Biochemistry of Lipids, Lipoproteins and Membranes

Transcription

1 Biochemistry of Lipids, Lipoproteins and Membranes Editors DENNIS E. VANCE and JEAN E. VANCE Lipid and Lipoprotein Research Group, Faculty of Medicine, 328 Heritage Medical Research Centre, Edmonton, Aha., Canada, T6G 2S ELSEVIER Amsterdam London New York Tokyo

2 IX Contents Preface List of contributors v vii Chapter 1. Physical properties and functional roles of lipids in membranes Pieter R. Cullis and Michael J. Hope 1. Introduction and overview 1 2. Lipid diversity and distribution Chemical diversity of lipids Membrane lipid compositions Transbilayer lipid asymmetry 7 3. Model membrane systems Lipid isolation and purification Techniques for making model membrane vesicles Techniques for making planar bilayers and monolayers Reconstitution of integral membrane protein into vesicles Physical properties of lipids Gel-liquid-crystalline phase behaviour Lipid polymorphism Factors which modulate lipid polymorphism The physical basis of lipid polymorphism Lipids and the permeability properties of membranes Theoretical considerations Permeability of water and non-electrolytes Permeability of ions Lipid-protein interactions Extrinsic proteins Intrinsic proteins Lipids and membrane fusion Fusion of model systems Fusion of biological membranes Model membranes and drug delivery Future directions 40 References 40 Chapter 2. Lipid metabolism in procaryotes S. Jackowski, J.E. Cronan Jr. and CO. Rock The study of bacterial lipid metabolism Historical introduction An overview of phospholipid metabolism in E. coli Genetic analysis of lipid metabolism Membrane systems of E. coli 48 l

3 6. Lipid biosynthetic pathways in E. coli Initiation of fatty acid biosynthesis Elongation of acyl chains Product diversification Transfer to the membrane Diversification of polar head groups Central role of acyl carrier protein Lipopolysaccharide biosynthesis Degradative pathways Phospholipases Thioesterases Fatty acid oxidation in bacteria Phospholipid turnover The diacylglycerol cycle The 2-acylglycerolphosphoethanolamine cycle Inhibitors of lipid metabolism Decynoyl-yV-acetylcysteamine Cerulenin Thiolactomycin Regulation of fatty acid composition in E. coli Role of 3-hydroxydecanoyl-ACP dehydrase Role of 3-ketoacyl-ACP synthase I Role of 3-ketoacyl-ACP synthase II Factors affecting fatty acid chain-length distribution Synthesis of cyclopropane fatty acids Importance of the fatty acid composition of the membrane phospholipids Regulation of phospholipid biosynthesis in E. coli Control of fatty acid positional distribution Regulation of total phospholipid synthesis Coordination of phospholipid synthesis with cellular metabolism Regulation of phospholipid head group composition E. coli tolerates variations in phospholipid composition Outer membrane lipoprotein Lipid metabolism in bacteria other than E. coli Bacteria lacking unsaturated fatty acids Bacteria containing phosphatidylcholine Bacteria synthesizing unsaturated fatty acids by an aerobic pathway Bacteria with a multifunctional fatty acid synthase Bacteria with intracytoplasmic membranes Other bacterial oddities Lipids of nonbacterial (but related) organisms Future directions 83 References 84 Chapter 3. Oxidation of fatty acids Horst Schulz The pathway of ^-oxidation: a historical account Uptake and activation of fatty acids in animal cells 89

4 XI 3. ^-Oxidation in mitochondria Mitochondrial uptake of fatty acids Enzymes of /J-oxidation in mitochondria /^-Oxidation of unsaturated and odd-chain fatty acids Regulation of mitochondrial /J-oxidation Inhibitors of mitochondrial /7-oxidation /J-Oxidation in peroxisomes Fatty acid oxidation in E. coli Inherited diseases of fatty acid oxidation Future directions 108 References 109 Chapter 4. Fatty acid synthesis in eucaryotes Alan G. Goodridge ill 1. Introduction Ill 2. Signals in blood that mediate the effects of diet Which enzymes regulate fatty acid synthesis? Regulation of substrate supply Production of pyruvate from glucose Production of citrate from pyruvate Production of NADPH Regulation of the catalytic efficiency of acetyl-coa carboxylase A key regulatory reaction Structure and reaction mechanism Regulation by citrate Regulation by long-chain fatty acyl-coa Regulation by covalent modification Fatty acid synthase Animal fatty acid synthase: the component reactions Animal fatty acid synthase: the subunits are identical Animal fatty acid synthase: structural organization Comparison of yeast and animal fatty acid synthases Regulation of enzyme concentration Messenger RNA levels regulate enzyme synthesis rates Transcription is usually the regulated step Regulation in cells in culture T3-L1 cells a pre-adipocyte cell line Hepatocytes in maintenance culture Future directions 137 References 138 Chapter 5. Fatty acid desaturation and chain elongation in eucaryotes Harold W. Cook Introduction Historical background Chain elongation of long chain fatty acids 144

5 Xll 3.1. The microsomal elongation system The mitochondrial elongation system Functions of the two elongation systems Formation of monounsaturated fatty acids by oxidative desaturation Nomenclature to describe double bonds Characteristics of the monoene-forming desaturation enzymes Modification of zl9 desaturase activities in vitro Dietary and hormonal regulation of J9 desaturase Formation of monounsaturated fatty acids in plants Formation of polyunsaturated fatty acids Characteristics and restrictions in animal systems Essential fatty acids a contribution of plant systems Families of fatty acids and their metabolism The (n-6) family The (n-3) family Competition between the (n-6) and (n-3) families The (n-9) family The (n-7) family Dietary and hormonal alterations of polyunsaturated acid synthesis Two or more double bonds in plants Unsaturated fatty acids with trans double bonds Abnormal patterns of distribution and metabolism of long chain saturated and unsaturated fatty acids Essential fatty acid deficiency Zinc deficiency Other clinical disorders Relationship to plasma cholesterol Future directions 167 References 168 Chapter 6. Metabolism of triacylglycerols David N. Brindley Introduction Biosynthesis of triacylglycerols Biosynthesis of phosphatidate Conversion of phosphatidate to triacylglycerol Conversion of monoacylglycerol to triacylglycerol Digestion, absorption and transport of lipids Digestion of lipids Absorption of lipids from the small intestine Formation of chylomicrons and VLDL Partitioning of fatty acids between the portal blood and the lymphatic system Control of triacylglycerol synthesis Control of phosphatidate synthesis in the liver Control of the conversion of phosphatidate to triacylglycerol in liver Diacylglycerol as a precursor of triacylglycerol, phosphatidylcholine and phosphatidylethanolamine Metabolism of triacylglycerols when the action of insulin is high Triacylglycerol metabolism in conditions of metabolic stress 198

6 Xlll 7. Future directions 200 References 201 Chapter 7. Phospholipid metabolism and cell signalling in eucaryotes Dennis E. Vance Introduction Phosphatidylcholine biosynthesis Historical background Choline transport and oxidation Enzymes of the CDP-choline pathway Phosphatidylethanolamine-JV-methyltransferase Regulation of phosphatidylcholine biosynthesis The rate-limiting reaction The translocation hypothesis Regulatory mechanisms Fatty acids are important regulators of phosphatidylcholine biosynthesis in cultured cells Diacylglycerol may also regulate phosphatidylcholine biosynthesis Phosphorylation-dephosphorylation reactions Feedback regulation Cholinephosphotransferase Substrate channeling Sphingomyelin biosynthesis Phosphatidylserine biosynthesis Historical developments and biosynthesis CHO mutants and regulation Phosphatidylethanolamine biosynthesis Historical background Enzymes of the CDP-ethanolamine pathway Regulation of the CDP-ethanolamine pathway Regulation at the cytidylyltransferase reaction Diacylglycerol Phosphatidylserine decarboxylation and the relative importance of the various pathways for phosphatidylethanolamine biosynthesis JV-acyl-phosphatidylethanolamine Polyglycerophospholipids Historical developments and biosynthetic pathways Enzymes and subcellular location Inositol phospholipids Historical developments Biosynthetic enzymes Phospholipids as precursors of cellular second messengers Discovery of the phosphatidylinositol cycle Degradation of phosphatidylinositol-4,5-bisphosphate by phospholipasec Metabolism of the inositol phosphates Function of inositol phosphates Diacylglycerol and protein kinase C Phosphatidylcholine cycles and formation of diacylglycerol 231

7 XIV 10. Phospholipid catabolism and remodeling of the acyl substituents Phospholipid biosynthesis in yeast Phosphonolipids Historical perspective Biosynthesis Glycosyl phosphatidylinositols for attachment of cell surface proteins Future directions References Chapter 8. Metabolism, regulation, and function of ether-linked glycerolipids and their bioactive species FredSnyder Introduction Nomenclature Historical events Analytical approaches Physical properties Occurrences in nature Biologically active ether lipids Biosynthesis Ether lipid precursors Acyl-CoA reductase Dihydroxyacetone-P acyltransferase Ether lipids in membranes Biosynthesis of the ether bond Biosynthesis of the alkyl analogue of phosphatidic acid Biosynthesis of complex neutral glycerolipids and phospholipids with 0-alkyl bonds Biosynthesis of plasmalogens Bioactive ether lipids Catabolism Ether lipid precursors Long-chain fatty alcohols Dihydroxyacetone-P and acyldihydroxyacetone-p Ether lipids in membranes Alkyl cleavage enzyme Plasmalogenases Phospholipases and lipases Bioactive ether lipids Regulatory controls Functional roles Membrane components Cell mediators (activities and mechanisms of action) Future directions 266 References 267

8 XV Chapter 9. Phospholipases Moseley Waite Overview Definition of phospholipases Assay of phospholipases Interaction of phospholipases with interfaces The phospholipases Phospholipase A Phospholipase B and lysophospholipases Phospholipase A Phospholipase C Phospholipase D Phospholipases in signal transduction Future directions 292 References 294 Chapter 10. The eicosanoids: cyclooxygenase, lipoxygenase, and epoxygenase pathways William L. Smith, Pierre Borgeat and Frank A. Fitzpatrick Introduction Prostanoids Structures and nomenclature Prostanoid chemistry Prostanoid biosynthesis Arachidonate release Prostaglandin endoperoxide formation Physico-chemical properties of PGH synthase PGH synthase and nonsteroidal anti-inflammatory drugs Anti-inflammatory steroids PGH synthase active site Regulation of PGH synthase gene expression PGH 2 metabolism Catabolism: prostanoids as local hormones Hydroxy- and hydroperoxy-eicosaenoic acids and leukotrienes Introduction and overview Mechanism of leukotriene biosynthesis in human neutrophils The enzymes of the 5-lipoxygenase pathway Regulation of leukotriene synthesis The metabolism of lipoxygenase products Biological activities of leukotrienes Epoxygenase products Introduction Structures, nomenclature, and biosynthesis Occurrence of epoxyeicosatrienoic acids Metabolism of epoxygenase metabolites of arachidonic acid Biological actions of 'epoxygenase' derived EpETrEs and HETrEs 322

9 XVI 5. Future directions Cyclooxygenase metabolites Lipoxygenase metabolites Epoxygenase metabolites 323 References 323 Chapter 11. Sphingolipids Charles C. Sweeley Introduction Chemistry and distribution Sphingoid bases Ceramides Glycosphingolipids Neutral glycosphingolipids Acidic glycosphingolipids Gangliosides Phosphorus-containing glycosphingolipids Sulfatoglycosphingolipids Biosynthesis of sphingolipids Sphingoid bases and ceramide Sphingomyelin Sulfatoglycosphingolipids Neutral glycosphingolipids Cell surface glycosyltransferases Gangliosides Turnover of sphingolipids Lysosomal metabolism of sphingolipids Sphingomyelin Ceramide Glycosphingolipids Glycosphingolipid storage diseases Tay-Sachs disease and related disorders a-subunit mutations /?-Subunit mutations Defective G M2 activator protein Fabry's disease and Schindler's disease Regulation of glycosphingolipid metabolism Developmental changes Glycosphingolipid markers in leukocyte differentiation Early embryonic markers Oncogenic transformation and immunomodulation by shed gangliosides Biological activities and functional roles of sphingolipids Adherence of microorganisms to cell surface glycosphingolipids Modulation of signal transduction Glycosphingolipids Sphingoid bases Future directions 359 References 360

10 XVII Chapter 12. Cholesterol: evolution of structure and function Konrad Bloch Natural occurrence of sterols Metabolic and precursor functions of the sterol molecule Sterol patterns Sterols and membrane function Function of sterols in animal membranes Sterol auxotrophs Metabolic regulation in the membrane environment Fluidity control Regulatory roles for sterols in membranes Fungi and invertebrates Sterol effects on hormone and neurotransmitter receptors Sterols and fusion of viral membranes Capping of surface immunoglobulin Sterol effects on enzyme activities Effects of cholesterol on phospholipid synthesis Evolution of the sterol structure Future directions 380 References 381 Chapter 13. Regulation Peter A. Edwards of sterol biosynthesis and isoprenylation of proteins Introduction 2. Regulation of cholesterol synthesis 3. Regulation of cholesteryl ester synthesis 4. Transcriptional control of cholesterol synthesis 5. Posttranscriptional regulation 6. Identification of the physiological regulators 1. Regulation of bile acid synthesis 8. Isoprenylation of proteins 9. Future directions References Chapter 14. Lipoprotein Roger A. Davis structure and secretion Introduction 2. Structure and function of plasma lipoproteins 2.1. Chylomicrons and very low density lipoproteins 2.2. Structure: surface components Core components 4Q S 2.4. Low density lipoproteins: structure ^ Origin of low density lipoproteins ^ High density lipoproteins: structure and function ^ Discoidal high density lipoproteins

11 XV Assembly of nascent lipoproteins Triacylglycerol-rich lipoproteins Role of lipids Core lipids Role of apolipoproteins Apolipoprotein B structure Vitellogenin: the primordial apolipoprotein Very low density lipoprotein assembly: ejection of a ball of fat out of the endoplasmic reticulum '*'' 3.5. Filling the hydrophobic core: a thermodynamic dilemma High density lipoprotein synthesis and secretion Future directions 423 References 424 Chapter 15. Dynamics of lipoprotein transport in the circulatory system Phoebe E. Fielding and Christopher J. Fielding Overview Lipoprotein lipase and the initial metabolism of lipoprotein triacylglycerol Initial events Lipoprotein lipase structure Synthesis and transport of lipoprotein lipase The lipoprotein lipase reaction and the role of apolipoprotein C Lipoprotein lipase activity at the vascular surface Regulation of lipoprotein lipase activity by products of lipolysis Physiological regulation of lipoprotein lipase Congenital lipoprotein lipase deficiency Hepatic triacylglycerol lipase and the later metabolism of lipoprotein triacylglycerol Introduction Structure of hepatic triacylglycerol lipase Acyl group hydrolysis and exchange catalyzed by hepatic triacylglycerol lipase Hepatic triacylglycerol lipase and the hydrolysis of lipoprotein lipids Regulation of hepatic triacylglycerol lipase activity Human hepatic triacylglycerol lipase deficiency Phospholipid exchange protein and its activity Lecithin:cholesterol acyltransferase and the initial metabolism of lipoprotein cholesterol Introduction 'Forward' cholesterol transport by very low density lipoprotein and its product, low density lipoprotein Origin of the major high density lipoprotein proteins Classification of plasma and lymph high density lipoprotein Apoprotein transfers in high density lipoprotein Origin of plasma lecithin:cholesterol acyltransferase Structure of plasma lecithin:cholesterol acyltransferase Mechanism of plasma lecithinxholesterol acyltransferase activity Role of apo A-l in the plasma lecithin:cholesterol acyltransferase reaction Transfer of cholesterol among high density lipoprotein species Physiological regulation of plasma lecithinxholesterol acyltransferase activity Studies of plasma lecithinxholesterol acyltransferase deficiency 452

12 XIX 5. Cholesteryl ester transfer protein and the later metabolism of lipoprotein cholesterol Introduction Structure of cholesteryl ester transfer protein Mechanism of cholesteryl ester transfer protein activity Quantitation of cholesteryl ester transfer Physiological regulation of cholesteryl ester transfer protein Congenital cholesteryl ester transfer protein deficiency Cholesteryl ester transfer protein inhibitor protein Summary and future directions 457 References 458 Chapter 16. Removal of lipoproteins from plasma Wolfgang J. Schneider Introduction Removal of low density lipoprotein from the circulation Receptor-mediated endocytosis The low density lipoprotein receptor pathway Familial hypercholesterolemia: clinical consequences of low density lipoprotein receptor dysfunction Biochemical findings in cultured fibroblasts from familial hypercholesterolemia homozygotes Biosynthesis and structure of the low density lipoprotein receptor The low density lipoprotein receptor protein The ligand binding domain The EGF precursor homology domain The third domain The membrane anchoring domain The cytoplasmic tail Molecular defects in low density lipoprotein receptors of patients with familial hypercholesterolemia The gene for the human low density lipoprotein receptor Four groups of low density lipoprotein receptor mutations Class 1: no detectable precursor Class 2: slow or absent processing of precursor Class 3: abnormal ligand binding Class 4: internalization defective Catabolism of chylomicrons High density lipoprotein as a transport vehicle Atherosclerosis Uptake and modification of low density lipoprotein in the intima Scavenger receptors Lipoprotein transport in the laying hen Low density lipoprotein metabolism by rat serosal mast cells Future directions 485 References 485

13 XX Chapter 17. Lipid assembly into cell membranes Dennis R. Voelker Introduction The diversity of lipids Methods to study intra- and inter-membrane lipid transport Fluorescent probes Spin labeled analogs Asymmetric chemical modification of membranes Phospholipid transfer proteins Rapid plasma membrane isolation Organelle specific lipid metabolism Lipid transport processes Intramembrane lipid translocation and model membranes Intramembrane lipid translocation and biological membranes Procaryotes Eucaryotes Transbilayer movement at the endoplasmic reticulum Transbilayer movement of phosphatidylcholine in erythrocytes Transbilayer movement of phosphatidylcholine in nucleated cells ATP dependent transbilayer movement of aminophospholipids at the plasma membrane of eukaryotic cells Intermembrane lipid transport Transport in procaryotes Transport in eucaryotes Phosphatidylcholine Phosphatidylethanolamine Phosphatidylserine Sphingolipids Cholesterol Phospholipid transfer proteins and phosphatidylinositol transport Future directions 521 References 522 Chapter 18. Assembly of proteins into membranes Reinhart A.F. Reithmeier Organization of membrane proteins Classification of membrane proteins Membrane protein structure and energetics Assembly of membrane proteins Secretion of proteins and the signal hypothesis The Palade secretion pathway The Blobel signal hypothesis In vitro translation and translocation systems The Milstein experiment: secreted proteins are made with an amino terminal signal sequence Signal sequences 540

14 XXI 3. The targeting and translocation machinery The signal recognition particle The signal recognition particle receptor Translocation components Ribosome-binding proteins Signal peptidase Biosynthesis of type I simple membrane proteins IgM and the relationship between the biosynthesis of secreted proteins and simple membrane proteins Vesicular stomatitis virus glycoprotein and hemagglutinin Loop models and insertion into the lipid bilayer Evidence for a loop structure for insertion of signal sequences Biosynthesis of type II simple membrane proteins Ovalbumin, a secreted protein made without a cleaved signal sequence Asialoglycoprotein receptor Sucrase-isomaltase Biosynthesis of cytochrome P-450 and cytochrome b Cytochrome P Cytochrome b Biosynthesis of complex membrane proteins Artificial membrane proteins Band 3, the anion transport protein of the erythrocyte membrane Glucose carrier Rhodopsin Ca 2+ ATPase and calsequestrin Glycosylation of proteins JV-glycosylation Processing of the oligosaccharide chain O-glycosylation Attachment of lipid to proteins Fatty acylation Phosphatidylinositol anchors Protein folding and exit from the endoplasmic reticulum Protein folding Disulfide formation Assembly of multisubunit systems Exit from the endoplasmic reticulum KDEL, an endoplasmic reticulum retention signal Transport and targeting of proteins Vesicles move proteins between organelles Role of GTP-binding proteins Lysosomal targeting Protein sorting in epithelial cells Future directions -^ References 577 Index 579