Biology 2315 Lecture Notes

Chapter 8: Lipids and Membranes

Outline

• Fatty acids
  
• Triacylglycerols
  
• Glycerophospholipids
  
• Sphingolipids
  
• Steroids
  
• Biological membranes are composed of lipid bilayers and proteins
  
• Lipid bilayers and membranes are dynamic structures
  
• Membrane transport
  
• Transduction of extracellular signals
  
• Lipid Soluble Vitamins
  
  • Vitamin A
    
  • Vitamin D
    
  • Vitamin E
    
  • Vitamin K
• Other lipids include
  • Prostaglandins
  • Leukotrienes
  • Thromboaxanes

Lipids are a structurally diverse group of compounds which are nonpolar in nature and insoluble in water. Lipids are readily soluble in organic solvents, such as chloroform or acetone. Lipids are natural compounds with very diverse functions, including, forming the structural basis of biological membranes, energy storage, insulation, padding, protection (waxes), signaling (hormones), cellular recognition, etc... Lipids are essential components of all living things.This chapter focuses on structure and function of the different classes of lipids.

• Highly varied structures.Two types:
  
  • 1. Hydrophobic (nonpolar): E.g. Triglycerides
    
  • 2. Amphipathic (contain both polar and nonpolar regions): E.g. phospholipids
    

Fatty acids

• Simplest lipids
  
• General formula: R–COOH (R = hydrocarbon tail)
  
• Components of many types of lipids.
  
• More than 100 have been identified: They differ in:
  
  • 1. length of carbon chain
    
  • 2. degree of unsaturation (C=C bonds)
    
• Most have a pK_a of about 4.5-5, therefore are ionized at physiological pH. Therefore, fatty acids are detergents. Their concentration in body is low because they can disrupt membranes.
  
• Table 8.1: most fatty acids have 12-20 carbons
  
  • usually even numbered because synthesized by addition of 2-C units (from acetyl-CoA).
    
  • carboxyl carbon labelled C-1. The rest sequentially.
    
  • w specifies carbon furthest from carboxyl group (regardless of length).
    
• Saturated fatty acids have no C=C double bonds.
  
• Unsaturated fatty acids have at least 1 C=C bond ( more than 2 = polyunsaturated)
  • stereochemistry at double bond is usually cis. Fatty acids with trans double bonds have shapes similar to that of saturated fatty acid in its fully extended conformation.
  • Double bonds in fatty acids not usually found side by side. Fatty acids do not normally have conjugated double-bond systems.
    
• Short-hand notation of fatty acids: eg: 18:2 D^9,12 where 18 = # carbons, 2 = number of double bonds, double bonds present at C-9 and C-12.
  
• Physical properties of Fatty acids (FA)
  
  • Differ considerably.
    
  • At RT, saturated FA are waxy solids, whereas unsaturated FA are liquids (oils).
    
  • Length of hydrocarbon chain of FA and degree of unsaturation influence melting point (Table 8.2): as tail length increases, so does melting point (due to van der Waals interactions).
    
  • Saturated hydrocarbon tail is flexible since rotation can occur around every carbon-carbon bond.
    
  • Unsaturated hydrocarbons have "kinks" due to presence of double bonds and do not pack well, resulting in little van der Waals interactions. As a result have a lower melting point. The higher the degree of unsaturation the lower the melting point.
    
  • Most fatty acids do not exist in free form and are usually esterified to form more complex lipid molecules
    
  • Relative abundance of particular fatty acids varies with type of organism and food source.
    
  • In animals, oleate (18:1), palmitate (16:0) and stearate are most abundant.
    
• Essential fatty acids = can not be synthesized therefore required from diet. Mammals must get inolate (18:2) from plants and fish oils.
• Fatty acids are transported in the bloodstream bound to albumin. Albumin accounts for half of the serum proteins.
• Fatty acids are the hearts favorite energy source. Fatty acids are degraded by into acetylCoA which is then oxidixed during cellular respiration.
  

Triacylglycerols

• Fatty acid molecules are important metabolic fuels because their carbon atoms are more reduced than proteins and carbohydrates (i.e. yield more energy in cellular respiration). Good light-weight fuel for animals on the go. Complete oxidation of fat yields 9 kcal/g, whereas both carbohydrates and proteins yield 4 kcal/g.
  
• Fatty acids stored as neutral lipids called triacylglyrerols in fat cells (adipose).

  
  

• Not found in membranes.
  
• Triacylglycerols are composed of 3 fatty acyl residues esterified to glycerol (Fig 8.2 ).
  • very hydrophobic.
    
  • fats and oils are mixtures of triacylglycerols
    
  • differ in their fatty acyl groups
    
  • most lipids in diet are triacylglycerols. Hydrolyzed in small intestine by Pancreatic lipases into fatty acids and glycerol..
    
• Lipases
  • synthesized and secreted as zymogens.
    
  • catalyzes hydrolysis of primary esters (C-1 and C-3), releasing fatty acids and monoacylglycerols (Fig 8.3).
    
  • lipid digestion occurs in presence of strong detergents called bile salts, which are amphipathic derivatives of cholesterol.
  • Saponification: hydrolysis of triglycerides in presence of strong base (NaOH) to form fatty acid salts (soap).
• Micelles solubilize fatty acids and monoglycerols.
  
  • lipids transported through the body as complexes of lipid and protein known as lipoproteins.
    
  • in adipose tissue, triacylglycerols aggregate in cytoplasm as droplets surrounded by layer of amphipathic phospholipids.
    

Glycerophospholipids

• Most abundant lipid in membranes (Fig8.4): simplest glycerophospholipid is phosphatidate.

  
  

  • composed of glycerol 3-phosphate with 2 fatty acyl groups esterified to C-1 and C-2
  • Amphipathic: phosphate group is charged (polar) and hydrocarbon tails are nonpolar
    
• In most glycerophospholipids, the phosphate group is esterified to both glycerol and another group(Fig 8.5).

  
  

• Each type of glycerophospholipid is a family of molecules that have the same polar head group and many different fatty acyl groups.
  
  • E.g. Red blood cells have about 21 different kinds of phosphatidylcholine
    
• In general, fatty acid at C-1 is saturated and fatty acid at C-2 is unsaturated.
  
• Different phospholipases are used to dissect glycerophospholipid structure.
  
  • Phospholipase A1
    
  • Phospholipase A2
    
  • Phospholipase C
    
  • Phospholipase D
    

Sphingolipids

• Second most abundant lipids in membranes
  
• In mammals, sphingolipids are abundant in CNS.
  
• Structural backbone of sphingolipids is sphingosine (Fig 8.6).
  
• Ceramide consists of a fatty acyl group linked to C-2 amino group of sphingosine by an amide bond. . Ceramides are the precursors to all sphingolipids.
  
• 3 families of sphingolipids:
  
  • 1. sphingomyelins (considered a phospholipid)(Fig 8.6)
    
    • present in plasma membranes of most mammalian cells
      
    • major component of myelin sheath surrounding some nerve cells.
      
  • 2. cerebrosides
    
    • contain monosacccharide residue attached by b-glycosidic linkage to C-1 (Fig 8-7)
      
    • account for 15% of lipid content of myelin sheath
      
  • 3. gangliosides
    
    • glycosphingolipids that contain oligosaccharide chains attached to C-1 (Fig 8-8).
      
    • embedded in membranes: ceremide portion embedded and the oligosaccharides are on surface of cell
      
    • many different types found
      
    • serve in cellular recognition and cell-cell communication
      
    • The human ABO blood group antigens on the surface of RBC are oligosaccharide chains of glycosphingolipids.
      
    • People afflicted with Tay-Sachs disease have inherited defects in their ganglioside metabolism.
      

Steroids

• Classfied as isoprenoids since derived from isoprene.
  
• Third class of membrane lipids.
  
• Contain 4 fused rings, making it rigid. (Fig 8.9).
  
• The steroid cholesterol is important component of animal plasma membranes. Rare in plants. Not found in prokaryotes.
  
• Steroids differ in the length of side chains attached to C-17 and in the number and placement of methyl groups, double bonds, and hydroxyl groups.
  
• Mammalian steroid hormones are derived from cholesterol.
  
• Cholesterol plays essentail role in mammalian biochemistry:
  
  • component of membranes (modulates fluidity).
    
  • precursor to steroid hormones and bile salts.
    
  • estrogens, androgens, progestins, and adrenal corticosteroids.
    
• Cholesterol is more hydrophobic than phospholipids and sphingolipids. Must also be complexed as lipoproteins for transport.
  
  

Biological membranes are composed of lipid bilayers and proteins

• Essential for existence of cells as independent entities.
  
• Not passive barriers, but dynamic with huge variety of complex functions.
  
  • selective pumps
    
  • generation of proton gradients and production of ATP by oxidative phosphorylation.
    
  • membrane receptors recognize extracellular signals and communicate to interior
    
• Lipid bilayers
  
  • Structural basis for all biological membranes
    
  • 5 to 6 nm thick
    
  • Consist of two leaflets (layers) (Fig 8.10). In each layer, polar head groups of amphipathic lipids are in contact with aqueous medium, and nonpolar hydrocarbon tails point toward interior of bilayer.
    
  • Noncovalent interactions among lipids in bilayers make membranes flexible and allow them to self seal.
    
  • Spontaneous formation of lipid bilayers is driven by the hydrophobic effect. When lipids molecules associate, the entropy of the solvent molecules increases.
    
  • Typical biological membranes consist of phospholipids, sphingolipids and in some eukaryotes, cholesterol.
    Fluid mosaic model of biological membranes (Fig 8.11)
    
  • typical membrane is 40% lipid, 60 % protein, and up to 10% carbohydates (varies a lot).
    
• Fluid mosaic model (Singer and Nicolson) describes the arrangement of protein within a membrane. Membrane proteins are visualized as globular icebergs floating in a highly fluid lipid-bilayer. Accordingly, membrane is seen as a dynamic structure in which both proteins and lipids diffuse laterally or rotate within the bilayer.
  

Lipid bilayers and membranes are dynamic structures

• Lateral diffusion of lipids is very rapid. Bilayer is a two-dimentional solution.
  
• Passage of lipids from one layer to another (transverse diffusion) occurs very slowly.
  
• energy barrier associated with this movement is too high.
  
• allows inner and outer layes of membrane to differ in lipid composition.
  
• Many proteins can also move laterally, but at much slower rates than lipids (100-500X slower).
  
  • Frye and Edidin experiment on fusion with fluorescently marked human and mouse cells. Demonstrated that at least some membrane proteins diffuse freely.
    
  • movement of some proteins is restricted by aggregation or by attachment to cytoskeleton..
    
• Freeze-fracture electron microscopy.
  
  • splitting the membrane along the interface of the two leaflets
    
  • exposes membrane proteins, which show up as protrusions. Inner leaflet has many more proteins then outer leaflet.
    
• Fluid properties of bilayers depend on the flexibility of their fatty-acyl chains.
  
  • saturated fatty acyl chains are fully extended at low temps , forming a crystaline array with max van der Waals forces. During phase transition (solid to liquid) chains become more loosely ordered and loosely packed (Fig 8.15).
    Phase transition temperature = temperature at which a lipid undergoes phase transition.
    
    • changes in membrane fluidity affects the catalytic properties of membrane proteins, so many organisms maintain membrane fluidity under different conditions by adjusting the the ratio of saturated to unsaturated fatty acyl grous in their membrane lipids.
      
  • Cholesterol accounts for 20-25% of the mass of typical mammalian plasma membrane and significantly affects membrane fluidity .
    
    • cholesterol broadens the phase-transition temperatures range of a lipid bilayer
      
  • at low temps, cholesterols prevents close packing. At higher temps, intercalation between hydrocarbon chains restricts movement of lipids and fluidity decreases.
    
• Three classes of membrane proteins
  
  • 1. integral membrane proteins
    
    • contain hydrophobic regions embedded into membrane
      
    • span entire membrane
      
  • 2. peripheral membrane proteins
    
  • associated with one face of the membrane
    
• 3. lipid-anchored membrane proteins
  
  • tethered to a membrane through covalent bond to a lipid anchor (Fig 8.16 and 8.17)
    

Membrane transport

• Pores and channels
  
• Passive transport
  
• Active transport (sodium/potassium pump Fig 8.24)
  
• Endocytosis and Exocytosis
  

Transduction of extracellular signals

• Plasma membranes of all cells contain specific receptors that allow the cell to respond to external chemical stimuli that can not cross the membrane ( e.g. LDL receptor (Fig 8.27).
  
• General mechanism for signal transduction: ligand binds receptor, signal passed through a membrane protein transducer to a membrane-bound effector enzyme. Action of effector enzyme generates an intracellular signal (second messenger) that leads to the activation of protein kinases.
  
• Signal gets amplified at each stage. This series of amplification events is called a cascade. Means that small amounts of extracellular compound can effect large changes in cell.
  
• The Neuromuscular Junction:
  
  • The neuromuscular junction is the interface between the nervous system and muscles. Gated channels are essential for excitable cells such as nerve and muscle cells. Two type of gated channels:
    
    • Ligand gated channels
      
      • ion flow regulated by the binding of some substance in the extracellular fluid to the receptor (e.g. acetylcholine receptor).
        
    • Voltage gated channels
      
      • these are sensitive to electric field across membrane. Switch between open and closed forms control ion flow (present along entire length of axons as well as at neuromuscular junction.
        

Lipid Soluble Vitamins

• Vitamin A (Fig 8.28)
  • Also known as retinol. Only present in animals. Animals make vit A from precursor b-carrotene (present in carrots and yellow vegetables).
  • A derivative of vit A plays a crucial role in vision when bound to a protein called opsin to produce rhodopsin (present in cones and rods of eye).
  • Deficiency of vit A may cause blindness.
    
• Vitamin D (Fig 8.30)
  • A group of structurally related compounds that play a role in regulation of calcium and phosphorous metabolism.
  • Vit D3 made from cholesterol by the action of UV radiation form the sun.
  • Presence of Vit D3 leads to increased absoption of dietary calcium .
  • Deficiency in Vit D can lead to Rickets (soft bones lead to deformities).
    
• Vitamin E
  
• Vitamin K (Fig 8.32)

Other lipids include

• Prostaglandins
  • A family of compounds that have a 20-carbon skeleton of prostanoic acid. Prostaglandins are synthesiszed from membrane-bound arachidonic acid (Fig 8.33) .
  • Present in many tissues and are involved in:
    • control of blood pressure
    • stimulation of smooth muscle contraction
    • induction of inflamation.
• Leukotrienes
  • Also derived from arachidonic acid (Fig 8.34).
  • Found in white blood cells (leukocytes).
  • Play important role in constriction of smooth muscles, especially in the lungs.
  • Allergic reations lead to synthesis and release of leukotrienes. Compounds that block leukotriene synthesis or leukotriene receptors are used as therapeutics in asthma.
• Thromboaxanes
  • Also derived from arachidonic acid.
  • Induce platelet aggregation (blood clotting) and smooth muscle contraction.

• End of Chapter Questions: 17 -23, 25, 27-29, 32-36, 38, 39, 41, 42, 43, 46, 49.
• Tay Sachs Disease
• More notes on lipids and membranes