase; Phospholipase D; Phospholipases A; Stress, Physiological; Type C Phospholipases
PubMed: 29580622
DOI: 10.1016/j.micres.2017.12.012 -
Biochemical Pharmacology Oct 2008Phospholipase A(2) (PLA(2)) are esterases that cleave glycerophospholipids to release fatty acids and lysophospholipids. Several studies demonstrate that PLA(2) regulate... (Review)
Review
Phospholipase A(2) (PLA(2)) are esterases that cleave glycerophospholipids to release fatty acids and lysophospholipids. Several studies demonstrate that PLA(2) regulate growth and signaling in several cell types. However, few of these studies have focused on Ca2+-independent phospholipase A(2) (iPLA(2) or Group VI PLA(2)). This class of PLA(2) was originally suggested to mediate phospholipid remodeling in several cell types including macrophages. As such, it was labeled as a housekeeping protein and thought not to play as significant of roles in cell growth as its older counterparts cytosolic PLA(2) (cPLA(2) or Group IV PLA(2)) and secretory PLA(2) (sPLA(2) or Groups I-III, V and IX-XIV PLA(2)). However, several recent studies demonstrate that iPLA(2) mediate cell growth, and do so by participating in signal transduction pathways that include epidermal growth factor receptors (EGFR), mitogen activated protein kinases (MAPK), mdm2, and even the tumor suppressor protein p53 and the cell cycle regulator p21. The exact mechanism by which iPLA(2) mediates these pathways are not known, but likely involve the generation of lipid signals such as arachidonic acid, lysophosphatidic acid (LPA) and lysophosphocholines (LPC). This review discusses the role of iPLA(2) in cell growth with special emphasis placed on their role in cell signaling. The putative lipid signals involved are also discussed.
Topics: Animals; Cell Line; Cell Proliferation; Group VI Phospholipases A2; Humans; Lipids; Signal Transduction
PubMed: 18775417
DOI: 10.1016/j.bcp.2008.07.044 -
Biochemistry Apr 2021Phospholipase A/acyltransferase 3 (PLAAT3) and PLAAT4 are enzymes involved in the synthesis of bioactive lipids. Despite sequential and structural similarities, the two...
Phospholipase A/acyltransferase 3 (PLAAT3) and PLAAT4 are enzymes involved in the synthesis of bioactive lipids. Despite sequential and structural similarities, the two enzymes differ in activity and specificity. The relation between the activity and dynamics of the N-terminal domains of PLAAT3 and PLAAT4 was studied. PLAAT3 has a much higher melting temperature and exhibits less nanosecond and millisecond dynamics in the active site, in particular in loop L2(B6), as shown by NMR spectroscopy and molecular dynamics calculations. Swapping the L2(B6) loops between the two PLAAT enzymes results in strongly increased phospholipase activity in PLAAT3 but no reduction in PLAAT4 activity, indicating that this loop contributes to the low activity of PLAAT3. The results show that, despite structural similarity, protein dynamics differ substantially between the PLAAT variants, which can help to explain the activity and specificity differences.
Topics: Catalytic Domain; Molecular Dynamics Simulation; Phospholipases; Substrate Specificity; Temperature
PubMed: 33749246
DOI: 10.1021/acs.biochem.0c00974 -
Brain : a Journal of Neurology Apr 2023Phospholipase C (PLC) is an essential isozyme involved in the phosphoinositide signalling pathway, which maintains cellular homeostasis. Gain- and loss-of-function... (Review)
Review
Phospholipase C (PLC) is an essential isozyme involved in the phosphoinositide signalling pathway, which maintains cellular homeostasis. Gain- and loss-of-function mutations in PLC affect enzymatic activity and are therefore associated with several disorders. Alternative splicing variants of PLC can interfere with complex signalling networks associated with oncogenic transformation and other diseases, including brain disorders. Cells and tissues with various mutations in PLC contribute different phosphoinositide signalling pathways and disease progression, however, identifying cryptic mutations in PLC remains challenging. Herein, we review both the mechanisms underlying PLC regulation of the phosphoinositide signalling pathway and the genetic variation of PLC in several brain disorders. In addition, we discuss the present challenges associated with the potential of deep-learning-based analysis for the identification of PLC mutations in brain disorders.
Topics: Humans; Type C Phospholipases; Phosphoinositide Phospholipase C; Deep Learning; Phosphatidylinositols; Brain Diseases; Mutation
PubMed: 36448305
DOI: 10.1093/brain/awac451 -
Reproduction, Nutrition, Development 2005Phospholipids are integral components of the nuclear membranes and intranuclear domains. Alterations in phospholipid metabolism occur during cellular differentiation,... (Review)
Review
Phospholipids are integral components of the nuclear membranes and intranuclear domains. Alterations in phospholipid metabolism occur during cellular differentiation, proliferation, and apoptosis, but the molecular mechanism involved in the above processes remains unknown. We propose that the coordinated expression of different genes responsible for the expression of transcription factors, neurotrophins, and cytokines, along with lipid mediators generated by the action of phospholipases A2, C, and D (PLA2, PLC, and PLD), play a very important role in differentiation, proliferation, and apoptosis. The purpose of this minireview is to discuss recent developments in PLA2, PLC, and PLD-mediated signaling in the nucleus of LA-N-1 neuroblastoma cell cultures. In brain tissue, arachidonic acid is mainly released by the action of PLA2 and phospholipase C/diacylglycerol lipase (PLC/DAG-lipase) pathways. We have used LA-N-1 cell cultures to study activities of PLA2, C, and D during retinoic acid (RA)-mediated differentiation. The treatment of LA-N-1 cells with RA produces an increase in PLA2 activity in the nuclear fraction. This increase in PLA2 activity can be prevented with BMS493, a pan retinoic acid receptor antagonist, suggesting that RA-induced stimulation of PLA2 activity is a RA receptor-mediated process. The treatment of LA-N-1 cells with 12-O-tetradecanoyl-phorbol-13 acetate (TPA) and RA increases diacylglycerol (DAG) levels indicating the stimulation of PLC activity. This stimulation is blocked by D609, tricyclodecan-9-yl potassium xanthate, a competitive PtdCho-specific PLC inhibitor. LA-N-1 cells also contain DAG-and monoacylglycerol (MAG) lipase activities. Two isoforms of PLD, oleate-dependent and TPA-dependent, are also present in LA-N-1 cell homogenates. RA stimulates the oleate-dependent isoform of PLD, whereas RA does not stimulate the TPA-dependent isoform. Our studies have indicated that lipid mediators generated by the action of PLA2, PLC, and PLD on nuclear phospholipids markedly affect neuritic outgrowth and neurotransmitter release in cells of neuronal and glial origin. We propose that RA receptors coupled with PLA2, PLC, and PLD activities in the nucleus may play an important role in the redistribution of arachidonic acid and its metabolites and DAG in nuclear and non-nuclear neuronal membranes during differentiation and growth suppression.
Topics: Apoptosis; Brain; Cell Division; Cell Nucleus; Humans; Isoenzymes; Phospholipase D; Phospholipases; Phospholipases A; Phospholipases A2; Receptors, Retinoic Acid; Signal Transduction; Tumor Cells, Cultured; Type C Phospholipases
PubMed: 16188211
DOI: 10.1051/rnd:2005049 -
Clinical Microbiology Reviews Jan 2000Microbial pathogens use a number of genetic strategies to invade the host and cause infection. These common themes are found throughout microbial systems. Secretion of... (Review)
Review
Microbial pathogens use a number of genetic strategies to invade the host and cause infection. These common themes are found throughout microbial systems. Secretion of enzymes, such as phospholipase, has been proposed as one of these themes that are used by bacteria, parasites, and pathogenic fungi. The role of extracellular phospholipase as a potential virulence factor in pathogenic fungi, including Candida albicans, Cryptococcus neoformans, and Aspergillus, has gained credence recently. In this review, data implicating phospholipase as a virulence factor in C. albicans, Candida glabrata, C. neoformans, and A. fumigatus are presented. A detailed description of the molecular and biochemical approaches used to more definitively delineate the role of phospholipase in the virulence of C. albicans is also covered. These approaches resulted in cloning of three genes encoding candidal phospholipases (caPLP1, caPLB2, and PLD). By using targeted gene disruption, C. albicans null mutants that failed to secrete phospholipase B, encoded by caPLB1, were constructed. When these isogenic strain pairs were tested in two clinically relevant murine models of candidiasis, deletion of caPLB1 was shown to lead to attenuation of candidal virulence. Importantly, immunogold electron microscopy studies showed that C. albicans secretes this enzyme during the infectious process. These data indicate that phospholipase B is essential for candidal virulence. Although the mechanism(s) through which phospholipase modulates fungal virulence is still under investigations, early data suggest that direct host cell damage and lysis are the main mechanisms contributing to fungal virulence. Since the importance of phospholipases in fungal virulence is already known, the next challenge will be to utilize these lytic enzymes as therapeutic and diagnostic targets.
Topics: Amino Acid Sequence; Bacteria; Fungi; Humans; Molecular Sequence Data; Mycoses; Phospholipases; Virulence
PubMed: 10627494
DOI: 10.1128/CMR.13.1.122 -
NPJ Biofilms and Microbiomes May 2022In rod-shaped bacteria, morphological plasticity occurs in response to stress, which blocks cell division to promote filamentation. We demonstrate here that...
In rod-shaped bacteria, morphological plasticity occurs in response to stress, which blocks cell division to promote filamentation. We demonstrate here that overexpression of the patatin-like phospholipase variant CapV, but not CapV, causes pronounced sulA-independent pyridoxine-inhibited cell filamentation in the Escherichia coli K-12-derivative MG1655 associated with restriction of flagella production and swimming motility. Conserved amino acids in canonical patatin-like phospholipase A motifs, but not the nucleophilic serine, are required to mediate CapV phenotypes. Furthermore, CapV production substantially alters the lipidome and colony morphotype including rdar biofilm formation with modulation of the production of the biofilm activator CsgD, and affects additional bacterial traits such as the efficiency of phage infection and antimicrobial susceptibility. Moreover, genetically diverse commensal and pathogenic E. coli strains and Salmonella typhimurium responded with cell filamentation and modulation in colony morphotype formation to CapV expression. In conclusion, this work identifies the CapV variant CapV as a pleiotropic regulator, emphasizes a scaffold function for patatin-like phospholipases, and highlights the impact of the substitution of a single conserved amino acid for protein functionality and alteration of host physiology.
Topics: Amino Acid Substitution; Escherichia coli; Escherichia coli K12; Phospholipases; Salmonella typhimurium
PubMed: 35546554
DOI: 10.1038/s41522-022-00294-z