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BBA - Molecular and Cell Biology of Lipids (v.1831, #3)
A retrospective: Use of Escherichia coli as a vehicle to study phospholipid synthesis and function
by William Dowhan (pp. 471-494).
Although the study of individual phospholipids and their synthesis began in the 1920s first in plants and then mammals, it was not until the early 1960s that Eugene Kennedy using Escherichia coli initiated studies of bacterial phospholipid metabolism. With the base of information already available from studies of mammalian tissue, the basic blueprint of phospholipid biosynthesis in E. coli was worked out by the late 1960s. In 1970s and 1980s most of the enzymes responsible for phospholipid biosynthesis were purified and many of the genes encoding these enzymes were identified. By the late 1990s conditional and null mutants were available along with clones of the genes for every step of phospholipid biosynthesis. Most of these genes had been sequenced before the complete E. coli genome sequence was available. Strains of E. coli were developed in which phospholipid composition could be changed in a systematic manner while maintaining cell viability. Null mutants, strains in which phospholipid metabolism was artificially regulated, and strains synthesizing foreign lipids not found in E. coli have been used to this day to define specific roles for individual phospholipid. This review will trace the findings that have led to the development of E. coli as an excellent model system to study mechanisms underlying the synthesis and function of phospholipids that are widely applicable to other prokaryotic and eukaryotic systems. This article is part of a Special Issue entitled Phospholipids and Phospholipid Metabolism. ► Escherichia coli is an excellent system in which to study phospholipid function. ► Historical aspects of phospholipid metabolism, enzymology and genetics are presented. ► Approaches available to determine specific phospholipid functions in cells are reviewed. ► Future studies of metabolic regulation and function of phospholipids are proposed.
Keywords: Abbreviations; ACP; acyl carrier protein; PA; phosphatidic acid; PE; phosphatidylethanolamine; P; i; PO; 4; GP; glycerophosphate; PG; phosphatidylglycerol; PGP; phosphatidylglycerophosphate; DAG; diacylglycerol; LPS; lipopolysaccharide; MDO; membrane derived oligosaccharide; CL; cardiolipin; PA; phosphatidic acid; PS; phosphatidylserine; PC; phosphatidylcholine; PI; phosphatidylinositol; GlcDAG; monoglucosyl diacylglycerol; GlcGlcDAG; diglucosyl diacylglycerol; PssA; phosphatidylserine synthase; PgsA; phosphatidylglycerophosphate synthase; Pgp; phosphatidylglycerophosphate phosphatase; Cds; CDP-diacylglycerol synthase; Cls; cardiolipin synthase; P; tet; tet; operon promoter; IPTG; isopropyl-ß-D-thiogalactoside; P; lacOP; lac; operon promotor; mAb; monoclonal antibody; TM; transmembrane domain; LacY; lactose permease; mAb; monoclonal antibody; NAO; Nonyl Acridine Orange; NBPAL; non-bilayer prone anionic lipid Escherichia coli; Phosphatidylethanolamine; Phosphatidylglycerol; Cardiolipin; Membrane protein; Genetics
Phosphatidic acid synthesis in bacteria
by Jiangwei Yao; Charles O. Rock (pp. 495-502).
Membrane phospholipid synthesis is a vital facet of bacterial physiology. Although the spectrum of phospholipid headgroup structures produced by bacteria is large, the key precursor to all of these molecules is phosphatidic acid (PtdOH). Glycerol-3-phosphate derived from the glycolysis via glycerol-phosphate synthase is the universal source for the glycerol backbone of PtdOH. There are two distinct families of enzymes responsible for the acylation of the 1-position of glycerol-3-phosphate. The PlsB acyltransferase was discovered in Escherichia coli, and homologs are present in many eukaryotes. This protein family primarily uses acyl–acyl carrier protein (ACP) endproducts of fatty acid synthesis as acyl donors, but may also use acyl-CoA derived from exogenous fatty acids. The second protein family, PlsY, is more widely distributed in bacteria and utilizes the unique acyl donor, acyl-phosphate, which is produced from acyl-ACP by the enzyme PlsX. The acylation of the 2-position is carried out by members of the PlsC protein family. All PlsCs use acyl-ACP as the acyl donor, although the PlsCs of the γ-proteobacteria also may use acyl-CoA. Phospholipid headgroups are precursors in the biosynthesis of other membrane-associated molecules and the diacylglycerol product of these reactions is converted to PtdOH by one of two distinct families of lipid kinases. The central importance of the de novo and recycling pathways to PtdOH in cell physiology suggest that these enzymes are suitable targets for the development of antibacterial therapeutics in Gram-positive pathogens. This article is part of a Special Issue entitled Phospholipids and Phospholipid Metabolism.► Phosphatidic acid is the key intermediate in bacterial phospholipid synthesis. ► Acyltransferases control the positional distribution of fatty acyl chains in the phospholipids. ► Acyl-ACP and acyl-CoA are important biochemical and transcriptional regulators.
Keywords: Bacteria; Acyltransferase; Phosphatidic acid; Acyl carrier protein; Coenzyme A; Diacylglycerol
Phosphatidylcholine biosynthesis and function in bacteria
by Otto Geiger; Lopez-Lara Isabel M. López-Lara; Christian Sohlenkamp (pp. 503-513).
Phosphatidylcholine (PC) is the major membrane-forming phospholipid in eukaryotes and is estimated to be present in about 15% of the domain Bacteria. Usually, PC can be synthesized in bacteria by either of two pathways, the phospholipid N-methylation (Pmt) pathway or the phosphatidylcholine synthase (Pcs) pathway. The three subsequent enzymatic methylations of phosphatidylethanolamine are performed by a single phospholipid N-methyltransferase in some bacteria whereas other bacteria possess multiple phospholipid N-methyltransferases each one performing one or several distinct methylation steps. Phosphatidylcholine synthase condenses choline directly with CDP-diacylglycerol to form CMP and PC. Like in eukaryotes, bacterial PC also functions as a biosynthetic intermediate during the formation of other biomolecules such as choline, diacylglycerol, or diacylglycerol-based phosphorus-free membrane lipids. Bacterial PC may serve as a specific recognition molecule but it affects the physicochemical properties of bacterial membranes as well. This article is part of a Special Issue entitled Phospholipids and Phospholipid Metabolism.► About 15% of the Bacteria have phosphatidylcholine. ► Phosphatidylcholine synthase exists exclusively in bacteria. ► Bacterial phosphatidylcholine can act as a metabolic precursor. ► Bacterial phosphatidylcholine affects physicochemical properties of membranes.
Keywords: Abbreviations; CL; cardiolipin; CPT; choline phosphotransferase; DAG; diacylglycerol; DMPE; dimethylphosphatidylethanolamine; MMPE; monomethylphosphatidylethanolamine; PAF; platelet-activating factor; PC; phosphatidylcholine; Pcs; phosphatidylcholine synthase; PE; phosphatidylethanolamine; PG; phosphatidylglycerol; PI; phosphatidylinositol; Pmt; phospholipid; N; -methyltransferase; PS; phosphatidylserine; SAM; S; -adenosylmethionine; SAH; S; -adenosylhomocysteineMembrane lipid biosynthesis; Bacterial phosphatidylcholine; Phosphatidylcholine synthase; Phospholipid; N; -methyltransferase
Phosphatidate phosphatase, a key regulator of lipid homeostasis
by Florencia Pascual; George M. Carman (pp. 514-522).
Yeast Pah1p phosphatidate phosphatase (PAP) catalyzes the penultimate step in the synthesis of triacylglycerol. PAP plays a crucial role in lipid homeostasis by controlling the relative proportions of its substrate phosphatidate and its product diacylglycerol. The cellular amounts of these lipid intermediates influence the synthesis of triacylglycerol and the pathways by which membrane phospholipids are synthesized. Physiological functions affected by PAP activity include phospholipid synthesis gene expression, nuclear/endoplasmic reticulum membrane growth, lipid droplet formation, and vacuole homeostasis and fusion. Yeast lacking Pah1p PAP activity are acutely sensitive to fatty acid-induced toxicity and exhibit respiratory deficiency. PAP is distinguished in its cellular location, catalytic mechanism, and physiological functions from Dpp1p and Lpp1p lipid phosphate phosphatases that utilize a variety of substrates that include phosphatidate. Phosphorylation/dephosphorylation is a major mechanism by which Pah1p PAP activity is regulated. Pah1p is phosphorylated by cytosolic-associated Pho85p–Pho80p, Cdc28p-cyclin B, and protein kinase A and is dephosphorylated by the endoplasmic reticulum-associated Nem1p–Spo7p phosphatase. The dephosphorylation of Pah1p stimulates PAP activity and facilitates the association with the membrane/phosphatidate allowing for its reaction and triacylglycerol synthesis. This article is part of a Special Issue entitled Phospholipids and Phospholipid Metabolism.► PAP catalyzes the penultimate step in triacylglycerol synthesis. ► PAP plays a crucial role in lipid homeostasis and cell physiology. ► Multiple protein kinases phosphorylate PAP. ► Nem1p-Spo7p dephosphorylates PAP. ► Phosphorylation/dephosphorylation regulates PAP function.
Keywords: Abbreviations; TAG; triacylglycerol; DAG; diacylglycerol; PA; phosphatidate; PAP; PA phosphatase; PC; phosphatidylcholine; PE; phosphatidylethanolamine; PI; phosphatidylinositol; PS; phosphatidylserine; CDP-DAG; CDP-diacylglycerol; CL; cardiolipin; DGPP; diacylglycerol pyrophosphate; ER; endoplasmic reticulum; NEM; N; -ethylmaleimide; UAS; INO; inositol-responsive upstream activating sequenceLipid synthesis; Triacylglycerol; Phosphatidate; Diacylglycerol; Phosphatidate phosphatase; Lipid phosphate phosphatase
Phosphatidylcholine and the CDP–choline cycle
by Paolo Fagone; Suzanne Jackowski (pp. 523-532).
The CDP–choline pathway of phosphatidylcholine (PtdCho) biosynthesis was first described more than 50years ago. Investigation of the CDP–choline pathway in yeast provides a basis for understanding the CDP–choline pathway in mammals. PtdCho is considered as an intermediate in a cycle of synthesis and degradation, and the activity of a CDP–choline cycle is linked to subcellular membrane lipid movement. The components of the mammalian CDP–choline pathway include choline transport, choline kinase, phosphocholine cytidylyltransferase, and choline phosphotransferase activities. The protein isoforms and biochemical mechanisms of regulation of the pathway enzymes are related to their cell‐ and tissue-specific functions. Regulated PtdCho turnover mediated by phospholipases or neuropathy target esterase participates in the mammalian CDP–choline cycle. Knockout mouse models define the biological functions of the CDP–choline cycle in mammalian cells and tissues. This article is part of a Special Issue entitled Phospholipids and Phospholipid Metabolism.► The yeast CDP–choline pathway provides a basis for the mammalian pathway. ► The elements of the CDP–choline pathway are related to their cellular functions. ► The CDP–choline cycle is regulated and linked to membrane movement.
Keywords: Phospholipid; Phosphatidycholine; Mammalian lipid metabolism
The ins and outs of phosphatidylethanolamine synthesis in Trypanosoma brucei
by Luce Farine; Butikofer Peter Bütikofer (pp. 533-542).
Phospholipids are not only major building blocks of biological membranes but fulfill a wide range of critical functions that are often widely unrecognized. In this review, we focus on phosphatidylethanolamine, a major glycerophospholipid class in eukaryotes and bacteria, which is involved in many unexpected biological processes. We describe (i) the ins, i.e. the substrate sources and biochemical reactions involved in phosphatidylethanolamine synthesis, and (ii) the outs, i.e. the different roles of phosphatidylethanolamine and its involvement in various cellular events. We discuss how the protozoan parasite, Trypanosoma brucei, has contributed and may contribute in the future as eukaryotic model organism to our understanding of phosphatidylethanolamine homeostasis. This article is part of a Special Issue entitled Phospholipids and Phospholipid Metabolism.► The substrates and pathways for PE synthesis differ considerably among organisms. ► PE is not only a membrane component but also a substrate for many cellular events. ► T. brucei is a valuable model eukaryote to study the many roles of PE. ► Depletion of PE in T. brucei results in morphological changes and parasite death
Keywords: Abbreviations; PE; phosphatidylethanolamine; PC; phosphatidylcholine; PS; phosphatidylserine; PI; phosphatidylinositol; SM; sphingomyelin; IPC; inositolphosphoryl ceramide; EPC; ethanolaminephosphoryl ceramide; EPT; ethanolamine phosphotransferase; CEPT; choline/ethanolamine phosphotransferase; PSD; PS decarboxylase; NAE; N; -acylethanolamine; GPI; glycosylphosphatidylinositol; eEF1A; eukaryotic elongation factor 1A; EPG; ethanolamine phosphoglycerol; LPS; lipopolysaccharide; DAG; diacylglycerol; AAG; alk-1-enyl-acylglycerolPhosphatidylethanolamine; Biosynthesis; Function; Trypanosoma brucei; Phospholipid
Formation and function of phosphatidylserine and phosphatidylethanolamine in mammalian cells
by Jean E. Vance; Guergana Tasseva (pp. 543-554).
Phosphatidylserine (PS) and phosphatidylethanolamine (PE) are metabolically related membrane aminophospholipids. In mammalian cells, PS is required for targeting and function of several intracellular signaling proteins. Moreover, PS is asymmetrically distributed in the plasma membrane. Although PS is highly enriched in the cytoplasmic leaflet of plasma membranes, PS exposure on the cell surface initiates blood clotting and removal of apoptotic cells. PS is synthesized in mammalian cells by two distinct PS synthases that exchange serine for choline or ethanolamine in phosphatidylcholine (PC) or PE, respectively. Targeted disruption of each PS synthase individually in mice demonstrated that neither enzyme is required for viability whereas elimination of both synthases was embryonic lethal. Thus, mammalian cells require a threshold amount of PS. PE is synthesized in mammalian cells by four different pathways, the quantitatively most important of which are the CDP-ethanolamine pathway that produces PE in the ER, and PS decarboxylation that occurs in mitochondria. PS is made in ER membranes and is imported into mitochondria for decarboxylation to PE via a domain of the ER [mitochondria-associated membranes (MAM)] that transiently associates with mitochondria. Elimination of PS decarboxylase in mice caused mitochondrial defects and embryonic lethality. Global elimination of the CDP-ethanolamine pathway was also incompatible with mouse survival. Thus, PE made by each of these pathways has independent and necessary functions. In mammals PE is a substrate for methylation to PC in the liver, a substrate for anandamide synthesis, and supplies ethanolamine for glycosylphosphatidylinositol anchors of cell-surface signaling proteins. Thus, PS and PE participate in many previously unanticipated facets of mammalian cell biology. This article is part of a Special Issue entitled Phospholipids and Phospholipid Metabolism.► The biosynthesis and functions of PS in mammalian cells are reviewed. ► The transport of PS to mitochondria via mitochondria-associated membranes is discussed. ► 4 Pathways for mammalian PE biosynthesis are reviewed.
Keywords: Abbreviations; CHO; Chinese hamster ovary; ER; endoplasmic reticulum; ET; CTP:phosphoethanolamine cytidylyltransferase; MAM; mitochondria-associated membranes; PC; phosphatidylcholine; PE; phosphatidylethanolamine; PS; phosphatidylserine; PSD; phosphatidylserine decarboxylase; PSS; PS synthaseMitochondria; Mitochondria-associated membranes; Knock-out mice
Mammalian P4-ATPases and ABC transporters and their role in phospholipid transport
by Jonathan A. Coleman; Faraz Quazi; Robert S. Molday (pp. 555-574).
Transport of phospholipids across cell membranes plays a key role in a wide variety of biological processes. These include membrane biosynthesis, generation and maintenance of membrane asymmetry, cell and organelle shape determination, phagocytosis, vesicle trafficking, blood coagulation, lipid homeostasis, regulation of membrane protein function, apoptosis, etc. P4-ATPases and ATP binding cassette (ABC) transporters are the two principal classes of membrane proteins that actively transport phospholipids across cellular membranes. P4-ATPases utilize the energy from ATP hydrolysis to flip aminophospholipids from the exocytoplasmic (extracellular/lumen) to the cytoplasmic leaflet of cell membranes generating membrane lipid asymmetry and lipid imbalance which can induce membrane curvature. Many ABC transporters play crucial roles in lipid homeostasis by actively transporting phospholipids from the cytoplasmic to the exocytoplasmic leaflet of cell membranes or exporting phospholipids to protein acceptors or micelles. Recent studies indicate that some ABC proteins can also transport phospholipids in the opposite direction. The importance of P4-ATPases and ABC transporters is evident from the findings that mutations in many of these transporters are responsible for severe human genetic diseases linked to defective phospholipid transport. This article is part of a Special Issue entitled Phospholipids and Phospholipid Metabolism.Display Omitted► Up to date review on phospholipid transport across cell membranes ► Review of the role of P4-ATPases in the flipping of aminophospholipids across cell membranes ► Review of the role of ABC transporters in the efflux and flipping of phospholipids across cell membranes ► Overview of the role of P4-ATases and ABC transporters in various cellular processes and diseases
Keywords: Phospholipid transport; P; 4; -ATPases; ABC transporters; Lipid homeostasis; Lipid transport diseases; Membrane asymmetry
Phospholipid metabolism and nuclear function: Roles of the lipin family of phosphatidic acid phosphatases
by Symeon Siniossoglou (pp. 575-581).
Phospholipids play important roles in nuclear function as dynamic building blocks for the biogenesis of the nuclear membrane, as well as signals by which the nucleus communicates with other organelles, and regulate a variety of nuclear events. The mechanisms underlying the nuclear roles of phospholipids remain poorly understood. Lipins represent a family of phosphatidic acid (PA) phosphatases that are conserved from yeasts to humans and perform essential functions in lipid metabolism. Several studies have identified key roles for lipins and their regulators in nuclear envelope organization, gene expression and the maintenance of lipid homeostasis in yeast and metazoans. This review discusses recent advances in understanding the roles of lipins in nuclear structure and function. This article is part of a Special Issue entitled Phospholipids and Phospholipid Metabolism.► Phospholipids play critical roles in nuclear structure and function. ► The lipin PA phosphatases localize to the cytoplasm and nucleus of many cell types. ► Lipins regulate gene expression of lipid metabolic enzymes through multiple mechanisms. ► Lipins play critical roles in nuclear architecture in many eukaryotes. ► Nuclear lipins may be important for the maintenance of cellular lipid homeostasis.
Keywords: Abbreviations; CDP-DAG; cytidine diphosphate diacylglycerol; DAG; diacylglycerol; ER; endoplasmic reticulum; mTORC; mammalian target of rapamycin complex; NES; nuclear export signal; NLS; nuclear localization signal; NEBD; nuclear envelope breakdown; PA; phosphatidic acid; PC; phosphatidylcholine; PE; phosphatidylethanolamine; PGC; peroxisome proliferator-activated receptor gamma co-activator; PI; phosphatidylinositol; PI-PLC; phosphatidylinositol-specific phospholipase C; PPAR; peroxisome proliferator-activated repressor; SREBP; sterol regulatory element-binding protein; TAG; triacylglycerol; UAS; INO; inositol-responsive upstream activating sequencePhosphatidic acid; Phosphatidic acid phosphatase; Lipin; Nucleus; Nuclear envelope; Nuclear lipids
Cardiolipin remodeling and the function of tafazzin
by Michael Schlame (pp. 582-588).
Cardiolipin, the specific phospholipid of mitochondria, is involved in the biogenesis, the dynamics, and the supramolecular organization of mitochondrial membranes. Cardiolipin acquires a characteristic composition of fatty acids by post-synthetic remodeling, a process that is crucial for cardiolipin homeostasis and function. The remodeling of cardiolipin depends on the activity of tafazzin, a non-specific phospholipid–lysophospholipid transacylase. This review article discusses recent findings that suggest a novel function of tafazzin in mitochondrial membranes. By shuffling fatty acids between molecular species, tafazzin transforms the lipid composition and by doing so supports changes in the membrane conformation, specifically the generation of membrane curvature. Tafazzin activity is critical for the differentiation of cardiomyocytes, in which the characteristic cristae-rich morphology of cardiac mitochondria evolves. This article is part of a Special Issue entitled Phospholipids and Phospholipid Metabolism.► Tafazzin is a non-specific phospholipid–lysophospholipid transacylase. ► Tafazzin senses curvature. ► Tafazzin modifies the acyl composition of cardiolipin.
Keywords: Cardiolipin; Mitochondrion; Molecular species; Tafazzin; Thermodynamics
Phospholipids and lipid droplets
by Anke Penno; Gregor Hackenbroich; Christoph Thiele (pp. 589-594).
Lipid droplets are ubiquitous cellular organelles that allow cells to store large amounts of neutral lipids for membrane synthesis and energy supply in times of starvation. Compared to other cellular organelles, lipid droplets are structurally unique as they are made of a hydrophobic core of neutral lipids and are separated to the cytosol only by a surrounding phospholipid monolayer. This phospholipid monolayer consists of over a hundred different phospholipid molecular species of which phosphatidylcholine is the most abundant lipid class. However, lipid droplets lack some indispensable activities of the phosphatidylcholine biogenic pathways suggesting that they partially depend on other organelles for phosphatidylcholine synthesis.Here, we discuss very recent data on the composition, origin, transport and function of the phospholipid monolayer with a particular emphasis on the phosphatidylcholine metabolism on and for lipid droplets. In addition, we highlight two very important quantitative aspects: (i) The amount of phospholipid required for lipid droplet monolayer expansion is remarkably small and (ii) to maintain the invariably round shape of lipid droplets, a cell must have a highly sensitive but so far unknown mechanism that regulates the ratio of phospholipid to neutral lipid in lipid droplets. This article is part of a Special Issue entitled Phospholipids and Phospholipid Metabolism.► Lipid droplets are surrounded by phospholipid monolayers. ► Biosynthesis of droplet phospholipids occurs at different sites. ► The amount of droplet phospholipid is tightly regulated. ► Geometrical factors determine the ratio of phospholipid and neutral lipid.
Keywords: Lipid droplet; Phosphatidylcholine; Steatosis
PAFAH Ib phospholipase A2 subunits have distinct roles in maintaining Golgi structure and function
by Marie E. Bechler; William J. Brown (pp. 595-601).
Recent studies showed that the phospholipase subunits of Platelet Activating Factor Acetylhydrolase (PAFAH) Ib, α1 and α2 partially localize to the Golgi complex and regulate its structure and function. Using siRNA knockdown of individual subunits, we find that α1 and α2 perform overlapping and unique roles in regulating Golgi morphology, assembly, and secretory cargo trafficking. Knockdown of either α1 or α2 reduced secretion of soluble proteins, but neither single knockdown reduced secretion to the same degree as knockdown of both. Knockdown of α1 or α2 inhibited reassembly of an intact Golgi complex to the same extent as knockdown of both. Transport of VSV-G was slowed but at different steps in the secretory pathway: reduction of α1 slowed trans Golgi network to plasma membrane transport, whereas α2 loss reduced endoplasmic reticulum to Golgi trafficking. Similarly, knockdown of either subunit alone disrupted the Golgi complex but with markedly different morphologies. Finally, knockdown of α1, or double knockdown of α1 and α2, resulted in a significant redistribution of kinase dead protein kinase D from the Golgi to the plasma membrane, whereas loss of α2 alone had no such effect. These studies reveal an unexpected complexity in the regulation of Golgi structure and function by PAFAH Ib. This article is part of a Special Issue entitled Phospholipids and Phospholipid Metabolism.► PLA2 regulation of the Golgi complex is more complicated than previously expected ► PAFAH Ib α1 and α2 have overlapping and unique roles in regulating the Golgi complex ► Loss of α1 or α2 have different effects on Golgi morphology and function
Keywords: PLA; 2; PAFAH Ib; Golgi complex; Secretory trafficking
Drug induced phospholipidosis: An acquired lysosomal storage disorder
by James A. Shayman; Akira Abe (pp. 602-611).
There is a strong association between lysosome enzyme deficiencies and monogenic disorders resulting in lysosomal storage disease. Of the more than 75 characterized lysosomal proteins, two thirds are directly linked to inherited diseases of metabolism. Only one lysosomal storage disease, Niemann–Pick disease, is associated with impaired phospholipid metabolism. However, other phospholipases are found in the lysosome but remain poorly characterized. A recent exception is lysosomal phospholipase A2 (group XV phospholipase A2). Although no inherited disorder of lysosomal phospholipid metabolism has yet been associated with a loss of function of this lipase, this enzyme may be a target for an acquired form of lysosomal storage, drug induced phospholipidosis. This article is part of a Special Issue entitled Phospholipids and Phospholipid Metabolism.► Lysosomal storage diseases may be either inherited or acquired. ► Drug induced phospholipidosis is a form of acquired lysosomal storage disease. ► The mechanism for and pathological significance of phospholipidosis is not well understood. ► LPLA2 is a recently characterized lysosomal hydrolase. ► LPLA2 is a target for amiodarone induced phospholipidosis.
Keywords: Abbreviations; BMP; bis(monoacylglycero)phosphate; CAD; cationic amphiphilic drug; DIP; drug induced phospholipidosis; GXVPLA2; group XV phospholipase A2; LPLA2; lysosomal phospholipase A2; MDCK; Madin Darby canine kidney; PDMP; d; -; threo; -1-phenyl-2-decanoylamino-3-morpholino-propanolLysosome; Phospholipase A2; Drug induced phospholipidosis; Cationic amphiphilic drug; Amiodarone
Surfactant phospholipid metabolism
by Marianna Agassandian; Rama K. Mallampalli (pp. 612-625).
Pulmonary surfactant is essential for life and is composed of a complex lipoprotein-like mixture that lines the inner surface of the lung to prevent alveolar collapse at the end of expiration. The molecular composition of surfactant depends on highly integrated and regulated processes involving its biosynthesis, remodeling, degradation, and intracellular trafficking. Despite its multicomponent composition, the study of surfactant phospholipid metabolism has focused on two predominant components, disaturated phosphatidylcholine that confers surface-tension lowering activities, and phosphatidylglycerol, recently implicated in innate immune defense. Future studies providing a better understanding of the molecular control and physiological relevance of minor surfactant lipid components are needed. This article is part of a Special Issue entitled Phospholipids and Phospholipid Metabolism.► Surfactant is composed of key phospholipids and proteins. ► Surfactant lipid components control lung stability and immunity. ► Availability of surfactant is reduced in acute and chronic lung disease. ► Studies are needed to understand the molecular regulation of phospholipid enzymes.
Keywords: Abbreviations; ABC; ATP-binding cassette transporter; ARDS; acute respiratory distress syndrome; CCT-CTP; phosphocholine cytidylyltransferase; CDP-choline; cytidine diphosphocholine; CDP-DAG; CDP-diacylglycerol; CDS-CDP; diacylglycerol synthase; CK; choline kinase; CL; cardiolipin; CPT; choline phosphotransferase; DAG; diacylglycerol; DAGK; DAG kinase; DHAP; dihydroxyacetone phosphate; DSPC; disaturated PC; DPPC; dipalmitoylphosphatidylcholine; ECT-CTP; phosphoethanolamine cytidylyltransferase; EK; ethanolamine kinase; EPT; ethanolaminephosphotransferase; ER; endoplasmic reticulum; FA; fatty acids; FAS; fatty acid synthase; GA; Golgi apparatus; GM-CSF; granulocyte-macrophage colony-stimulating factor; G3P; glycerol-3 phosphate; LPCAT1; lysophosphatidylcholine acyltransferase 1; Lyso-PA; lysophosphatidic acid; KGF; keratinocyte growth factor; LA; large aggregates; LB; lamellar bodies; NES; nuclear export signal; NLS; nuclear localization signal; PA; phosphatidic acid; PAP; PA phosphatase; PC; phosphatidylcholine; PE; phosphatidylethanolamine; PG; phosphatidylglycerol; PI; phosphatidylinositol; PI-PLC; phosphoinositide-specific phospholipase C; PLA; 2; phospholipase A; 2; PLD; phospholipase D; PL; phospholipids; POPG; palmitoyl-oleoyl phosphatidylglycerol; PPARγ; peroxisome proliferator-activated receptor γ; PPI-PLC; phosphoinositide-specific phospholipase C; PSR; phosphatidylserine receptor; PSS; PS synthase; SA; small aggregates; SMS; sphingomyelin synthase; SM; sphingomyelin; SP-A; surfactant protein A; SP-B; surfactant protein B; SP-C; surfactant protein C; SP-D; surfactant protein D; TGF-β1; transforming growth factor β1; TM; tubular myelin; V-ATPase; vacuolar ATPaseSurfactant; Apoprotein; Phospholipid
Physiological roles of phosphatidylethanolamine N-methyltransferase
by Dennis E. Vance (pp. 626-632).
Phosphatidylethanolamine N-methyltransferase (PEMT) catalyzes the methylation of phosphatidylethanolamine to phosphatidylcholine (PC). This 22.3kDa protein is localized to the endoplasmic reticulum and mitochondria associated membranes of liver. The supply of the substrates AdoMet and phosphatidylethanolamine, and the product AdoHcy, can regulate the activity of PEMT. Estrogen has been identified as a positive activator, and Sp1 as a negative regulator, of transcription of the PEMT gene. Targeted inactivation of the PEMT gene produced mice that had a mild phenotype when fed a chow diet. However, when Pemt−/− mice were fed a choline-deficient diet steatohepatitis and liver failure developed after 3days. The steatohepatitis was due to a decreased ratio of PC to phosphatidylethanolamine that caused leakage from the plasma membrane of hepatocytes. Pemt−/− mice exhibited attenuated secretion of very low-density lipoproteins and homocysteine. Pemt−/− mice bred with mice that lacked the low-density lipoprotein receptor, or apolipoprotein E were protected from high fat/high cholesterol-induced atherosclerosis. Surprisingly, Pemt−/− mice were protected from high fat diet-induced obesity and insulin resistance compared to wildtype mice. If the diet were supplemented with additional choline, the protection against obesity/insulin resistance in Pemt−/− mice was eliminated. Humans with a Val-to-Met substitution in PEMT at residue 175 may have increased susceptibility to nonalcoholic liver disease. This article is part of a Special Issue entitled Phospholipids and Phospholipid Metabolism.► Lack of PEMT protects against atherosclerosis and lipotoxic cardiac dysfunction. ► Lack of PEMT protects against obesity and insulin resistance. ► The PEMT reaction is important for formation of choline and homocysteine. ► Lack of PEMT and dietary choline results in liver failure in 3days.
Keywords: Abbreviations; AdoMet; S; -adenosylmethionine; AdoHcy; S; -adenosylhomocysteine; CT; CTP:phosphocholine cytidylyltransferase; DHA; docosahexaenoic acid; ER; endoplasmic reticulum; Hcy; homocysteine; LCTαKO; liver-specific CTα knockout; PC; phosphatidylcholine; PE; phosphatidylethanolamine; PEMT; phosphatidylethanolamine; N; -methyltransferase; TG; triacylglycerol; VLDL; very low density lipoproteinsPhosphatidylcholine; Phosphatidylethanolamine; Obesity; Steatosis; Atherosclerosis; Choline
Neuronal phospholipid deacylation is essential for axonal and synaptic integrity
by Paul Glynn (pp. 633-641).
Recessively-inherited deficiency in the catalytic activity of calcium-independent phospholipase A2-beta (iPLA2β) and neuropathy target esterase (NTE) causes infantile neuroaxonal dystrophy and hereditary spastic paraplegia, respectively. Thus, these two related phospholipases have non-redundant functions that are essential for structural integrity of synapses and axons. Both enzymes are expressed in essentially all neurons and also have independent roles in glia. iPLA2β liberates sn-2 fatty acid and lysophospholipids from diacyl-phospholipids. Ca2+-calmodulin tonically-inhibits iPLA2β, but this can be alleviated by oleoyl-CoA. Together with fatty acyl-CoA-mediated conversion of lysophospholipid to diacyl-phospholipid this may regulate sn-2 fatty acyl composition of phospholipids. In the nervous system, iPLA2β is especially important for the turnover of polyunsaturated fatty acid-associated phospholipid at synapses. More information is required on the interplay between iPLA2β and iPLA2‐gamma in deacylation of neuronal mitochondrial phospholipids. NTE reduces levels of phosphatidylcholine (PtdCho) by degrading it to glycerophosphocholine and two free fatty acids. The substrate for NTE may be nascent PtdCho complexed with a phospholipid-binding protein. Protein kinase A-mediated phosphorylation enhances PtdCho synthesis and may allow PtdCho accumulation by coordinate inhibition of NTE activity. NTE operates primarily at the endoplasmic reticulum in neuronal soma but is also present in axons. NTE-mediated PtdCho homeostasis facilitates membrane trafficking and this appears most critical for the integrity of axon terminals in the spinal cord and hippocampus. For maintenance of peripheral nerve axons, iPLA2β activity may be able to compensate for NTE-deficiency but not vice-versa. Whether agonists acting at neuronal receptors modulate the activity of either enzyme remains to be determined. This article is part of a Special Issue entitled Phospholipids and Phospholipid Metabolism.► Genetic deficiency of iPLA2β or NTE causes neurological disease. ► iPLA2β and NTE phospholipase activities maintain synaptic and axonal integrity. ► iPLA2β mediates synaptic PUFA-associated phospholipid turnover. ► NTE mediates phosphatidylcholine homeostasis.
Keywords: Neurological disease; Axon degeneration; Phospholipid turnover
Phospholipids: “Greasing the wheels” of humoral immunity
by Joseph W. Brewer (pp. 642-651).
Phospholipids are major structural components of all cellular membranes. In addition, certain phospholipids execute regulatory activities that affect cell behavior, function and fate in critically important physiological settings. The influence of phospholipids is especially obvious in the adaptive immune system, where these macromolecules mediate both intrinsic and extrinsic effects on B and T lymphocytes. This review article highlights the action of lysophospholipid sphingosine-1-phosphate as a lymphocyte chemoattractant, the function of phosphatidylinositol phosphates as signaling conduits in lymphocytes and the role of phospholipids as raw materials for membrane assembly and organelle biogenesis in activated B lymphocytes. Special emphasis is placed on the means by which these three processes push humoral immune responses forward. This article is part of a Special Issue entitled Phospholipids and Phospholipid Metabolism.► Diverse roles of phospholipids in the generation of humoral immunity are discussed. ► Sphingosine-1-phosphate is a major chemoattractant for B and T cells. ► Phosphatidylinositol phosphates are vital signaling conduits in B and T cells. ► Phospholipids are key for proliferation and differentiation of activated B cells.
Keywords: Abbreviations; AP-1; activator protein-1; BLNK; B cell linker protein; BTK; Bruton's tyrosine kinase; CCT; choline cytidylyltransferase; CDP-choline; cytidine diphosphocholine; CEPT1; choline/ethanolamine phosphotransferase 1; Cer; ceramide; CK; choline kinase; CPT1; choline phosphotransferase 1; CRAC; Ca; 2; +; -release activated entry channel; DAG; diacylglycerol; ER; endoplasmic reticulum; ERK; extracellular signal-regulated kinase; FA; fatty acid; FOXO; forkhead box subgroup O; FDC; follicular dendritic cell; H; heavy chain; T; H; helper T cell; Ig; immunoglobulin; InsP; 3; inositol(1,4,5)-trisphosphate; IRE1; inositol requiring enzyme 1; ITAM; immunoreceptor tyrosine-based activation motif; KLF; Kruppel-like factor; LPS; lipopolysaccharide; MEK; mitogen-activated protein kinase/ERK kinase; NFAT; nuclear factor of activated T cells; NF-κB; nuclear factor-kappa B; PH; pleckstrin homology; PLCγ2; phospholipase Cγ2; PKCβ; protein kinase Cβ; PtdCho; phosphatidylcholine; PtdEtn; phosphatidylethanolamine; PtdIns; phosphatidylinositol; PtdIns(4,5)P; 2; PtdIns 4,5-bisphosphate; PtdIns(3,4,5)P; 3; PtdIns 3,4,5-trisphosphate; PI-4K; PtdIns 4-kinase; PIP5K; PtdIns(4)P-5-kinase; PI3K; PtdIns 3-kinase; PTEN; phosphatase and tensin homolog deleted on chromosome ten; RASGRP; Ras guanyl nucleotide releasing protein; SM; sphingomyelin; S1P; sphingosine-1-phosphate; S1PR; S1P-receptor; Ser; serine; SH2; Src-homology 2 domain; SLP-65; SH2-containing leucocyte protein of 65; kDa; SHIP; SH2-containing inositol phosphatase; SPHK; sphingosine kinase; STIM1; stromal interaction molecule 1; TCR; T cell antigen receptor; Thr; threonine; TLR; Toll-like receptor; UPR; unfolded protein response; XBP1; X-box binding protein 1Phospholipid; B lymphocyte; Plasma cell; Antibody
N-acylation of phosphatidylethanolamine and its biological functions in mammals
by Niels Wellner; Thi Ai Diep; Christian Janfelt; Harald Severin Hansen (pp. 652-662).
N-acylphosphatidylethanolamine (NAPE) and N-acylplasmenylethanolamine (pNAPE) are widely found phospholipids, and they are precursors for N-acylethanolamines, a group of compounds that has a variety of biological effects and encompasses the endocannabinoid anandamide. NAPE and pNAPE are synthesized by the transfer of an acyl chain from a donor phospholipid, to the amine in phosphatidylethanolamine or plasmenylethanolamine. NAPE has been reported to stabilize model membranes during brain ischemia, and to modulate food intake in rodents, thus having bioactive effects besides its precursor role. This paper reviews the metabolism, occurrence and assay of NAPE and pNAPE, and discusses the putative biological functions in mammals of these phospholipids. This article is part of a Special Issue entitled Phospholipids and Phospholipid Metabolism.► N-acylphosphatidylethanolamines (NAPE) are precursors for bioactive acylethanolamides. ► NAPE may have membrane stabilizing effects. ► NAPE turnover may influence cholesterol localization in membranes. ► NAPE has been suggested to be an anorectic hormone, but new data questions this role.
Keywords: Abbreviations; NAE; N; -acylethanolamine; PA; phosphatidic acid; OEA; N; -oleoylethanolamine; PEA; N; -palmitoylethanolamine; LEA; N; -linoleoylethanolamine; AEA; N; -arachidonoylethanolamine; SEA; N; -stearoylethanolamine; NAPE; N; -acylphosphatidylethanolamine; pNAPE; N; -acylplasmenylethanolamine; NAPE-PLD; N; -acylphosphatidylethanolamine phospholipase D; PC; phosphatidylcholine; NAT; N; -acyltransferase; 20:4; arachidonic acid; 18:1; oleic acid; 16:0; palmitic acid; PE; phosphatidylethanolamine; RLP-1; rat lecithin-retinol acyltransferase-like protein 1; DAG; diacylglycerol; PLD; phospholipase D; PLC; phospholipase C; Abh4; serine hydrolase α/β-hydrolase 4; GP-NAE; glycerophospho-; N; -acylethanolamine; GDE1; glycerophosphodiester phosphodiesterase 1; PI; phosphatidylinositol; PS; phosphatidylserine; Q-TOF; quadropole time-of-flight; ESI; electrospray ionization; DESI; desorption electrospray ionization; MALDI; matrix assisted laser desorption ionization; DPPC; di-palmitoylphosphatidylcholine; MC4R; melanocortin receptor-4; I.p.; intraperitoneal N; -acylphosphatidylethanolamine; N; -acylphosphatidylethanolamine-hydrolyzing phospholipase D; N; -acyltransferase; Phospholipid; N; -acylplasmenylethanolamine; Food intake
Anticancer mechanisms and clinical application of alkylphospholipids
by Wim J. van Blitterswijk; Marcel Verheij (pp. 663-674).
Synthetic alkylphospholipids (ALPs), such as edelfosine, miltefosine, perifosine, erucylphosphocholine and erufosine, represent a relatively new class of structurally related antitumor agents that act on cell membranes rather than on DNA. They selectively target proliferating (tumor) cells, inducing growth arrest and apoptosis, and are potent sensitizers of conventional chemo- and radiotherapy. ALPs easily insert in the outer leaflet of the plasma membrane and cross the membrane via an ATP-dependent CDC50a-containing ‘flippase’ complex (in carcinoma cells), or are internalized by lipid raft-dependent endocytosis (in lymphoma/leukemic cells). ALPs resist catabolic degradation, therefore accumulate in the cell and interfere with lipid-dependent survival signaling pathways, notably PI3K-Akt and Raf-Erk1/2, and de novo phospholipid biosynthesis. At the same time, stress pathways (e.g. stress-activated protein kinase/JNK) are activated to promote apoptosis. In many preclinical and clinical studies, perifosine was the most effective ALP, mainly because it inhibits Akt activity potently and consistently, also in vivo. This property is successfully exploited clinically in highly malignant tumors, such as multiple myeloma and neuroblastoma, in which a tyrosine kinase receptor/Akt pathway is amplified. In such cases, perifosine therapy is most effective in combination with conventional anticancer regimens or with rapamycin-type mTOR inhibitors, and may overcome resistance to these agents. This article is part of a Special Issue entitled Phospholipids and Phospholipid Metabolism.► Alkylphospholipids (ALPs) inhibit PI3K-Akt, Raf-Erk1/2 pathways and PC biosynthesis. ► Cells internalize ALPs via CDC50a flippase and via raft-mediated endocytosis. ► ALPs activate stress pathways and induce apoptosis in proliferating cells. ► ALP (perifosine) sensitizes rapamycin- and traditional chemo- and radiotherapy. ► Akt inhibitor perifosine overcomes tumor cell resistance to other anticancer agents.
Keywords: Abbreviations; ALP; alkylphospholipid; ASK1; apoptosis signal-regulating kinase 1; CT; CTP:phosphocholine cytidylyltransferase; DISC; death-inducing signaling complex; EGF; epidermal growth factor; ER; endoplasmic reticulum; ERK; extracellular-signal-regulated kinase; JNK; c-Jun N-terminal kinase; ErPC; erucylphosphocholine; ErPC3; erucylphosphohomocholine (erufosine); FADD; Fas-associated protein with death domain; c-FLIP; L; cellular FLICE (FADD-like interleukin 1β-converting enzyme)-inhibitory protein long form; MAPK; mitogen-activated protein kinase; MM; multiple myeloma; PC; phosphatidylcholine; PI; phosphatidylinositol; PIP; 2; phosphatidylinositol-4,5 bisphosphate; PIP; 3; phosphatidylinositol-3,4,5 trisphosphate; PI3K; phosphatidylinositol 3-kinase; PH; pleckstrin homology domain; PLC; phospholipase C; PKD; protein kinase D; ROS; reactive oxygen species; SAPK; Stress-activated protein kinase; SHIP-1; SH2 (Src homology 2)-domain-containing inositol phosphatase-1; SMS; sphingomyelin synthase; mTOR; mammalian target of rapamycin; TNF; tumor necrosis factor; TRAIL; TNF-related apoptosis-inducing ligandAlkylphospholipid; Perifosine; Akt; Chemo-/radiosensitization; Anticancer therapy; Lipid-dependent signaling
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