Preface The first edition of this textbook was published in 1985. Since that time, studies on the biochemistry and molecular biology of lipids and lipoproteins have underscored the phys- iological importance of lipids. Important new roles of genes involved in lipid metabolism, and their relationship to diseases such as heart disease, diabetes, obesity, stroke, cancer, and neurological disorders, have been revealed. The 5th edition of this textbook, therefore, takes into account the major advances in these fields and, in addition, provides basic knowledge of the genes and proteins involved in lipid metabolic processes. This edition has been written with two major objectives in mind. The first is to provide students and teachers with an advanced up-to-date textbook coveting the major areas in the biochem- istry and molecular biology of lipids, lipoproteins, and membranes. As in previous editions of this book, the chapters are written at a level that is accessible to students who have already taken an introductory course in biochemistry and are therefore familiar with the basic con- cepts and principles of biochemistry and lipid metabolism. Thus, we hope that this volume will provide the basis for an advanced course for the undergraduate and graduate students with an interest in the lipid field. The second objective of this book is to satisfy the need for a general reference book for scientists and researchers who are presently working in, or are about to enter, the lipid and related fields. This book is unique in that it is not a col- lection of exhaustive reviews on the topics covered in each chapter, but rather is a current, readable, and critical summary of the field. Our goal was to present a clear summary of each research area. This book should allow scientists to become familiar with recent discover- ies related to their own research interests, and should also help clinical researchers and medical students keep abreast of developments in basic science that are important for clin- ical advances in the future. All of the chapters have been extensively revised since the 4th edition appeared in 2002. We have not attempted to describe in detail the structure and function of biological mem- branes or the mechanism by which proteins are assembled into membranes as these topics are covered elsewhere in a number of excellent books. The first chapter, however, contains an up-to-date summary of the principles of membrane structure as a basis for the material covered in the subsequent chapters. As the chapters do not constitute comprehensive reviews of the various topics, we have limited the number of references cited at the end of each chapter and have emphasized recent review articles. Additional up-to-date reviews are available on all the topics inclu- ded in this book. In addition, some of the primary literature is cited within the body of the text by providing the name of one of the authors and the year in which the article was pub- lished. Using this system, readers should be able to find the original citations by searching an on-line database. vi ecaferP The editors and contributors assume full responsibility for the content of the chapters. We shall be pleased to receive any comments and suggestions for future editions of this book. Dennis E. Vance and Jean E. Vance Edmonton, Alberta, Canada August, 2007 List of contributors* Khosrow Adeli 507 Molecular Structure and Function Research Institute, ehT Hospital for Sick Children, University of ,otnoroT Toronto, ON M5G1X8, Canada Luis B. Agellon 423 McGill University School of Dietetics and Human Nutrition, Ste. Anne de Bellevue, QC H9X 3 ,9V Canada David A. Bernlohr 277 Department of Biochemistry, Molecular Biology and Biophysics, ehT University of Minnesota, 123 Church .tS ,ES Minneapolis, MN 55455, ASU Mikhail Bogdanov 1 Department of Biochemistry and Molecular Biology, University of ,notsuoH-saxeT Medical School 6431 Fannin, Suite 6.200, Houston, TX 77030, ASU William Dowhan 1 Department of Biochemistry and Molecular Biology, University of ,notsuoH-saxeT Medical School, 6431 Fannin, Suite 6.200, Houston, TX 77030, ASU Christopher .J Fielding 5 33 Cardiovascular Research Institute and Departments of Physiology and Medicine, University of California, San Francisco, AC 94143-0130, ASU Phoebe E. Fielding 5 33 Cardiovascular Research Institute and Departments of Physiology and Medicine, University of California, San Francisco, AC 94143-0 13A0S, U Ann .V Hertzel 277 Department of Biochemistry, Molecular Biology and Biophysics, ehT University of Minnesota, 123 Church .tS ,ES Minneapolis, MN 55455, ASU Ana Jonas 485 Department of Biochemistry, College of Medicine, University of Illinois at Urbana-Champaign, 506 South Mathews Avenue, Urbana, IL 61801, ASU Authors' * names era followed by the starting page number(s) of their contribution(s). viii List of srotubirtnoc Laura Liscum 399 Department of ,ygoloisyhP Tufts School University of Medicine, 631 Harrison ,eunevA Boston, MA 02111, ASU Gopal K. Marathe 245 Department of Cell Lerner Biology, Research Institute, Cleveland Clinic, ,dnalevelC OH 44195, ASU Thomas M. Mclntyre 245 Department of Cell Biology, Lerner Research Institute, Cleveland Clinic, ,dnalevelC OH 44195, ASU Anant K. Menon 39 Department of Biochemistry, Weill Cornell Medical ,egelloC 1300 kroY ,eunevA New ,kroY NY 10065, ASU Alfred H. Merrill, .rJ 363 School of ,ygoloiB Petit Institute for Bioengineering and Biosciences, Georgia Institute of ,ygolonhceT Atlanta, AG 30332-0230, ASU Eugenia Mileykovskaya 1 Department of Biochemistry and Molecular Biology, University of ,notsuoH-saxeT Medical School 6431 Fannin, Suite 6.200, Houston, TX 77030, ASU Makoto Miyazaki 191 Departments of yrtsimehcoiB Nutritional and ,secneicS University of ,nosidaM-nisnocsiW 334 Babcock Drive, Madison, WI 53706, ASU and Department of Medicine, Division of Renal Diseases and Hypertension, University of Colorado Health Sciences ,retneC 4200 East ht9 Ave., Denver, OC 80262, ASU Robert C. Murphy 331 Department of ,ygolocamrahP University of ,revneD-odaroloC Health Sciences ,retneC 1CR South ,rewoT L18-6121, 12801 .E 17th Avenue, Aurora, OC 80045, ASU James M. Ntambi 191 Departments of Biochemistry Nutritional and Sciences, University of ,nosidaM-nisnocsiW 334 Babcock Drive, Madison, WI 53706, ASU John B. Ohlrogge 97 Department of Plant Biology, Michigan State ,ytisrevinU East Lansing, M148824, ASU Michael C. Phillips 485 LipidR esearch Group, Children's Hospital of Philadelphia, University of ainavlysnneP School of Medicine, 3615 Civic Center Blvd., Philadelphia, AP 19104-4318, ASU List of contributors ix Charles O. Rock 59 Department of Infectious Diseases, .tS Jude Children's Research Hospital, Memphis, TN 38105, ASU and Department of Molecular Biosciences, University of Tennessee Health Science Center, Memphis, TN 38163, ASU Katherine M. Schmid 97 Department of Biology, Butler University, Indianapolis, IN 46208-3485, ASU Wolfgang .J Schneider 555 Department of Medical Biochemistry, Max E Perutz Laboratories, Medical University of Vienna, .rD Bohr Gasse 9/2, A-1030 Vienna, Austria Horst Schulz 131 Department of Chemistry, City College of CUNY, Convent Avenue at 138th Street, New ,kroY NY 10031, ASU Stuart Smith 155 Children's Hospital Oakland Research Institute, 5700 Martin Luther King .rJ ,yaW Oakland, AC 94611, ASU William .L Smith 31 3 Department of Biological Chemistry, University of Michigan Medical School, Ann Arbor, M148108-0606, ASU Fred Snyder 245 Oak Ridge Associated Universities, Retired, Oak Ridge, TN 37831, ASU Hei Sook Sul 155 Department of Nutritional Sciences and Toxicology, University of California, Berkeley, AC 94720, ASU arI Tabas 5 79 Departments of Medicine, Pathology and Cell Biology, and Physiology and Cellular Biophysics, Columbia University, 630 West 168th Street, New ,kroY NY 10032, ASU Brian R. Thompson 277 Department of Biochemistry, Molecular Biology and Biophysics, The University of Minnesota, 321 Church .tS ,ES Minneapolis, MN 55455, ASU Dennis E. Vance 213 Group on Molecular and Cell Biology of Lipids and Departments of Biochemistry and Medicine, University of Alberta, Edmonton, Alta. T6G 2S2, Canada x List of srotubirtnoc Jean E. Vance 213,507 puorG no Molecular and Cell Biology of Lipids and Department of ,enicideM Heritage Medical Research ,retneC University of Alberta, Edmonton, AB G6T ,2S2 adanaC Dennis R. Voelker 441 ehT Lord and Laboratory Taylor for Lung Biochemistry, Program ni Cell ,ygoloiB Department of Medicine, ehT National Jewish Medical Research ,retneC ,revneD OC 80206, ASU Brian M. Wiczer 277 Department of ,yrtsimehcoiB Molecular Biology and Biophysics, ehT University of Minnesota, 123 Church .tS ,ES Minneapolis, MN 55455, ASU David C. Wilton 305 School of Biological Sciences, University of Southampton, Bassett Crescent ,tsaE Southampton S016 7PX, KU D.E. Vance and J.E. Vance (Eds.) yrtsimehcoiB of snietorpopiL ,sdipiL dna senarbmeM ht5( ).ndE (cid:14)9 2008 Elsevier B.V. All rights reserved CHAPTER 1 Functional roles of lipids in membranes ,nahwoD mailliW Mikhail ,vonadgoB dna Eugenia ayaksvokyeliM Department of Biochemistry and Molecular Biology, University of Texas-Houston, Medical School 6431 Fannin, Suite 6.200, Houston, TX 77030, USA, Tel.: +1 (713) 500-6051; Fax: +1 (713) 500-0652; uth.tmc.edu E-mail: @ William.Dowhan Contents .1 Introduction and overview .......................................................... 2 2. Diversity in lipid structure .......................................................... 3 2.1. Glycerolipids ............................................................... 4 2.2. Saccharolipids .............................................................. 6 2.3. Sphingolipids ............................................................... 6 3. Properties of lipids in solution ....................................................... 7 3.1. Why do polar lipids self-associate? .............................................. 8 3.2. Physical properties of membrane bilayers .......................................... 11 3.3. Special properties of CL ...................................................... 13 3.4. What does the membrane bilayer look like? ........................................ 14 4. Engineering of membrane lipid composition ............................................ 14 4.1. Alteration of lipid composition in bacteria ......................................... 16 4.2. Alteration of lipid composition in yeast ........................................... 16 5. Role of lipids in cell function ....................................................... 17 5.1. The bilayer as a supermolecular lipid matrix ....................................... 17 5.1.1. Physical organization of the bilayer ........................................ 18 5.1.2. Biological importance of non-bilayer lipids .................................. 19 5.2. Selectivity of protein-lipid interactions ........................................... 20 5.2.1. Lipid association with a-helical proteins .................................... 20 5.2.2. Lipid association with 13-barrel proteins ..................................... 22 5.2.3. Organization of protein complexes .......................................... 22 5.2.4. Supermolecular complex formation ........................................ 23 5.2.5. Binding sites for peripheral membrane proteins ............................... 24 5.3. Translocation of proteins across membranes ........................................ 26 5.4. Assembly of integral membrane proteins .......................................... 27 5.4.1. Lipid-assisted folding of membrane proteins ................................. 27 5.4.2. Molecular determinants of protein topology .................................. 30 5.5. Lipid domains .............................................................. 31 5.5.1. Lipid rafts ........................................................... 32 5.5.2. Lipid domains in bacteria ............................................... 33 5.6. Cytokinesis ................................................................ 34 6. Summary and future directions ...................................................... 35 Abbreviations ...................................................................... 36 References ........................................................................ 36 2 William Dowhan et al. .1 Introduction and overview Lipids as a class of molecules display a wide diversity in structure and biological function. A primary role of lipids in cellular function is to form the lipid bilayer permeability barrier of cells and organelles (Fig. 1). Glycerophospholipids (termed phospholipids hereafter) are the primary building blocks of membranes but other lipids are important components. Table 1 shows the major lipids found in the membranes of various cells and organelles but does not take into account the minor lipids, many of which are functionally important. Sterols are present in all eukaryotic cells and in a few bacterial membranes. The ceramide-based sphin- golipids are also present in the membranes of all eukaryotes. Neutral diacylglycerol glycans are major membrane-forming components in many gram-positive bacteria and in the mem- branes of plants, while gram-negative bacteria utilize a saccharolipid (Lipid A) as a major structural component of the outer membrane. The variety of hydrophobic domains of lipids results in additional diversity. In eukaryotes and eubacteria, these domains are saturated and j derohcna-IPG nietorp Exterior nietorpocylG loretselohC cilihpordyH noiger cibohpordyH noiger cilihpordyH ~-- region largetnI nietorp larehpireP ~-'-~-"(~ ~ "~'-'"-~- \ dipilohpsohP nietorp Interior .giF .1 Model rof enarbmem .erutcurts This model of plasma eht enarbmem of a citoyrakue cell si na noitatpada of eht lanigiro model desoporp yb Singer dna noslohciN (S.J. ,regniS .)2791 ehT dipilohpsohp bilayer si nwohs htiw largetni enarbmem snietorp ylegral gniniatnoc a-helical enarbmemsnart .sniamod larehpireP enarbmem -orp sniet etaicossa with either eht surface lipid ro with other .snietorp enarbmem Lipid rafts (dark gray head )spuorg era enriched ni loretselohc dna a contain lotisonilyditahpsohp deknil-nacylg (GPI) .nietorp ehT light gray daeh spuorg depict sdipil ni close noitaicossa with .nietorp ehT ralugerri ecafrus dna chains acyl wavy etoned eht diulf erutan of eht .reyalib Functional roles of lipids in membranes 3 Table 1 Lipid composition of various biological membranes Lipid Erythrocyte"' CHO cells b Mitochondria c Endoplasmic reticulum d E. coli ~ Outer Inner Cholesterol 25 - N.D. N.D. 20 N.D. PE 81 12 33 24 12 75 PC 19 51 46 38 46 N.D. Sphingomyelin 81 9 - - 9 N.D. PS 9 7 1 4 2 <1 PG 0 1 N.D. N.D. - 20 CL 0 2.3 6 16 - 5 PI 1 8 10 16 2 N.D. Glycosphingolipid 10 . . . . N.D. PA - I 4 2 - <2 The data are expressed as mole% of total lipid. N.D. indicates not detected and blank indicates not analyzed. aHuman [5]. bChinese hampster cells (T. Ohtsuka, 1993). cs. cerevisiae inner and outer mitochondrial membrane (E. Zinser, 1991). dMurine L cells (E.J. Murphy, 2000). einner and outer membrane excluding Lipid A (C.R. Raetz, 1990). unsaturated fatty acids or alkyl alcohols. Archaebacteria contain long-chain reduced poly- isoprene moieties in ether linkage to glycerol instead of fatty acids. If one considers a sim- ple organism such as Escherichia coli with three major phospholipids and several different fatty acids along with many minor precursors and modified products, the number of individ- ual phospholipid species ranges in hundreds. In more complex eukaryotic organisms with greater diversity in both the phospholipids and fatty acids, the number of individual species is in thousands. Sphingolipids also show a similar degree of diversity and when added to the steroids, the size of the eukaryotic lipodome approaches the size of the proteome. In this chapter, the diversity in structure, chemical properties, and physical properties of lipids will be outlined. The various genetic approaches available to study lipid function in vivo will be summarized. Finally, how the physical and chemical properties of lipids relate to their multiple functions in living systems will be reviewed to provide a molecular basis for the diversity of lipid structures in natural membranes 1[ .] 2. Diversity in lipid structure Lipids are defined as the biological molecules readily soluble in organic solvents such as chloroform, ether, or toluene. However, many peptides and some very hydrophobic pro- teins are soluble in chloroform, and lipids with large hydrophilic domains such as saccha- rolipids are not soluble in these solvents. Here we will consider only those lipids that contribute significantly to membrane structure or have a role in determining protein struc- ture or function. The broad area of lipids as second messengers is covered in Chapters 12-14. The LIPID Metabolites and Pathways Strategy (LIPID MAPS)consortium is iden- tifying, characterizing, and classifying the components of the lipidome and developing a 4 William Dowhan et al. web-based systematic nomenclature for lipids and repository for structural information on lipids. The website of this consortium ]2[ provides a comprehensive and evolving picture of the lipodome. 2.1. Glycerolipids The diacylglycerol backbone in eubacteria and eukaryotes is sn-3-glycerol esterified at positions 1 and 2 with long-chain fatty acids (Fig. 2). In archaebacteria (Fig. 3), the opposite isomer sn-1-glycerol forms the lipid backbone and the hydrophobic domain is composed of phytanyl (saturated isoprenyl) groups in ether linkage at positions 2 and 3 (an archaeol) [3]. In addition, two sn-1-glycerol groups are connected in ether linkage by two biphytanyl groups (dibiphytanyldiglycerophosphatetetraether) to form a covalently linked bilayer. Some eubacteria (mainly hyperthermophiles) have dialkyl (long-chain alcohols in ether I o , enilohC )enilohclyditahpsohP( o enimalonahtE O-( ~ +3HN )enimalonahtelyditahpsohP( o 3HN + ~ (_0~. enir~, )enireslyditahpsohP( "OOC (-O"~~"~'OH Glycerol )lorecylglyditahpsohP( OH (-0 " "T" "O-) Glycerol (2) )nipiloidraC( OH lotisoni-oyM H O ~ O H )lotisonilyditahpsohP( ( - O ~ O H Fig. 2. Structure of glycerophosphate-based lipids. The complete lipid structure shown is 1,2-distearoyl-sn- glycerol-3-phosphocholine or phosphatidylcholine (PC). Substitution of choline in the box with the head groups listed below results in the other phospholipid structures. CDP--diacylglycerol has a CMP and phosphatidic acid (PA) has a hydroxyl group in place of choline (not shown). Cardiolipin (CL) is also referred to as diphos- phatidylglycerol since it contains two PAs joined by a glycerol.