• sheet-like structures, a few molecules thick, forming closed boundaries (self-sealing)
• amphipathic lipids - polar "head" groups and nonpolar "tails"
  • with 2 hydrophobic "tails", amphipathic lipids form BILAYERS instead of micelles.
• Proteins carry out most of the specific functions.
• carbohydrate components (covalently attached to lipids = glycolipids, or to proteins = glycoproteins) - important in communication/recognition
• noncovalent assembly (interactions between components) into a FLUID 2-dimensional solution
  • Proteins & lipids can diffuse rapidly in the plane of the membrane, but
  • Proteins and lipids DO NOT ROTATE across the membrane (no "flip-flop" in orientation across membrane).
• asymmetric arrangement - 2 sides (faces) different (biosynthesized that way)
  • Membranes always synthesized by growth of preexisting membranes
  • Components don’t "flip-flop" their orientation.
    
• Amphipathic nature of membrane lipids
  • hydrophilic portion and hydrophobic portion
  • hydrophilic moiety = "head"; hydrophobic chain(s) = "tails"
    
  • Consequence: Amphipathic lipids form micelles or bilayers, to bury their hydrophobic tails so they're NOT exposed to H₂O, but keep the hydrophilic head groups in contact with H₂O.
    
  • Lipids with single hydrophobic tails can form micelles, but
  • MEMBRANE LIPIDS ALMOST ALL HAVE 2 TAILS, AND THUS FORM BILAYERS.
    
• The hydrophobic effect provides the major driving force for the formation of lipid bilayers.
  

  Berg,Tymoczko & Stryer, 6th ed. Fig. 12.9: "slice" through a micelle

  Berg,Tymoczko & Stryer, 6th ed. Fig. 12.10: "slice" through a bilayer membrane

  
  
• Liposomes: lipid vesicles, aqueous compartments enclosed by a lipid bilayer
  • experimental tools for studying membrane permeability
  • vehicles for delivery to cells of chemicals/drugs/DNA for gene therapy

• Berg,Tymoczko & Stryer, 6th ed. Fig. 12.12: "slice" through a liposome

  
  
  
• MEMBRANE FUNCTIONS:
  
  • 1) HIGHLY SELECTIVE PERMEABILITY BARRIERS
    • regulate molecular and ionic compositions of cells and intracellular organelles
    • a) channels & pumps (proteins that act as selective transport systems)
  • b) electrical polarization of membrane (inside of plasma membrane negative, typically - 60 millivolts)
    • maintenance of different ionic concentrations on opposite sides of membrane
  • 2) INFORMATION PROCESSING - biological communication
  • a) signal reception by specific protein receptors (BINDING)
  • b) transmission/transduction of signals (via protein conformational changes)
    • sometimes generation of signals, chemical or electrical, e.g., nerve impulses
  • 3) ENERGY CONVERSION - ordered arrays of enzymes & other proteins, organization of reaction sequences
  • a) photosynthesis (light energy → chemical bond energy)
    • inner membranes of chloroplasts, and plasma membranes of some prokaryotes
  • b) oxidative phosphorylation (oxidation of fuel molecules → chemical bond energy "stored" in ATP)
    • inner membranes of mitochondria, and plasma membranes of prokaryotes
      
• LIPIDS (definition): water-insoluble biomolecules that are highly soluble in organic solvents
  
  • Biological functions: fuels (highly concentrated energy stores), signal molecules, membrane components
    
    
• LIPID COMPONENTS OF MEMBRANES (emphasis here is on ANIMAL CELL membranes)
  
• Membrane LIPID functions:
  • bilayer structure → compartments/permeability barriers
  • provide environment for proteins to work
  • electrical insulation (e.g., myelin sheath on myelinated nerve fibers, but also maintenance of electrical potential in other cells)
    
• Membrane lipid distribution: functional significance of all the differences not really understood
  • proportions of different lipids vary by
    • type of membrane (plasma membrane vs. mitochondrial membrane vs. nuclear membrane, etc.)
    • type of cell
      
  • asymmetry (inner vs. outer "leaflets" [layers of bilayer])
    • can be maintained because of extremely slow rate of rotation of components across membrane
    • "flip-flop" essentially doesn’t occur except when catalyzed by "flippases" (proteins that may be involved in creating and maintaining lipid asymmetries across the membrane)
      
  • environment (esp. temperature - lipid composition regulates fluidity)
    
  • NOTE: GLYCOLIPIDS (have carbohydrate components) found only in the OUTER leaflet of plasma membranes.
  • Carbohydrate components of GLYCOPROTEINS are found only on the OUTSIDES of cells, even when protein itself spans the membrane.)
    
    
• FATTY ACID COMPONENTS of membrane lipids:
  • longchain carboxylic acids, typically 14-24 C atoms
  • C16 & C18 most common (amphipathic) RCOO^– with 0 - 4 double bonds, usually cis
  • Berg,Tymoczko & Stryer, 6th ed. Fig. 12.2: Structures of 2 fatty acids:
    

• palmitate (16-C saturated F.A.) oleate (18-C unsat. F.A., with 1 cis double bond --note "kink" in structure) amphipathic molecules

• 3 TYPES OF BACKBONE in membrane lipids (all 3 types are amphipathic lipids):

  • GLYEROL (glycerophospholipids), a 3-carbon tri-alcohol: CH2OH-CHOH-CH2OH
  • SPHINGOSINE (sphingolipids, both sphingophospholipids and sphingoglycolipids)
  • CHOLESTEROL (a steroid compound)
    
  • 1. PHOSPHOGLYCERIDES (glycerophospholipids, sometimes called "glycerophosphatides")

    • parent compound = phosphatidic acid (phosphatidate at pH 7)
    • start with glycerol backbone (3 carbon tri-alcohol, CH₂OH-CHOH-CH₂OH)
    • diacylglycerol (fatty acids esterified to the C1 and C2 OH groups on glycerol; R₁ usually saturated, R₂ usually unsaturated -- F.A.s usually 16-18 C's)
    • C3 esterified to phosphate
    • PLUS a 2nd substituent also esterified to phosphate (any one of several alcohols):
      ethanolamine, choline, serine, glycerol, inositol, phosphatidyl glycerol

Berg, Tymoczko & Stryer, 6th ed. Fig. 12.3: Schematic structure of glycerophospholipids

Berg, Tymoczko & Stryer, 6th ed. Fig. 12.4: Phosphatidate structure -- note fatty acyl groups esterified to #1 and #2 OH groups

• Results of esterifying different alcohols to the phosphate on C3:

• phosphatidyl choline (lecithin)
• phosphatidyl ethanolamine (cephalin)
• phosphatidyl serine
• phosphatidyl inositol
• phosphatidyl glycerol
• diphosphatidyl glycerol (cardiolipin)
• Berg, Tymoczko & Stryer Fig. 12.5: Some common phosphoglycerides found in membrane

• different net charges on different phosphoglyerides at pH 7
  • (1 - charge on phosphate, zero or 1 + charge on the "alcohol" substituent on the phosphate)
    
• phospholipase (PL) cleavage sites (phospholipases catalyze hydrolysis of ester bonds in phospholipids)
• Nelson & Cox, Lehninger Principles of Biochemistry, 4th ed. (2004) Fig. 10-15: Specificities of phospholipases (catalyze hydrolysis of the ester bonds at the specific positions indicated on glycerophospholipids)
  • phospholipases A₁, A₂, C, D
  • PL A₁ cleaves ester bond to C1 OH
  • PL A₂ cleaves ester bond to C2 OH
  • PL C cleaves phosphate ester bond to C3 OH
  • PL D cleaves phosphate ester bond to the other alcohol (choline, ethanolamine, or whatever)
  • activity of phospholipases important in signaling pathways
    
• 2. SPHINGOLIPIDS (backbone = sphingosine)
  
  • Similarity/differences with glycerol-based lipids (easier to see in Lehninger Principles figure below):
    
    • C1 has an OH group (can be esterified to phosphate, or in a glycosidic bond to carbohydrate)
    • C2 has amino group (-NH³⁺) instead of -OH on glycerol → F.A.s in amide linkage (not ester)
    • C3 has long hydrocarbon chain, with 1 double bond, instead of one H atom on glycerol
      
  • Ceramides have fatty acid in AMIDE linkage to amino group of C2 in ALL the sphingolipids.
• Nelson & Cox, Lehninger Principles of Biochemistry, 4th ed. (2004): Structures of a ceramide (parent structure for the other sphingolipids) and of classes of sphingolipids (see also Berg, Tymoczko & Stryer Fig. 12-6)
• • Phosphosphingolipids have phosphate esterified to C1 OH.
    
    • SPHINGOMYELINS have choline (OH group) (or sometimes ethanolamine) esterified to the C1 phosphate.
• Glycosphingolipids (especially abundant in nerve cell membranes)
  • no phosphate group on C1 OH of sphingosine
  • Glycosphingolipids have 1 or more SUGARS attached to C1 OH group in a glycosidic bond (same kind of bond that connects sugar units in polysaccharides like glycogen)
    • cerebrosides (1 sugar unit, either glucose or galactose) (see structure on p. 325 of Berg et al.)
• gangliosides (complex oligosaccharides with branched sugar chains on C1 OH)
• Membrane lipids undergo constant metabolic turnover, rate of synthesis and rate of breakdown being balanced.
• Degradation of lipids: specific enzymes required for each different bond hydrolyzed
• Genetic defects (deficiencies in specific enzymes) in glycosphingolipid breakdown → abnormal accumulation of partially degraded lipids, with toxic results (genetic diseases).
  examples:
  • Tay-Sachs disease -- lack of hexosaminidase A, needed to hydrolyze glycosidic bond attaching terminal N-acetylgalactosamine residue in ganglioside GM2
    • causes mental retardation, blindness, muscular weakness, death by age 3-4

• Nelson & Cox, Lehninger Principles of Biochemistry, Box 10-2, Fig. 2: electron micrograph of portion of a brain cell from infant with Tay-Sachs disease, showing abnormal ganglioside GM2 deposits in the lysosomes

  • Niemann-Pick disease type A,B -- lack of sphingomyelinase, enzyme needed to hydrolyze phosphate ester linkage of phosphocholine to ceramide
    • symptoms include enlarged liver and spleen, mental retardation, early death
• 3. CHOLESTEROL
  
  • structure: 4 fused hydrocarbon rings, 3 with 6 C's, 1 with 5 C's (steroid nucleus)
  • planar, rigid, electrically neutral
  • amphipathic ("head" group = OH)
  • mainly in plasma membranes of animal cells, whereas organelle membranes generally have less (rarely found in bacteria)
    
  • functions:
    • important membrane constituent (influences fluidity)
    • precursor of bile acids (emulsifiers)
    • precursor of hormones (steroid hormones)
  • 
    
• Other lipids (not structural components of membranes, but biologically important): eicosanoids, steroid hormones, vitamins A, D, E, and K, electron carriers (ubiquinone in mitochondrial membranes, plastoquinone in chloroplast membranes), sugar carriers (dolichols)
  • Eicosanoids: paracrine hormones (locally acting)
    • all synthesized starting from arachidonic acid (a 20-carbon fatty acid with 4 double bonds, removed by phospholipase A₂ from position 2 of membrane glycerophospholipids)
  • prostaglandins: mediate fever, inflammation and pain, among other functions
  • thromboxanes (involved in blood clotting)
  • leukotrienes (smooth muscle contraction, e.g. muscle lining airways to lungs -- overproduction causes asthmatic attacks and is involved in anaphylactic shock, potentially fatal allergic reaction)
  • isoprenoid lipids
    • all synthesized by condensation of isoprene units
    • cholesterol and other steroids
    • fat-soluble vitamins
    • ubiquinone and plastoquinone (mobile electron carriers in membranes)
    • dolichols
      
      
• MEMBRANE FLUIDITY -- controlled by lipid composition
  
  • hydrocarbon chains: close packing, maximum interaction between chains at low temperatures → rigid "gel"; the longer the chains and the more saturated (fewer double bonds), the more ordered/rigid the state of the lipid bilayer
    
  • transition temperature: lipid bilayer undergoes phase change ("melting") to more disorderly, FLUID state (HC chains not so closely packed)
    
  • transition temperature is lowered (so relative fluidity increases) by fatty acid structures that reduce favorable packing interactions:
    
    • a) shorter hydrocarbon chainlength, and
    • b) more double bonds (which make "bends" in the chain)
      
  • Berg, Tymoczko & Stryer, 6th ed. Fig. 12.33: Highly ordered packing of fatty acid side chains (stabilized by lots of close van der Waals interactions) is disrupted by cis double bonds (kinks). With more double bonds, the membrane remains fluid at lower temperatures (transition temp. is lowered).
    
    
    
• MEMBRANES OF LIVING CELLS MUST BE FLUID, i.e. must have transition temperatures BELOW body temperature of the organism.
  
  • Regulation of fluidity (especially in organisms that don’t rigorously control their body temp.)
  • 1) fatty acid chainlength
  • 2) number of double bonds
  • 3) Cholesterol (animal cells) "stiffens" membrane by packing between unsaturated HC tails, but also disrupts close packing between saturated tails, so broadens the transition sort of like a fluidity "buffer", when temperature or fatty acid composition changes
  • Jmol structure of bilayer
    

• Berg, Tymoczko & Stryer, 6th ed. Fig. 12.8: Spacefilling models, membrane lipids shorthand depiction of an amphipathic membrane lipid with a polar head group and 2 hydrophobic "tails"	Berg, Tymoczko & Stryer, 6th ed. Fig. 12.11: Spacefilling model of section of phospholipid bilayer

  
  
  • LIPID BILAYERS
    
  • formed spontaneously by phospholipids
    • Single-tailed amphipathic lipids form micelles in H₂O (spheres with polar head groups out, exposed to H₂O, nonpolar tails buried in center)
    • "2-tailed" amphipathic lipids spontaneously form BILAYERS, burying the tails between the 2 layers.
      • 2 tails (e.g., phosphoglycerides and sphingolipids) don’t fit in middle of a micelle -- surface with head groups not large enough to bury double tails
  • self-assembling and self-sealing -- form and grow spontaneously, and close in on themselves spontanously, because a "hole" would expose the lipid tails to the H₂O.
    
  • bilayer structure stabilized by
    • hydrophobic effect (the driving force for their formation)
    • hydration of polar/charged head groups
    • van der Waals interactions (packing between atoms in hydrophobic core).
      
  • highly impermeable to ions and most polar molecules
    • Permeability coefficients correlated with solubility in nonpolar solvent relative to solubility in H₂O
    • Hydrophobic core of the membrane is analogous to a nonpolar solvent.
    • Membrane permeabilities to ions and molecules vary --
      • least permeable to charged species
      • also not very permeable to polar species
      • more permeable to nonpolar species