Principles of Biochemistry Fourth EditionChapter 9Lipids and MembranesCopyright 2006 Pearson Prentice Hall, Inc.Horton Moran Scrimgeour Perry Rawn

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Lipids

Storage energy: triacylglycerol (fat, oil)Cell membrane: glycerophospholipids, sphingolipids, sterolsProtective surface: wax (in cell wall, exoskeleton, skin)Enzyme cofactor:Electron carrier: cytochrome P450Light-absorbing pigments: chlorophyllHydrphobic anchorsEmulsifying agentsHormones: testosterone, estradiolInteracellular messengers: sialic acid

Structural relationships of the major classes of lipidsp. 254

*Figure 9.1Structural relationships of the major classes of lipids. Fatty acids are the simplest lipids. Many other types of lipids either contain or are derived from fatty acids. Glycerophospholipids and sphingomyelins contain phosphate and are classified as phospholipids. Cerebrosides and gangliosides contain sphingosine and carbohydrate and are classified as glycosphingolipids. Steroids, lipid vitamins, and terpenes are called isoprenoids because they are related to the five-carbon molecule isoprene rather than to fatty acids.

Fatty acid

p. 255Saturatedfatty acidUnsaturatedfatty acidIUPC: International Union of Pure and Applied Chemistry

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Structure and nomenclature of fatty acidsp. 256: tail, farthest from the carboxyl carbon-3, e.g. 18:39,12,15-6, e.g. 18:29,12-9, e.g. 18:19Fatty acid: Fuel:~37 kJ/g fatty acid~16 kJ/g protein or cabohydratepKa 4.5~5.0, ionized at physiological pHAs a detergent, with polar head and hydrophobic tailLow concentration in membraneJoined to other molecular with ester linkage

*Figure 9.2Structure and nomenclature of fatty acids. Fatty acids consist of a long hydrocarbon tail terminating with a carboxyl group. Since the pKa of the carboxyl group is approximately 4.5 to 5.0, fatty acids are anionic at physiological pH. In IUPAC nomenclature, carbons are numbered beginning with the carboxyl carbon. In common nomenclature, the carbon atom adjacent to the carboxyl carbon is designated , and the remaining carbons are lettered , , , and so on. The carbon atom farthest from the carboxyl carbon is designated the carbon, whatever the length of the tail. The fatty acid shown, laurate (or dodecanoate), has 12 carbon atoms and contains no carboncarbon double bonds.

Chemical structures of three C18 fatty acidsp. 257

*Figure 9.3Chemical structures of three C18 fatty acids. (a) Stearate (octadecanoate), a saturated fatty acid. (b) Oleate (cis-9-octadecenoate) a monounsaturated fatty acid. (c) Linolenate (all-cis-9,12,15-octadecatrienoate), a polyunsaturated fatty acid. The cis double bonds produce kinks in the tails of the unsaturated fatty acids. Linolenate is a very flexible molecule, and can assume a variety of conformations.

Triacylglycerol

Structure of glycerol and triacylglycerolp. 258Fat (solid) and oil (liquid) are mixture of tricaylglycerols.Most diet lipids: tricaylglycerols.Most abundant lipid in animal.Not found in cell membrane.Pancreatic lipases hydrolyse the ester (at C1 and C3) of gtracylglycerol.Pancreatic lipases

*Figure 9.5Structure of a triacylglycerol. Glycerol (a) is the backbone to which three fatty acyl residues are esterified (b). Although glycerol is not chiral, C-2 of a triacylglycerol is chiral when the acyl groups bound to C-1 and C-3 (R1 and R3) differ. The general structure of a triacylglycerol is shown in (c), oriented for comparison with the structure of L-glyceraldehyde (Figure 8.1). This orientation allows stereospecific numbering of glycerol derivatives with C-1 at the top and C-3 at the bottom.

Glycerolphospholipids

p. 260Glycerolphospholipids

Most abundant in cell membrane

Contain:Glycerol backboned2 acyl groups at C1, C2Phosphate at C3Named: Phosphatidyl-X

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p. 261

*Figure 9.7Structures of (a) phosphatidylethanolamine, (b) phosphatidylserine, and (c) phosphatidylcholine. Functional groups derived from esterified alcohols are shown in blue. Since each of these lipids can contain many combinations of fatty acyl groups, the general name refers to a family of compounds, not to a single molecule.

Action of four phospholipasesp. 261

Disrupt cell membrane.Present in pancreatic juice, snake, bee, and wasp venom.

*Figure 9.8Action of four phospholipases. Phospholipases A1, A2, C, and D can be used to dissect glycerophospholipid structure. Phospholipases catalyze the selective removal of fatty acids from C-1 or C-2 or convert glycerophospholipids to diacylglycerols or phosphatidates.

Structure of an ethanolamine plasmalogenp. 262Ethanolamine and coline are the commonly esterified to plasmalogen.

About 23% of the glycerophospho-lipid in the human central nerve system, also found in the membrane of peripheral nerve and muscle.

Ethanolamine

*Figure 9.9Structure of an ethanolamine plasmalogen. A hydrocarbon is linked to the C-1 hydroxyl group of glycerol to form a vinyl ether.

Sphingolipids

Structures of sphingosine, ceramide, and sphingomyelin.p. 262

*Figure 9.10Structures of sphingosine, ceramide, and sphingomyelin. (a) Sphingosine, the backbone for sphingolipids, is a long-chain alcohol with an amino group at C-2. (b) Ceramides have a long-chain fatty acyl group attached to the amino group of sphingosine. (c) Sphingomyelins have a phosphate group (red) attached to the C-1 hydroxyl group of a ceramide and a choline group (blue) attached to the phosphate.

Structure of a galactocerebrosidep. 263Galactocerebrosides are abundant in nerve tissue, about 15% lipid of myelin sheaths.

*Figure 9.11Structure of a galactocerebroside.-D-Galactose (blue) is attached to the C-1 hydroxyl group of a ceramide (black).

Ganglioside GM2p. 263GM2 is the 2nd monosialo ganglioside caracterized.Now >60 gangliosides.Gangliosides: ceramide + C1 Glc + GlaPresent on cell surface

*Figure 9.12Ganglioside GM2 The N-acetylneuraminic acid residue is shown in blue.

Inherited human diseases resulting from abnormal accumulation of membrane lipids.Pathway for the breakdown of GM1, globoside and sphigomyelin.

GM2 Lysosomes swell nerve cells enlargement nerve cells die blindness, mental retardation, death

Lehninger, p 356

ABO Blood Groupp. 249ABO blood group is determined by a single gene on chromosome 9.Single deletion at N-terminal: non-functional O alleleA enzyme: N-acetylaminogalactosyltrnasferaseB enzyme: galactosyltrnasferaseLehninger, p 354

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Steroids

Steroids, lipid Vitamins and terpenes are classified as isopropenoids. Chemical structureCarbon backboneIsoprene unitp. 264Isoprene(2-methyl-1,3-butadiene)

*Figure 9.13Isoprene (2-methyl-1,3-butadiene), the basic structural unit of isoprenoids. (a) Chemical structure. (b) Carbon backbone. (c) Isoprene unit where dashed lines indicate covalent bonds to adjacent units.

Structures of several steroidsp. 265Based on 5C isopropene3 X 6C ring + 1 X 5C ringCholesterol: OH at C3Cardiovascular diseaseMammalian HormonesBile slatPlant sterolsCell membrane component

*Figure 9.14Structures of several steroids. Structures of several steroids. Squalene (a) is the precursor of most steroids. Steroids contain four fused rings (lettered A, B, C, and D). (b) Cholesterol. (c) Stigmasterol, a common component of plant membranes. (d) Testosterone, a steroid hormone involved in male development in animals. (e) Sodium cholate, a bile salt, which aids in the digestion of lipids. (f) Ergosterol, a compound from fungi and yeast.

Cholesteryl esterp. 267Cholesterol is converted to cholesteryl esters for storage in cells or for transport through the bloodstream. Since insoluble in water, cholesterol and its esters must be complexed with phospholipids and amphipathic proteins in lipoproteins for transport.

*Figure 9.16Cholesteryl ester.

Myricyl palmitate, a waxp. 267Waxesnonpolar esters of long-chain fatty acids and long-chain monohydroxylic alcoholsprotective waterproof coatings Beeswax, myricyl palmitate, ester of palmitate (16:0) and the 30-C myricyl alcohol Ear wax, cerumen (from the Latin word cera, wax)secreted by cells lining the auditory canalcontains squalene, triacylglycerols and waxes (about 10% of the weight).

*Figure 9.17Myricyl palmitate, a wax.

Some isoprenoidsp. 268Lemon flavorArchaebacteria cell membraneDevelopment regulation in insect

*Figure 9.19Some isoprenoids.

Flowchart of lipid extraction and purificationp. 269

*Flowchart of lipid extraction and purification. Silicic acid column chromatography, thin-layer chromatography, and gas chromatography are used to separate and analyze lipid classes and component fatty acids.

Biological membraneLipid bilayers and proteins External boundaries of cellsSeparate compartments within cellsSelective pumps: transport of ions and small moleculesGenerating and maintaining the proton concentration gradients for ATP productionRecognize extracellular signals and communicate them to the cell interior.

Membrane lipid and bilayerp. 2705 to 6 nm thick, flexible, self-seal two sheets, or monolayers (leaflets)polar head groups: contact with the aqueous mediumnonpolar hydrocarbon tails: toward the interior of the bilayerlipid bilayers is driven by the hydrophobic interactions

*Figure 9.20Membrane lipid and bilayer. (a) An amphipathic membrane lipid. (b) Cross-section of a lipid bilayer. The hydrophilic head groups (blue) of each leaflet face the aqueous medium, and the hydrophobic tails (yellow) pack together in the interior of the bilayer.

Typical biological membrane

6-10 nmLipids: 25%~50%Proteins: 50%~75%Carbohydrate: 10%

Cholesterol and some other liplds: ~30% of total lipid

Components of inner and outer membranes are different. Red blood cells: rich in proteinsBrain cells: rich in phosphotidylserinesE. coli: inner-70% phosphatidylethanolaminesouter-lipopolysaccharidesMammalian: outer surface-90% sphingomylin

Structure of a typical eukaryotic plasma membranep. 271fluid mosaic model: 1972 S. Jonathan Singer and Garth L. Nicolson membrane is a dynamic structure proteins and lipids can rapidly and randomly diffuse laterally or rotate

*Figure 9.21Structure of a typical eukaryotic plasma membrane. A lipid bilayer forms the basic matrix of biological membranes, and proteins (some of which are glycoproteins) are associated with it in various ways (Section 9.10). The oligosaccharides of glycoproteins and glycolipids are on the exterior surface of the membrane.

Diffusion of lipids within a bilayerp. 2722 m/sec flip-flop210-6 m/secflippases and floppases: membrane-bound enzymesgenerated and maintained lipid asymmetry ATP-dependant move specific phospholipids from one monolayer to the other

*Figure 9.22Diffusion of lipids within a bilayer. (a) Lateral diffusion of lipids is relatively rapid. (b) Transverse diffusion, or flip-flop, of lipids is very slow.

Diffusion of membrane proteinsp. 2731970 L. D. Frye and Michael A. Edidin: proteins diffuse within the lipid bilayer.

Majority of membrane proteins diffuse ~100 to 500 times slowly than lipids.

Immobile membrane proteins: act as fences or cages, restricting the movement of other proteins; produces protein patches, or domains, areas of membrane.

*Figure 9.23Diffusion of membrane proteins. Human cells whose membrane proteins had been labeled with a red fluorescent marker were fused with mouse cells whose membrane proteins had been labeled with a green fluorescent marker. The initially localized markers became dispersed over the entire surface of the fused cell within 40 minutes.

Freeze fracturing a biological membranep. 274

*Figure 9.24Freeze fracturing a biological membrane. (a) Splitting the lipid bilayer along the interface of the two leaflets. A platinum replica of the exposed internal surface is examined in an electron microscope. Membrane proteins appear as protrusions or cavities in the replica. (b) Electron micrograph of a freeze-fractured erythrocyte membrane. The bumps on the inner membrane surface show the locations of membrane proteins.

Phase transition of a lipid bilayer.p. 274In the ordered gel state, the hydrocarbon chains are extended.Above the phase-transition temperature, rotation around CC bonds disorders the chains in the liquid crystalline phase.Phase transitions in biological membranes can be localized, so fluid- and gel-phase regions can coexist at certain temperatures.Thickness15%

*Figure 9.25Phase transition of a lipid bilayer. In the ordered gel state, the hydrocarbon chains are extended. Above the phase-transition temperature, rotation around CC bonds disorders the chains in the liquid crystalline phase.

Fluidity and phasetransition temperature

The structure of a phospholipid: incorporating an unsaturated fatty acyl group into a phospholipid lowers the phase-transition temperature.

Cholesterol accounts for 20% to 25% of the mass of lipids in a typical mammalian plasma membrane and significantly affects membrane fluidity.lipid rafts:Cholestreol and sphingolipidMaintained by membrane proteinsp. 274

Schematic cross-section of a lipid vesicle, or liposomep. 275

*Box 9-4Schematic cross-section of a lipid vesicle, or liposome. The bilayer is made up of two leaflets. In each leaflet, the polar head groups of the amphipathic lipids extend into the aqueous medium, and the nonpolar hydrocarbon tails point inward and are in van der Waals contact with each other.

Membrane proteins

Integral membrane proteinsPeripheral membrane proteinsLipid-anchored membrane proteinsp. 271

Bacteriorhodopsin from Halobacterium salinarumHarness light energy for ATP synthesisp. 276

Integral membrane proteins (transmembrane proteins)Hydrophobic core (transmembrane region) + exposed proteins on the surface.-helix~20 aaloopslight-harvesting prosthetic group (in yellow)

*Figure 9.27Bacteriorhodopsin from Halobacterium salinarum. Seven membrane-spanning helices, connected by loops, form a bundle that spans the bilayer. The light-harvesting prosthetic group is shown in yellow. [PDB 1FBB]

Ribbon structure of the transmembrane portion of porin FhuA from Escherichia coli.p. 276This porin forms a channel for the passage of protein- bound iron into the bacterium. The channel is formed from 22 antiparallel strands

*Figure 9.28Ribbon structure of the transmembrane portion of porin FhuA from Escherichia coli. This porin forms a channel for the passage of protein- bound iron into the bacterium. The channel is formed from 22 antiparallel strands. [PDB 1BY3].

Peripheral membrane proteins

Associated with one face of the membrane through chargecharge interactions and hydrogen bonding with integral membrane proteins or with the polar head groups of membrane lipids.

A change in pH or ionic strength is often sufficient to remove these proteins from the membrane.

Lipid-anchored membrane proteins attached to the plasma membraneA fatty acyl-anchored proteins. A prenyl-anchored membrane proteins (prenylated proteins).Proteins anchored by glycosylphosphatidylinositol. Outer leaflet only, and found in lipid (cholesterol-spingolipid) rafts.

p. 277

*Figure 9.29Lipid-anchored membrane proteins attached to the plasma membrane. The three types of anchors can be found in the same membrane, but they do not form a complex as shown here. (a) A fatty acyl-anchored protein. (b) A prenyl-anchored membrane protein. Note that fatty acyl- and prenyl-anchored membrane proteins can also occur on the cytoplasmic (outer) leaflet of intracellular membranes. (c) Protein anchored by glycosylphosphatidylinositol. Shown here is the variant surface glycoprotein of the parasitic protozoan Trypanosoma brucei. The protein is covalently bound to a phosphoethanolamine residue, which in turn is bound to a glycan. The glycan (blue) includes a mannose residue, to which the phosphoethanolamine residue is attached, and a glucosamine residue, which is attached to the phosphoinositol group (red) of phosphatidylinositol. Abbreviations: GlcN, glucosamine; Ins, inositol; Man, mannose.

p. 278Membrane Transport(Non-polar gases, Hydrophobic molecules)

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Thermodynamics of Membrane Transport

Thermodynamics of Membrane TransportCharge compounds: membrane potential (in volts)F : Faradayss constant (96.485 kJV-1 mol-1)z: charge on the molecule being transported

Membrane transport through a pore or channelp. 280pore: for bacteriachannel: for animals

No energy neededNot substrate saturableRate id diffusion-controlled

Some always open.Some open or close response to signal.

In nerve tissue: gated potassium channel rapid outward transport of K+ 10,000 times faster than transport of Na+.

*Figure 9.30Membrane transport through a pore or channel. A central passage allows molecules and ions of the appropriate size, charge, and geometry to traverse the membrane in either direction.

Types of passive and active transport.p. 281

*Figure 9.31Types of passive and active transport. Although the transport proteins are depicted as having an open central pore, passive and active transporters actually undergo conformational changes when transporting their solutes (Figure 9.33). (a) Uniport. (b) Symport. (c) Antiport.

Kinetics of passive transport.p. 281MichaelisMenten equationV0: initial rate of inward [S]out: external concentration Vmax: maximum rate of transport of the substrateKtr: constant analogous to the Michaelis constant Km

*Figure 9.32Kinetics of passive transport. The initial rate of transport increases with substrate concentration until a maximum is reached. Ktr is the concentration of substrate at which the rate of transport is half-maximal.

Passive and active transport protein function.p. 282protein binds its specific substrateconformational change allow the molecule or ion to be released on the other side of the membrane

*Figure 9.33Passive and active transport protein function. The protein binds its specific substrate and then undergoes a conformational change allowing the molecule or ion to be released on the other side of the membrane. Cotransporters have specific binding sites for each transported species.

Primary active transportpowered by a direct source of energy/ATP or light.p. 276light-harvesting prosthetic group (in yellow)Bacteriorhodopsin: uses light energy to generate a transmembrane proton concentration gradient that can be used for ATP formation.

Secondary active transport in Escherichia colidriven by an ion concentration gradientp. 282The oxidation of reduced substrates (Sred) generates a transmembrane proton concentration gradient. The energy released by protons moving down their concentration gradient drives the transport of lactose into the cell by lactose permease.

*Figure 9.34Secondary active transport in Escherichia coli. The oxidation of reduced substrates (Sred) generates a transmembrane proton concentration gradient. The energy released by protons moving down their concentration gradient drives the transport of lactose into the cell by lactose permease.

Secondary-active transport in animalsp. 283

*Figure 9.35Secondary-active transport in animals. The Na+-K+ ATPase generates a sodium ion gradient that drives secondary active transport of glucose in intestinal cells.

Endocytosis and Exocytosisp. 283Movement for large molecule, such as proteins.

Receptor-mediated endocytosis: binding of macromolecules to specific receptor proteins in the plasma membrane of the cell, fusing with endosome then with lysosome.

Exocytosis: materials for secretion are enclosed in vesicles by the Golgi apparatus, then fuse with the plasma membrane, releasing the vesicle contents into the extracellular space.

Transduction of Extracellular SignalsSignals:chemotaxishormonesneurotransmittersgrowth factors

The Hot Spice of Chili Peppers

Pain, temperature increasingVanilloid (capsacin) receptor (inactive)Vanilloid receptor (active)

Na+ and K+ flow into nerve cellOpiod ()

General mechanism of signal transduction across the plasma membrane of a cell.p. 285Cascade: series amplification eventsG proteins are signal transducers

*Figure 9.37General mechanism of signal transduction across the plasma membrane of a cell.

Summary of the adenylyl cyclase signaling pathwayp. 288

*Figure 9.43Summary of the adenylyl cyclase signaling pathway. Binding of a hormone to a stimulatory transmembrane receptor (Rs) leads to activation of the stimulatory G protein (Gs) on the inside of the membrane. Other hormones can bind to inhibitory receptors (Ri) which are coupled to adenylyl cyclase by the inhibitory G protein Gi. Gs activates the integral membrane enzyme adenylyl cyclase, whereas Gi inhibits it. cAMP activates protein kinase A, resulting in the phosphorylation of cellular proteins.

Hydrolysis of GTP to GDP and Pip. 286G proteins have GTPase activity

*Figure 9.38Hydrolysis of guanosine 5'-triphosphate (GTP) to guanosine 5'-diphosphate (GDP) and phosphate (Pi).

G-protein cyclep. 286: fatty-acyl anchored protein: prenyl-anchored proteinhttp://upload.wikimedia.org

*Figure 9.39G-protein cycle. G proteins undergo activation after binding to a receptorligand complex and are slowly inactivated by their own GTPase activity. Both GGTP/GDP and G are membrane-bound.

Production and inactivation of cAMPp. 287The cyclic nucleotides 3,5-cyclic adenosine monophosphate (cAMP) and its guanine analog cGMP are second messengers that help transmit signals from external sources to intracellular enzymes.Methylated purines caffeine and theophylline inhibit cAMP phosphodiesterase.

*Figure 9.40Production and inactivation of cAMP. ATP is converted to cAMP by the transmembrane enzyme adenylyl cyclase. The second messenger is subsequently converted to 5'-AMP by the action of a cytosolic cAMP phosphodiesterase.

Activation pf protein kinase Ap. 288The assembled complex is inactive. When four molecules of cAMP bind to the regulatory subunit (R) dimer, the catalytic subunits (C) are released.

*Figure 9.41Activation of protein kinase A. The assembled complex is inactive. When four molecules of cAMP bind to the regulatory subunit (R) dimer, the catalytic subunits (C) are released.

Activation of receptor tyrosine kinasesp. 291Insulin receptor

*Figure 9.46Activation of receptor tyrosine kinases. Activation occurs as a result of ligand-induced receptor dimerization. Each kinase domain catalyzes phosphorylation of its partner. The phosphorylated dimer can catalyze phosphorylation of various target proteins.

Insulin-stimulated formation of phosphatidylinositol 3,4,5-trisphosphate PIP3p. 292insulin-receptor substrates

*Figure 9.48Insulin-stimulated formation of phosphatidylinositol 3,4,5-trisphosphate PIP3. Binding of insulin to its receptor activates the protein tyrosine kinase activity of the receptor, leading to the phosphorylation of insulin-receptor substrates (IRSs). The phosphorylated IRSs interact with phosphatidylinositide 3-kinase (PI kinase) at the plasma membrane, where the enzyme catalyzes the phosphorylation of PIP2 to PIP3. PIP3 acts as a second messenger, carrying the message from extracellular insulin to certain intracellular protein kinases.

PIP2 produces two 2nd messengers, IP3 and diacylglycerol.p. 289IP3 diffuses to the endoplasmic reticulum, where it binds to and opens a Ca2+ channel in the membrane, releasing stored Ca2+. Diacylglycerol remains in the plasma membrane, where italong with Ca2+activates the enzyme protein kinase C (PKC).

*Figure 9.44Phosphatidylinositol 4,5-bisphosphate (PIP2) produces two second messengers, inositol 1,4,5-trisphosphate (IP3) and diacylglycerol. PIP2 is synthesized by the addition of two phosphoryl groups (red) to phosphatidylinositol and hydrolyzed to IP3 and diacylglycerol by the action of a phosphoinositide-specific phospholipase C.

Inositolphospholipid signaling pathway.p. 290

*Figure 9.45Inositolphospholipid signaling pathway. Binding of a ligand to its transmembrane receptor (R) activates the G protein (Gq) This in turn stimulates a specific membrane-bound phospholipase C (PLC), which catalyzes hydrolysis of the phospholipid PIP2 in the inner leaflet of the plasma membrane. The resulting second messengers, IP3 and diacylglycerol (DAG), are responsible for carrying the signal to the interior of the cell. IP3 diffuses to the endoplasmic reticulum, where it binds to and opens a Ca2+ channel in the membrane, releasing stored Ca2+. Diacylglycerol remains in the plasma membrane, where italong with Ca2+activates the enzyme protein kinase C (PKC).

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*Figure 9.1Structural relationships of the major classes of lipids. Fatty acids are the simplest lipids. Many other types of lipids either contain or are derived from fatty acids. Glycerophospholipids and sphingomyelins contain phosphate and are classified as phospholipids. Cerebrosides and gangliosides contain sphingosine and carbohydrate and are classified as glycosphingolipids. Steroids, lipid vitamins, and terpenes are called isoprenoids because they are related to the five-carbon molecule isoprene rather than to fatty acids.*

*Figure 9.2Structure and nomenclature of fatty acids. Fatty acids consist of a long hydrocarbon tail terminating with a carboxyl group. Since the pKa of the carboxyl group is approximately 4.5 to 5.0, fatty acids are anionic at physiological pH. In IUPAC nomenclature, carbons are numbered beginning with the carboxyl carbon. In common nomenclature, the carbon atom adjacent to the carboxyl carbon is designated , and the remaining carbons are lettered , , , and so on. The carbon atom farthest from the carboxyl carbon is designated the carbon, whatever the length of the tail. The fatty acid shown, laurate (or dodecanoate), has 12 carbon atoms and contains no carboncarbon double bonds.*Figure 9.3Chemical structures of three C18 fatty acids. (a) Stearate (octadecanoate), a saturated fatty acid. (b) Oleate (cis-9-octadecenoate) a monounsaturated fatty acid. (c) Linolenate (all-cis-9,12,15-octadecatrienoate), a polyunsaturated fatty acid. The cis double bonds produce kinks in the tails of the unsaturated fatty acids. Linolenate is a very flexible molecule, and can assume a variety of conformations.*Figure 9.5Structure of a triacylglycerol. Glycerol (a) is the backbone to which three fatty acyl residues are esterified (b). Although glycerol is not chiral, C-2 of a triacylglycerol is chiral when the acyl groups bound to C-1 and C-3 (R1 and R3) differ. The general structure of a triacylglycerol is shown in (c), oriented for comparison with the structure of L-glyceraldehyde (Figure 8.1). This orientation allows stereospecific numbering of glycerol derivatives with C-1 at the top and C-3 at the bottom.*

*Figure 9.7Structures of (a) phosphatidylethanolamine, (b) phosphatidylserine, and (c) phosphatidylcholine. Functional groups derived from esterified alcohols are shown in blue. Since each of these lipids can contain many combinations of fatty acyl groups, the general name refers to a family of compounds, not to a single molecule.*Figure 9.8Action of four phospholipases. Phospholipases A1, A2, C, and D can be used to dissect glycerophospholipid structure. Phospholipases catalyze the selective removal of fatty acids from C-1 or C-2 or convert glycerophospholipids to diacylglycerols or phosphatidates.*Figure 9.9Structure of an ethanolamine plasmalogen. A hydrocarbon is linked to the C-1 hydroxyl group of glycerol to form a vinyl ether.*Figure 9.10Structures of sphingosine, ceramide, and sphingomyelin. (a) Sphingosine, the backbone for sphingolipids, is a long-chain alcohol with an amino group at C-2. (b) Ceramides have a long-chain fatty acyl group attached to the amino group of sphingosine. (c) Sphingomyelins have a phosphate group (red) attached to the C-1 hydroxyl group of a ceramide and a choline group (blue) attached to the phosphate.*Figure 9.11Structure of a galactocerebroside.-D-Galactose (blue) is attached to the C-1 hydroxyl group of a ceramide (black).*Figure 9.12Ganglioside GM2 The N-acetylneuraminic acid residue is shown in blue.*

*Figure 9.13Isoprene (2-methyl-1,3-butadiene), the basic structural unit of isoprenoids. (a) Chemical structure. (b) Carbon backbone. (c) Isoprene unit where dashed lines indicate covalent bonds to adjacent units.*Figure 9.14Structures of several steroids. Structures of several steroids. Squalene (a) is the precursor of most steroids. Steroids contain four fused rings (lettered A, B, C, and D). (b) Cholesterol. (c) Stigmasterol, a common component of plant membranes. (d) Testosterone, a steroid hormone involved in male development in animals. (e) Sodium cholate, a bile salt, which aids in the digestion of lipids. (f) Ergosterol, a compound from fungi and yeast.*Figure 9.16Cholesteryl ester.*Figure 9.17Myricyl palmitate, a wax.*Figure 9.19Some isoprenoids.*Flowchart of lipid extraction and purification. Silicic acid column chromatography, thin-layer chromatography, and gas chromatography are used to separate and analyze lipid classes and component fatty acids.*Figure 9.20Membrane lipid and bilayer. (a) An amphipathic membrane lipid. (b) Cross-section of a lipid bilayer. The hydrophilic head groups (blue) of each leaflet face the aqueous medium, and the hydrophobic tails (yellow) pack together in the interior of the bilayer.*Figure 9.21Structure of a typical eukaryotic plasma membrane. A lipid bilayer forms the basic matrix of biological membranes, and proteins (some of which are glycoproteins) are associated with it in various ways (Section 9.10). The oligosaccharides of glycoproteins and glycolipids are on the exterior surface of the membrane.*Figure 9.22Diffusion of lipids within a bilayer. (a) Lateral diffusion of lipids is relatively rapid. (b) Transverse diffusion, or flip-flop, of lipids is very slow.*Figure 9.23Diffusion of membrane proteins. Human cells whose membrane proteins had been labeled with a red fluorescent marker were fused with mouse cells whose membrane proteins had been labeled with a green fluorescent marker. The initially localized markers became dispersed over the entire surface of the fused cell within 40 minutes.*Figure 9.24Freeze fracturing a biological membrane. (a) Splitting the lipid bilayer along the interface of the two leaflets. A platinum replica of the exposed internal surface is examined in an electron microscope. Membrane proteins appear as protrusions or cavities in the replica. (b) Electron micrograph of a freeze-fractured erythrocyte membrane. The bumps on the inner membrane surface show the locations of membrane proteins.*Figure 9.25Phase transition of a lipid bilayer. In the ordered gel state, the hydrocarbon chains are extended. Above the phase-transition temperature, rotation around CC bonds disorders the chains in the liquid crystalline phase.*Box 9-4Schematic cross-section of a lipid vesicle, or liposome. The bilayer is made up of two leaflets. In each leaflet, the polar head groups of the amphipathic lipids extend into the aqueous medium, and the nonpolar hydrocarbon tails point inward and are in van der Waals contact with each other.*Figure 9.27Bacteriorhodopsin from Halobacterium salinarum. Seven membrane-spanning helices, connected by loops, form a bundle that spans the bilayer. The light-harvesting prosthetic group is shown in yellow. [PDB 1FBB]*Figure 9.28Ribbon structure of the transmembrane portion of porin FhuA from Escherichia coli. This porin forms a channel for the passage of protein- bound iron into the bacterium. The channel is formed from 22 antiparallel strands. [PDB 1BY3].*Figure 9.29Lipid-anchored membrane proteins attached to the plasma membrane. The three types of anchors can be found in the same membrane, but they do not form a complex as shown here. (a) A fatty acyl-anchored protein. (b) A prenyl-anchored membrane protein. Note that fatty acyl- and prenyl-anchored membrane proteins can also occur on the cytoplasmic (outer) leaflet of intracellular membranes. (c) Protein anchored by glycosylphosphatidylinositol. Shown here is the variant surface glycoprotein of the parasitic protozoan Trypanosoma brucei. The protein is covalently bound to a phosphoethanolamine residue, which in turn is bound to a glycan. The glycan (blue) includes a mannose residue, to which the phosphoethanolamine residue is attached, and a glucosamine residue, which is attached to the phosphoinositol group (red) of phosphatidylinositol. Abbreviations: GlcN, glucosamine; Ins, inositol; Man, mannose.*

*Figure 9.30Membrane transport through a pore or channel. A central passage allows molecules and ions of the appropriate size, charge, and geometry to traverse the membrane in either direction.*Figure 9.31Types of passive and active transport. Although the transport proteins are depicted as having an open central pore, passive and active transporters actually undergo conformational changes when transporting their solutes (Figure 9.33). (a) Uniport. (b) Symport. (c) Antiport.*Figure 9.32Kinetics of passive transport. The initial rate of transport increases with substrate concentration until a maximum is reached. Ktr is the concentration of substrate at which the rate of transport is half-maximal.*Figure 9.33Passive and active transport protein function. The protein binds its specific substrate and then undergoes a conformational change allowing the molecule or ion to be released on the other side of the membrane. Cotransporters have specific binding sites for each transported species.*Figure 9.34Secondary active transport in Escherichia coli. The oxidation of reduced substrates (Sred) generates a transmembrane proton concentration gradient. The energy released by protons moving down their concentration gradient drives the transport of lactose into the cell by lactose permease.*Figure 9.35Secondary-active transport in animals. The Na+-K+ ATPase generates a sodium ion gradient that drives secondary active transport of glucose in intestinal cells.*Figure 9.37General mechanism of signal transduction across the plasma membrane of a cell.*Figure 9.43Summary of the adenylyl cyclase signaling pathway. Binding of a hormone to a stimulatory transmembrane receptor (Rs) leads to activation of the stimulatory G protein (Gs) on the inside of the membrane. Other hormones can bind to inhibitory receptors (Ri) which are coupled to adenylyl cyclase by the inhibitory G protein Gi. Gs activates the integral membrane enzyme adenylyl cyclase, whereas Gi inhibits it. cAMP activates protein kinase A, resulting in the phosphorylation of cellular proteins.*Figure 9.38Hydrolysis of guanosine 5'-triphosphate (GTP) to guanosine 5'-diphosphate (GDP) and phosphate (Pi).*Figure 9.39G-protein cycle. G proteins undergo activation after binding to a receptorligand complex and are slowly inactivated by their own GTPase activity. Both GGTP/GDP and G are membrane-bound.*Figure 9.40Production and inactivation of cAMP. ATP is converted to cAMP by the transmembrane enzyme adenylyl cyclase. The second messenger is subsequently converted to 5'-AMP by the action of a cytosolic cAMP phosphodiesterase.*Figure 9.41Activation of protein kinase A. The assembled complex is inactive. When four molecules of cAMP bind to the regulatory subunit (R) dimer, the catalytic subunits (C) are released.*Figure 9.46Activation of receptor tyrosine kinases. Activation occurs as a result of ligand-induced receptor dimerization. Each kinase domain catalyzes phosphorylation of its partner. The phosphorylated dimer can catalyze phosphorylation of various target proteins.*Figure 9.48Insulin-stimulated formation of phosphatidylinositol 3,4,5-trisphosphate PIP3. Binding of insulin to its receptor activates the protein tyrosine kinase activity of the receptor, leading to the phosphorylation of insulin-receptor substrates (IRSs). The phosphorylated IRSs interact with phosphatidylinositide 3-kinase (PI kinase) at the plasma membrane, where the enzyme catalyzes the phosphorylation of PIP2 to PIP3. PIP3 acts as a second messenger, carrying the message from extracellular insulin to certain intracellular protein kinases.*Figure 9.44Phosphatidylinositol 4,5-bisphosphate (PIP2) produces two second messengers, inositol 1,4,5-trisphosphate (IP3) and diacylglycerol. PIP2 is synthesized by the addition of two phosphoryl groups (red) to phosphatidylinositol and hydrolyzed to IP3 and diacylglycerol by the action of a phosphoinositide-specific phospholipase C.*Figure 9.45Inositolphospholipid signaling pathway. Binding of a ligand to its transmembrane receptor (R) activates the G protein (Gq) This in turn stimulates a specific membrane-bound phospholipase C (PLC), which catalyzes hydrolysis of the phospholipid PIP2 in the inner leaflet of the plasma membrane. The resulting second messengers, IP3 and diacylglycerol (DAG), are responsible for carrying the signal to the interior of the cell. IP3 diffuses to the endoplasmic reticulum, where it binds to and opens a Ca2+ channel in the membrane, releasing stored Ca2+. Diacylglycerol remains in the plasma membrane, where italong with Ca2+activates the enzyme protein kinase C (PKC).