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BBA - Molecular and Cell Biology of Lipids (v.1771, #3)
Special issue: Regulation of lipid metabolism in yeast
by George M. Carman; Susan A. Henry (pp. 239-240).
The emergence of yeast lipidomics by Maria L. Gaspar; Manuel A. Aregullin; Stephen A. Jesch; Lilia R. Nunez; Manuel Villa-García; Susan A. Henry (pp. 241-254).
The emerging field of lipidomics, driven by technological advances in lipid analysis, provides greatly enhanced opportunities to characterize, on a quantitative or semi-quantitative level, the entire spectrum of lipids, or lipidome, in specific cell types. When combined with advances in other high throughput technologies in genomics and proteomics, lipidomics offers the opportunity to analyze the unique roles of specific lipids in complex cellular processes such as signaling and membrane trafficking. The yeast system offers many advantages for such studies, including the relative simplicity of its lipidome as compared to mammalian cells, the relatively high proportion of structural and regulatory genes of lipid metabolism which have been assigned and the excellent tools for molecular genetic analysis that yeast affords. The current state of application of lipidomic approaches in yeast and the advantages and disadvantages of yeast for such studies are discussed in this report.
Keywords: Abbreviations; ESI; electrospray ionization; MALDI; matrix assisted laser desorption ionization; PKC; protein kinase C; Cho; choline; Cho-P; choline phosphate; DAG; diacylglycerol; CDP-DAG; cytidinediphosphate diacylglycerol; CDP-Cho; cytidinediphosphate choline; Etn; ethanolamine; Glu; glucose; Glu-6-P; glucose 6-phosphate; Gro-3-P; glycerol-3-phosphate; Ins; inositol; Ins-3-P; inositol-3-phosphate; IP; 3; inositol trisphosphate; IP; 4; inositol tetrakisphosphate; IP; 5; inositol pentakisphosphate; IP; 6; inositol hexakisphosphate; Lyso-PtdOH; lysophosphatidic acid; PtdIns; phosphatidylinositol; PI(4)P; phosphatidylinositol 4-phosphate; PI(4,5)P; 2; phosphatidylinositol 4,5-biphosphate; PtdCho; phosphatidylcholine; PtdEtn; phosphatidylethanolamine; PtdOH; phosphatidic acid; PtdSer; phosphatidylserine; DMPtdCho; 1,2-dimyristoyl-; sn; -glycero-3-phosphocholine; GPI; glycosylphosphatidylinositol; ER; endoplasmic reticulum; UPR; unfolded protein response pathway; AMPK; AMP-dependent kinase; LORE, low oxygen response element; SREBP; sterol regulatory-element binding protein; GFP; green fluorescent protein; ESI-MS/MS; electrospray ionization tandem mass spectrometry; TAG; triacylglycerols; HMG-CoA; hydroxymethylglutaryl coenzyme ALipidomics; Yeast; Phospholipids; Inositol; Lipid remodeling; Signaling
Fatty acid synthesis and elongation in yeast by Oksana Tehlivets; Kim Scheuringer; Sepp D. Kohlwein (pp. 255-270).
Fatty acids are essential compounds in the cell. Since the yeast Saccharomyces cerevisiae does not feed typically on fatty acids, cellular function and growth relies on endogenous synthesis. Since all cellular organelles are involved in – or dependent on – fatty acid synthesis, multiple levels of control may exist to ensure proper fatty acid composition and homeostasis. In this review, we summarize what is currently known about enzymes involved in cellular fatty acid synthesis and elongation, and discuss potential links between fatty acid metabolism, physiology and cellular regulation.
Keywords: Yeast; Saccharomyces cerevisiae; Fatty acid; Fatty acid elongation; Regulation; Lipid metabolism
Regulation of long chain unsaturated fatty acid synthesis in yeast by Charles E. Martin; Chan-Seok Oh; Yide Jiang (pp. 271-285).
Saccharomyces cerevisiae forms monounsaturated fatty acids using the ER membrane-bound Δ-9 fatty acid desaturase, Ole1p, an enzyme system that forms a double bond in saturated fatty acyl CoA substrates. Ole1p is a chimeric protein consisting of an amino terminal desaturase domain fused to cytochrome b5. It catalyzes the formation of the double bond through an oxygen-dependent mechanism that requires reducing equivalents from NADH. These are transferred to the enzyme via NADH cytochrome b5 reductase to the Ole1p cytochrome b5 domain and then to the diiron-oxo catalytic center of the enzyme. The control of OLE1 gene expression appears to mediated through the ER membrane proteins Spt23p and Mga2p. N-terminal fragments of these proteins are released by an ubiquitin/proteasome mediated proteolysis system and translocated to the nucleus where they appear to act as transcription coactivators of OLE1. OLE1 is regulated through Spt23p and Mga2p by multiple systems that control its transcription and mRNA stability in response to diverse stimuli that include nutrient fatty acids, carbon source, metal ions and the availability of oxygen.
Keywords: Abbreviation; ROS; reactive oxygen speciesFatty acid; Saccharomyces; Unsaturated fatty acid; Desaturase; Yeast; Hypoxia; Diiron-oxo
Yeast acyl-CoA synthetases at the crossroads of fatty acid metabolism and regulation by Paul N. Black; Concetta C. DiRusso (pp. 286-298).
Acyl-CoA synthetases (ACSs) are a family of enzymes that catalyze the thioesterification of fatty acids with coenzymeA to form activated intermediates, which play a fundamental role in lipid metabolism and homeostasis of lipid-related processes. The products of the ACS enzyme reaction, acyl-CoAs, are required for complex lipid synthesis, energy production via β-oxidation, protein acylation and fatty-acid dependent transcriptional regulation. ACS enzymes are also necessary for fatty acid import into cells by the process of vectorial acylation. The yeast Saccharomyces cerevisiae has four long chain ACS enzymes designated Faa1p through Faa4p, one very long chain ACS named Fat1p and one ACS, Fat2p, for which substrate specificity has not been defined. Pivotal roles have been defined for Faa1p and Faa4p in fatty acid import, β-oxidation and transcriptional control mediated by the transcription factors Oaf1p/Pip2p and Mga2p/Spt23p. Fat1p is a bifunctional protein required for fatty acid transport of long chain fatty acids, as well as activation of very long chain fatty acids. This review focuses on the various roles yeast ACS enzymes play in cellular metabolism targeting especially the functions of specific isoforms in fatty acid transport, metabolism and energy production. We will also present evidence from directed experimentation, as well as information obtained by mining the molecular biological databases suggesting the long chain ACS enzymes are required in protein acylation, vesicular trafficking, signal transduction pathways and cell wall synthesis.
Keywords: Acyl-CoA synthetase; Lipogenesis; β-oxidation; Acyl-CoA; Protein acylation; Fatty acid transport; Vectorial acylation; Yeast
Synthesis, storage and degradation of neutral lipids in yeast by Tibor Czabany; Karin Athenstaedt; Günther Daum (pp. 299-309).
The single cell eukaryote Saccharomyces cerevisiae is an attractive model to study the complex process of neutral lipid (triacylglycerol and steryl ester) synthesis, storage and turnover. In mammals, defects in the metabolism of these lipids are associated with a number of severe diseases such as atherosclerosis, obesity and type II diabetes. Since the yeast harbors many counterparts of mammalian enzymes involved in these pathways, conclusions drawn from research with the microorganism can be readily applied to the higher eukaryotic system. Here, we summarize our current knowledge of yeast neutral lipid metabolism, report about pathways and enzymes contributing to formation and degradation of triacylglycerols and steryl esters, and describe storage of these components in lipid particles. The interplay of different subcellular compartments in neutral lipid metabolism, regulatory aspects of this process and cell biological consequences of dysfunctions will be discussed.
Keywords: Abbreviations; 1-acyl DHAP; 1-acyl dihydroxyacetone phosphate; 1-acyl G-3-P; 1-acyl glycerol-3-phosphate; ACAT; acyl-CoA:cholesterol acyltransferase; AGAT; 1-acyl glycerol-3-phosphate acyltransferase; DAG; diacylglycerol; DGAT; diacylglycerol acyltransferase; DHAP; dihydroxyacetone phosphate; ER; endoplasmic reticulum; G-3-P; glycerol-3-phosphate; LCAT; lecithin:cholesterol acyltransferase; LP; lipid particle(s); PtdOH; phosphatidic acid; SE; steryl ester(s); TAG; triacylglycerol(s)Triacylglycerol; Steryl ester; Lipid particle; Acyltransferase; Lipase; Yeast
Transcriptional regulation of yeast phospholipid biosynthetic genes by Meng Chen; Leandria C. Hancock; John M. Lopes (pp. 310-321).
The last several years have been witness to significant developments in understanding transcriptional regulation of the yeast phospholipid structural genes. The response of most phospholipid structural genes to inositol is now understood on a mechanistic level. The roles of specific activators and repressors are also well established. The knowledge of specific regulatory factors that bind the promoters of phospholipid structural genes serves as a foundation for understanding the role of chromatin modification complexes. Collectively, these findings present a complex picture for transcriptional regulation of the phospholipid biosynthetic genes. The INO1 gene is an ideal example of the complexity of transcriptional control and continues to serve as a model for studying transcription in general. Furthermore, transcription of the regulatory genes is also subject to complex and essential regulation. In addition, databases resulting from a plethora of genome-wide studies have identified regulatory signals that control one of the essential phospholipid biosynthetic genes, PIS1. These databases also provide significant clues for other regulatory signals that may affect phospholipid biosynthesis. Here, we have tried to present a complete summary of the transcription factors and mechanisms that regulate the phospholipid biosynthetic genes.
Keywords: Transcription; Regulation; Chromatin modification; Chromatin remodelling; Regulators; Activators; Repressors; INO1; Basic Helix-Loop-Helix; Auto-regulation
Regulation of phospholipid synthesis in Saccharomyces cerevisiae by zinc depletion by George M. Carman; Gil-Soo Han (pp. 322-330).
The synthesis of phospholipids in the yeast Saccharomyces cerevisiae is regulated by zinc, an essential mineral required for growth and metabolism. Cells depleted of zinc contain increased levels of phosphatidylinositol and decreased levels of phosphatidylethanolamine. In addition to the major phospholipids, the levels of the minor phospholipids phosphatidate and diacylglycerol pyrophosphate decrease in the vacuole membrane of zinc-depleted cells. Alterations in phosphatidylinositol and phosphatidylethanolamine can be ascribed to an increase in PIS1-encoded phosphatidylinositol synthase activity and to decreases in the activities of CDP-diacylglycerol pathway enzymes including the CHO1-encoded phosphatidylserine synthase, respectively. Alterations in the minor vacuole membrane phospholipids are due to the induction of the DPP1-encoded diacylglycerol pyrophosphate phosphatase. These changes in the activities of phospholipid biosynthetic enzymes result from differential regulation of gene expression at the level of transcription. Under zinc-deplete conditions, the positive transcription factor Zap1p stimulates the expression of the DPP1 and PIS1 genes through the cis-acting element UASZRE. In contrast, the negative regulatory protein Opi1p, which is involved in inositol-mediated regulation of phospholipid synthesis, represses the expression of the CHO1 gene through the cis-acting element UASINO. Regulation of phospholipid synthesis may provide an important mechanism by which cells cope with the stress of zinc depletion, given the roles that phospholipids play in the structure and function of cellular membranes.
Keywords: Abbreviations; PC; phosphatidylcholine; PE; phosphatidylethanolamine; PI; phosphatidylinositol; PS; phosphatidylserine; PA; phosphatidate; CDP-DG; CDP-diacylglycerol; DGPP; diacylglycerol pyrophosphate; UAS; ZRE; upstream activating sequence zinc-responsive element; UAS; INO; upstream activating sequence inositol-responsive elementPhospholipid synthesis; Phosphatidylinositol synthase; Phosphatidylserine synthase; Transcriptional regulation; Yeast; Zinc
Phosphatidylcholine synthesis and its catabolism by yeast neuropathy target esterase 1 by J. Pedro Fernández-Murray; Christopher R. McMaster (pp. 331-336).
Phosphatidylcholine (PtdCho) is the major phospholipid component of eukaryotic membranes and deciphering the molecular mechanisms regulating PtdCho homeostasis is necessary to fully understand many pathophysiological situations where PtdCho metabolism is altered. This concept is illustrated in this review by summarizing recent evidence on Nte1p, a yeast endoplasmic reticulum resident phospholipase B that deacylates PtdCho producing intracellular glycerophosphocholine. The mammalian and Drosophila homologues, neuropathy target esterase and swiss cheese, respectively, have been implicated in normal brain development with increased intracytoplasmic vesicularization and multilayered membrane stacks as cytological signatures of their absence. Consistent with a role in lipid and membrane homeostasis, Nte1p-mediated PtdCho deacylation is strongly affected by Sec14p, a component of the yeast secretory machinery characterized by its ability to interface between lipid metabolism and vesicular trafficking. The preference of Nte1p toward PtdCho produced through the CDP–choline pathway and the downstream production of choline by the Gde1p glycerophosphodiesterase for resynthesis of PtdCho by the CDP–choline pathway are also highlighted.
Keywords: Phospholipase; Metabolism; Phosphatidylcholine; Neuropathy target esterase; Saccharomyces cerevisiae
Transport and metabolism of glycerophosphodiesters produced through phospholipid deacylation by Jana Patton-Vogt (pp. 337-342).
Phospholipid deacylation results in the formation of glycerophosphodiesters and free fatty acids. In Saccharomyces cerevisiae, four gene products with phospholipase B (deacylating) activity have been characterized ( PLB1, PLB2, PLB3, NTE1), and those activities account for most, if not all, of the glycerophosphodiester production observed to date. The glycerophosphodiesters themselves are hydrolyzed into glycerol-3-phosphate and the corresponding alcohol by glycerophosphodiester phosphodiesterases. Although only one glycerophosphodiester phosphodiesterase-encoding gene ( GDE1) has been characterized in S. cerevisiae, others certainly exist. Both internal and external glycerophosphodiesters (primarily glycerophosphocholine and glycerophosphoinositol) are formed as a result of phospholipid turnover in S. cerevisiae. A permease encoded by the GIT1 gene imports extracellular glycerophosphodiesters across the plasma membrane, where their hydrolytic products can provide crucial nutrients such as inositol, choline, and phosphate to the cell. The importance of this metabolic pathway in various aspects of S. cerevisiae cell physiology is being explored.
Keywords: Phospholipid deacylation; Glycerophosphoinositol; Glycerophosphocholine; Glycerophosphodiesterase; Git1p permease
Metabolism of phosphatidylcholine and its implications for lipid acyl chain composition in Saccharomyces cerevisiae by Anton I.P.M. de Kroon (pp. 343-352).
Phosphatidylcholine (PC) is a very abundant membrane lipid in most eukaryotes including the model organism Saccharomyces cerevisiae. Consequently, the molecular species profile of PC, i.e. the ensemble of PC molecules with acyl chains differing in number of carbon atoms and double bonds, is important in determining the physical properties of eukaryotic membranes, and should be tightly regulated. In this review current insights in the contributions of biosynthesis, turnover, and remodeling by acyl chain exchange to the maintenance of PC homeostasis at the level of the molecular species in yeast are summarized. In addition, the phospholipid class-specific changes in membrane acyl chain composition induced by PC depletion are discussed, which identify PC as key player in a novel regulatory mechanism balancing the proportions of bilayer and non-bilayer lipids in yeast.
Keywords: Phosphatidylcholine; Yeast; Lipid metabolism; Acyl chain remodeling; Lipid composition; Non-bilayer lipid
Synthesis and function of membrane phosphoinositides in budding yeast, Saccharomyces cerevisiae by Thomas Strahl; Jeremy Thorner (pp. 353-404).
It is now well appreciated that derivatives of phosphatidylinositol (PtdIns) are key regulators of many cellular processes in eukaryotes. Of particular interest are phosphoinositides (mono- and polyphosphorylated adducts to the inositol ring in PtdIns), which are located at the cytoplasmic face of cellular membranes. Phosphoinositides serve both a structural and a signaling role via their recruitment of proteins that contain phosphoinositide-binding domains. Phosphoinositides also have a role as precursors of several types of second messengers for certain intracellular signaling pathways. Realization of the importance of phosphoinositides has brought increased attention to characterization of the enzymes that regulate their synthesis, interconversion, and turnover. Here we review the current state of our knowledge about the properties and regulation of the ATP-dependent lipid kinases responsible for synthesis of phosphoinositides and also the additional temporal and spatial controls exerted by the phosphatases and a phospholipase that act on phosphoinositides in yeast.
Keywords: Phosphoinositide; Phosphatidylinositol kinases; Phosphoinositide phosphatases; Secretory pathway; Vesicle-mediated protein transport; Exocytosis; Endocytosis; Vacuolar protein sorting; Autophagy; Plasma membrane; Golgi membrane; Nucleus
Biosynthesis and function of GPI proteins in the yeast Saccharomyces cerevisiae by Martine Pittet; Andreas Conzelmann (pp. 405-420).
Like most other eukaryotes, Saccharomyces cerevisiae harbors a GPI anchoring machinery and uses it to attach proteins to membranes. While a few GPI proteins reside permanently at the plasma membrane, a majority of them gets further processed and is integrated into the cell wall by a covalent attachment to cell wall glucans. The GPI biosynthetic pathway is necessary for growth and survival of yeast cells. The GPI lipids are synthesized in the ER and added onto proteins by a pathway comprising 12 steps, carried out by 23 gene products, 19 of which are essential. Some of the estimated 60 GPI proteins predicted from the genome sequence serve enzymatic functions required for the biosynthesis and the continuous shape adaptations of the cell wall, others seem to be structural elements of the cell wall and yet others mediate cell adhesion. Because of its genetic tractability S. cerevisiae is an attractive model organism not only for studying GPI biosynthesis in general, but equally for investigating the intracellular transport of GPI proteins and the peculiar role of GPI anchoring in the elaboration of fungal cell walls.
Keywords: Abbreviations; aa; amino acids; CPY; carboxypeptidase Y; CWP; cell wall protein; Dol-P-Man; dolicholphosphomannose; EtN-P; phosphorylethanolamine; GlcNAc; N-Acetyl-Glucosamine; GlcNH; 2; , GlcN; Glucosamine; GPI; glycosylphosphatidylinositol; Man; mannose; PE; phosphatidylethanolamine; PI; phosphatidylinositol; PI-PLC; PI-specific phospholipase C; PMP; plasma membrane protein; TM; transmembrane domainGlycosylphosphatidylinositol; Saccharomyces cerevisiae; Biosynthesis; Cell wall; Ceramide; Lipid remodeling
Yeast sphingolipids: Recent developments in understanding biosynthesis, regulation, and function by L. Ashley Cowart; Lina M. Obeid (pp. 421-431).
Sphingolipids function as required membrane components of virtually all eukaryotic cells. Data indicate that members of the sphingolipid family of lipids, including sphingoid bases, sphingoid base phosphates, ceramides, and complex sphingolipids, serve vital functions in cell biology by both direct mechanisms (e.g., binding to G-protein coupled receptors to transduce an extracellular signal) and indirect mechanisms (e.g., facilitating correct intracellular protein transport). Because of the diverse roles these lipids play in cell biology, it is important to understand not only their biosynthetic pathways and regulation of sphingolipid synthesis, but also the mechanisms by which some sphingolipid species with specific functions are modified or converted to other sphingolipid species with alternate functions. Due to many factors including ease of culture and genetic modification, and conservation of major sphingolipid metabolic pathways, Saccharomyces cerevisiae has served as an ideal model system with which to identify enzymes of sphingolipid biosynthesis and to dissect sphingolipid function. Recent exciting developments in sphingolipid synthesis, transport, signaling, and overall biology continue to fuel vigorous investigation and inspire investigations in mammalian sphingolipid biology.
Keywords: Sphingolipid; Heat stress response; Endocytosis; Sphingoid base; Ceramide; Sphingosine-1-phosphate
New insights into the regulation of cardiolipin biosynthesis in yeast: Implications for Barth syndrome by Guiling Li; Shuliang Chen; Morgan N. Thompson; Miriam L. Greenberg (pp. 432-441).
Recent studies have revealed an array of novel regulatory mechanisms involved in the biosynthesis and metabolism of the phospholipid cardiolipin (CL), the signature lipid of mitochondria. CL plays an important role in cellular and mitochondrial function due in part to its association with a large number of mitochondrial proteins, including many which are unable to function optimally in the absence of CL. New insights into the complexity of regulation of CL provide further evidence of its importance in mitochondrial and cellular function. The biosynthesis of CL in yeast occurs via three enzymatic steps localized in the mitochondrial inner membrane. Regulation of this process by general phospholipid cross-pathway control and factors affecting mitochondrial development has been previously established. In this review, novel regulatory mechanisms that control CL biosynthesis are discussed. A unique form of inositol-mediated regulation has been identified in the CL biosynthetic pathway, independent of the INO2–INO4–OPI1 regulatory circuit that controls general phospholipid biosynthesis. Inositol leads to decreased activity of phosphatidylglycerolphosphate (PGP) synthase, which catalyzes the committed step of CL synthesis. Reduced enzymatic activity does not result from alteration of expression of the structural gene, but is instead due to increased phosphorylation of the enzyme. This is the first demonstration of phosphorylation in response to inositol and may have significant implications in understanding the role of inositol in other cellular regulatory pathways. Additionally, synthesis of CL has been shown to be dependent on mitochondrial pH, coordinately controlled with synthesis of mitochondrial phosphatidylethanolamine (PE), and may be regulated by mitochondrial DNA absence sensitive factor (MIDAS). Further characterization of these regulatory mechanisms holds great potential for the identification of novel functions of CL in mitochondrial and cellular processes.
Keywords: Abbreviations; CL; cardiolipin; CDP-DG; CDP-diacylglycerol; PGP; phosphatidylglycerolphosphate; PG; phosphatidylglycerol; PE; phosphatidylethanolamine; PC; phosphatidylcholine; PS; phosphatidylserine; PI; phosphatidylinositol; MLCL; monolyso-CL; VPA; valproate; AAC; ADP/ATP carrier; MIDAS; mitochondrial DNA absence sensitive factor; mtDNA; mitochondrial DNA; DCMA; dilated cardiomyopathy with ataxiaCardiolipin; Mitochondrial lipid; Barth Syndrome
Lipid requirements for endocytosis in yeast by Cleiton Martins Souza; Harald Pichler (pp. 442-454).
Endocytosis is, besides secretion, the most prominent membrane transport pathway in eukaryotic cells. In membrane transport, defined areas of the donor membranes engulf solutes of the compartment they are bordering and bud off with the aid of coat proteins to form vesicles. These transport vehicles are guided along cytoskeletal paths, often matured and, finally, fuse to the acceptor membrane they are targeted to. Lipids and proteins are equally important components in membrane transport pathways. Not only are they the structural units of membranes and vesicles, but both classes of molecules also participate actively in membrane transport processes. Whereas proteins form the cytoskeleton and vesicle coats, confer signals and constitute attachment points for membrane–membrane interaction, lipids modulate the flexibility of bilayers, carry protein recognition sites and confer signals themselves. Over the last decade it has been realized that all classes of bilayer lipids, glycerophospholipids, sphingolipids and sterols, actively contribute to functional membrane transport, in particular to endocytosis. Thus, abnormal bilayer lipid metabolism leads to endocytic defects of different severity. Interestingly, there seems to be a great deal of interdependence and interaction among lipid classes. It will be a challenge to characterize this plenitude of interactions and find out about their impact on cellular processes.
Keywords: Yeast; Membrane transport; Endocytosis; Lipids; Sterol; Sphingolipid