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International Journal of Molecular... Jan 2011Phospholipase A(1) (PLA(1)) is an enzyme that hydrolyzes phospholipids and produces 2-acyl-lysophospholipids and fatty acids. This lipolytic activity is conserved in a... (Review)
Review
Phospholipase A(1) (PLA(1)) is an enzyme that hydrolyzes phospholipids and produces 2-acyl-lysophospholipids and fatty acids. This lipolytic activity is conserved in a wide range of organisms but is carried out by a diverse set of PLA(1) enzymes. Where their function is known, PLA(1)s have been shown to act as digestive enzymes, possess central roles in membrane maintenance and remodeling, or regulate important cellular mechanisms by the production of various lysophospholipid mediators, such as lysophosphatidylserine and lysophosphatidic acid, which in turn have multiple biological functions.
Topics: Animals; Humans; Lysophospholipids; Phospholipases A; Phospholipases A1; Substrate Specificity; Type C Phospholipases
PubMed: 21340002
DOI: 10.3390/ijms12010588 -
Gut Microbes 2023utilizes the Type VI secretion system (T6SS) to gain an advantage in interbacterial competition by delivering anti-prokaryotic effectors in a contact-dependent manner....
utilizes the Type VI secretion system (T6SS) to gain an advantage in interbacterial competition by delivering anti-prokaryotic effectors in a contact-dependent manner. However, the impact of T6SS and its secreted effectors on physiological behavior remains poorly understood. In this study, we present Tle1, a phospholipase effector in atypical pathogenic E1 that is secreted by T6SS via its interaction with VgrG1. Tle1 contains a DUF2235 domain and belongs to the Tle1 (type VI lipase effector) family. Bacterial toxicity assays, lipase activity assays and site-directed mutagenesis revealed that Tle1 possessed phospholipase A activity and phospholipase A activity, and that Tle1-induced toxicity required a serine residue (S356) and two aspartic acid residues (D417 and D496). Cells intoxication with Tle1 lead to membrane depolarization and alter membrane permeability. Tli1, a cognate immunity protein, directly interacts with Tle1 to neutralize its toxicity. Moreover, Tle1 can kill multiple microorganisms by T6SS and promote fitness of through mediating antibacterial activity. Tle1 induces bacterial motility by increasing the expression of flagellar-related genes independently of functional T6SS and the tit-for-tat (TFT) response, where uses its T6SS-H1 cluster to counterattack other offensive attackers. Our study also demonstrated that the physical puncture of E1 T6SS can induce a moderate TFT response, which is essential to the Tle1-mediated strong TFT response, maximizing effector functions. Overall, our study characterized the antibacterial mechanism of phospholipase effector Tle1 and its multiple physiological significance.
Topics: Virulence; Phospholipases; Vibrio cholerae; Bacterial Proteins; Gastrointestinal Microbiome; Lipase; Anti-Bacterial Agents; Gene Expression
PubMed: 37526354
DOI: 10.1080/19490976.2023.2241204 -
Journal of Lipid Research Apr 2009Tremendous advances in understanding the structure and function of the superfamily of phospholipase A2 (PLA2) enzymes has occurred in the twenty-first century. The... (Review)
Review
Tremendous advances in understanding the structure and function of the superfamily of phospholipase A2 (PLA2) enzymes has occurred in the twenty-first century. The superfamily includes 15 groups comprising four main types including the secreted sPLA2, cytosolic cPLA2, calcium-independent iPLA2, and platelet activating factor (PAF) acetyl hydrolase/oxidized lipid lipoprotein associated (Lp)PLA2. We review herein our current understanding of the structure and interaction with substrate phospholipids, which resides in membranes for a representative of each of these main types of PLA2. We will also briefly review the development of inhibitors of these enzymes and their roles in lipid signaling.
Topics: 1-Alkyl-2-acetylglycerophosphocholine Esterase; Animals; Calcium; Cytosol; Humans; Lipid Metabolism; Phospholipases A2; Signal Transduction
PubMed: 19011112
DOI: 10.1194/jlr.R800033-JLR200 -
Progress in Lipid Research Apr 2022Cell membranes are the initial site of stimulus perception from environment and phospholipids are the basic and important components of cell membranes. Phospholipases... (Review)
Review
Cell membranes are the initial site of stimulus perception from environment and phospholipids are the basic and important components of cell membranes. Phospholipases hydrolyze membrane lipids to generate various cellular mediators. These phospholipase-derived products, such as diacylglycerol, phosphatidic acid, inositol phosphates, lysophopsholipids, and free fatty acids, act as second messengers, playing vital roles in signal transduction during plant growth, development, and stress responses. This review focuses on the structure, substrate specificities, reaction requirements, and acting mechanism of several phospholipase families. It will discuss their functional significance in plant growth, development, and stress responses. In addition, it will highlight some critical knowledge gaps in the action mechanism, metabolic and signaling roles of these phospholipases and their products in the context of plant growth, development and stress responses.
Topics: Humans; Hydrolysis; Phosphatidic Acids; Phospholipase D; Phospholipases; Phospholipids; Type C Phospholipases
PubMed: 35134459
DOI: 10.1016/j.plipres.2022.101158 -
Journal of Biomedical Science Oct 2015The H-RAS-like suppressor (HRASLS) subfamily consists of five enzymes (1-5) in humans and three (1, 3, and 5) in mice and rats that share sequence homology with... (Review)
Review
The H-RAS-like suppressor (HRASLS) subfamily consists of five enzymes (1-5) in humans and three (1, 3, and 5) in mice and rats that share sequence homology with lecithin:retinol acyltransferase (LRAT). All HRASLS family members possess in vitro phospholipid metabolizing abilities including phospholipase A1/2 (PLA1/2) activities and O-acyltransferase activities for the remodeling of glycerophospholipid acyl chains, as well as N-acyltransferase activities for the production of N-acylphosphatidylethanolamines. The in vivo biological activities of the HRASLS enzymes have not yet been fully investigated. Research to date indicates involvement of this subfamily in a wide array of biological processes and, as a consequence, these five enzymes have undergone extensive rediscovery and renaming within different fields of research. This review briefly describes the discovery of each of the HRASLS enzymes and their role in cancer, and discusses the biochemical function of each enzyme, as well as the biological role, if known. Gaps in current understanding are highlighted and suggestions for future research directions are discussed.
Topics: Acyltransferases; Animals; Humans; Mice; Phospholipases A; Phospholipases A1; Phospholipases A2; Proteins; Rats
PubMed: 26503625
DOI: 10.1186/s12929-015-0210-7 -
Accounts of Chemical Research Dec 2022Water-soluble proteins as well as membrane-bound proteins associate with membrane surfaces and bind specific lipid molecules in specific sites on the protein. Membrane...
Water-soluble proteins as well as membrane-bound proteins associate with membrane surfaces and bind specific lipid molecules in specific sites on the protein. Membrane surfaces include the traditional bilayer membranes of cells and subcellular organelles formed by phospholipids. Monolayer membranes include the outer monolayer phospholipid surface of intracellular lipid droplets of triglycerides and various lipoproteins including HDL, LDL, VLDL, and chylomicrons. These lipoproteins circulate in our blood and lymph systems and contain triglycerides, cholesterol, cholesterol esters, and proteins in their interior, and these are sometimes interspersed on their surfaces. Similar lipid-water interfaces also occur in mixed micelles of phospholipids and bile acids in our digestive system, which may also include internalized triglycerides and cholesterol esters. Diacyl phospholipids constitute the defining molecules of biological membranes. Phospholipase A (PLA) hydrolyzes phospholipid acyl chains at the -1 position of membrane phospholipids, phospholipase A (PLA) hydrolyzes acyl chains at the -2 position, phospholipase C (PLC) hydrolyzes the glycerol-phosphodiester bond, and phospholipase D (PLD) hydrolyzes the polar group-phosphodiester bond. Of the phospholipases, the PLAs have been the most well studied at the mechanistic level. The PLA superfamily consists of 16 groups and numerous subgroups, and each is generally described as one of 6 types. The most well studied of the PLAs include extensive genetic and mutational studies, complete lipidomics specificity characterization, and crystallographic structures. This Account will focus principally on results from deuterium exchange mass spectrometric (DXMS) studies of PLA interactions with membranes and extensive molecular dynamics (MD) simulations of their interactions with membranes and specific phospholipids bound in their catalytic and allosteric sites. These enzymes either are membrane-bound or are water-soluble and associate with membranes before extracting their phospholipid substrate molecule into their active site to carry out their enzymatic hydrolytic reaction. We present evidence that when a PLA associates with a membrane, the membrane association can result in a conformational change in the enzyme whereby the membrane association with an allosteric site on the enzyme stabilizes the enzyme in an active conformation on the membrane. We sometimes refer to this transition from a "closed" conformation in aqueous solution to an "open" conformation when associated with a membrane. The enzyme can then extract a single phospholipid substrate into its active site, and catalysis occurs. We have also employed DXMS and MD simulations to characterize how PLAs interact with specific inhibitors that could lead to potential therapeutics. The PLAs constitute a paradigm for how membranes interact allosterically with proteins, causing conformational changes and activation of the proteins to enable them to extract and bind a specific phospholipid from a membrane for catalysis, which is probably generalizable to intracellular and extracellular transport and phospholipid exchange processes as well as other specific biological functions. We will focus on the four main types of PLA, namely, the secreted (sPLA), cytosolic (cPLA), calcium-independent (iPLA), and lipoprotein-associated PLA (Lp-PLA) also known as platelet-activating factor acetyl hydrolase (PAF-AH). Studies on a well-studied specific example of each of the four major types of the PLA superfamily demonstrate clearly that protein subsites can show precise specificity for one of the phospholipid hydrophobic acyl chains, often the one at the -2 position, including exquisite sensitivity to the number and position of double bonds.
Topics: Cholesterol Esters; Phospholipases A2; Phospholipids; Phospholipases; Lipoproteins; Triglycerides; Water; Polyesters; Substrate Specificity
PubMed: 36315840
DOI: 10.1021/acs.accounts.2c00497 -
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 -
Molecules (Basel, Switzerland) Mar 2010New synthetic methods for the preparation of biologically active phospholipids and lysophospholipids (LPLs) are very important in solving problems of membrane-chemistry... (Review)
Review
New synthetic methods for the preparation of biologically active phospholipids and lysophospholipids (LPLs) are very important in solving problems of membrane-chemistry and biochemistry. Traditionally considered just as second-messenger molecules regulating intracellular signalling pathways, LPLs have recently shown to be involved in many physiological and pathological processes such as inflammation, reproduction, angiogenesis, tumorogenesis, atherosclerosis and nervous system regulation. Elucidation of the mechanistic details involved in the enzymological, cell-biological and membrane-biophysical roles of LPLs relies obviously on the availability of structurally diverse compounds. A variety of chemical and enzymatic routes have been reported in the literature for the synthesis of LPLs: the enzymatic transformation of natural glycerophospholipids (GPLs) using regiospecific enzymes such as phospholipases A1 (PLA1), A2 (PLA2) phospholipase D (PLD) and different lipases, the coupling of enzymatic processes with chemical transformations, the complete chemical synthesis of LPLs starting from glycerol or derivatives. In this review, chemo-enzymatic procedures leading to 1- and 2-LPLs will be described.
Topics: Biocatalysis; Lysophospholipids; Phospholipase D; Phospholipases A1
PubMed: 20335986
DOI: 10.3390/molecules15031354 -
IUBMB Life 2006Phosphatidylcholine (PC) is a major constituent of biological membranes and a component of serum lipoproteins and pulmonary surfactants. The PC and other... (Review)
Review
Phosphatidylcholine (PC) is a major constituent of biological membranes and a component of serum lipoproteins and pulmonary surfactants. The PC and other glycerophospholipid compositions of membranes change dynamically through stimulus-dependent and independent pathways, principally by the action of two different types of enzymes; phospholipase A2 [EC 3.1.1.4] and acyl-CoA:lysophospholipid acyltransferase [EC 2.3.1.23]. Phospholipase A2 is a key enzyme that catalyzes deacylation of the sn-2 position of glycerophospholipids. This enzyme is critical in the remodeling of membrane lipids and formation of two subclasses of lipid mediators, fatty acid derivatives and lysophospholipids. Among many different subtypes of phospholipase A2 enzymes, we found that cytosolic phospholipase A2alpha (cPLA2alpha) is important in various pathological and physiological responses. Here, we summarize the phenotypes resulting from genetic ablation of cPLA2alpha, and the properties of newly discovered enzymes in the cPLA2 family. Comprehensive analysis of lipid mediators using liquid chromatography-tandem mass spectrometry (LC-MS/MS) is useful for understanding the roles of individual mediators in physiological and pathological processes.
Topics: Animals; Cytosol; Group IV Phospholipases A2; Humans; Isoenzymes; Multigene Family; Phospholipases A; Phospholipases A2
PubMed: 16754327
DOI: 10.1080/15216540600702289 -
Journal of Lipid Research Apr 2009Signal-activated phospholipases are a recent focus of the rapidly growing field of lipid signaling. The extent of their impact on the pathways regulating diverse cell... (Review)
Review
Signal-activated phospholipases are a recent focus of the rapidly growing field of lipid signaling. The extent of their impact on the pathways regulating diverse cell functions is beginning to be appreciated. A critical step in inflammation is the attraction of leukocytes to injured or diseased tissue. Chemotaxis of leukocytes, a requisite process for monocyte and neutrophil extravasation from the blood into tissues, is a critical step for initiating and maintaining inflammation in both acute and chronic settings. Recent studies have identified new important and required roles for two signal-activated phospholipases A2 (PLA2) in regulating chemotaxis. The two intracellular phospholipases, cPLA2alpha (Group IVA) and iPLA2beta (Group VIA), act in parallel to provide distinct lipid mediators at different intracellular sites that are both required for leukocytes to migrate toward the chemokine monocyte chemoattractant protein-1. This review will summarize the separate roles of these phospholipases as well as what is currently known about the influence of two other classes of intracellular signal-activated phospholipases, phospholipase C and phospholipase D, in regulating chemotaxis in eukaryotic cells, but particularly in human monocytes. The contributions of these phospholipases to chemotaxis both in vitro and in vivo will be highlighted.
Topics: Animals; Chemotaxis, Leukocyte; Humans; Phosphoinositide Phospholipase C; Phospholipase D; Phospholipases; Phospholipases A2; Signal Transduction
PubMed: 19109234
DOI: 10.1194/jlr.R800096-JLR200