1. Chapter 9 - Lipids and Membranes Lipids are essential components of all living organisms Lipids are water insoluble organic compounds They are hydrophobic (nonpolar) or amphipathic (containing both nonpolar and polar regions )

2. Structural and Functional Diversity of Lipids Fatty acids - R-COOH (R=hydrocarbon chain) are components of triacylglycerols, glycerophospholipids, sphingolipids Phospholipids - contain phosphate moieties Glycosphingolipids - contain both sphingosine and carbohydrate groups Isoprenoids - (related to the 5 carbon isoprene) include steroids, lipid vitamins and terpenes

3. Structural relationships of major lipid classes

4. Fatty Acids Fatty acids (FA) differ from one another in: (1) Length of the hydrocarbon tails (2) Degree of unsaturation (double bond) (3) Position of the double bonds in the chain

5. Nomenclature of fatty acids Most fatty acids have 12 to 20 carbons Most chains have an even number of carbons (synthesized from two-carbon units) IUPAC nomenclature: carboxyl carbon is C-1 Common nomenclature:  etc. from C-1 Carbon farthest from carboxyl is 

6. Structure and nomenclature of fatty acids Saturated FA - no C-C double bonds Unsaturated FA - at least one C-C double bond Monounsaturated FA - only one C-C double bond Polyunsaturated FA - two or more C-C double bonds

7. Double bonds in fatty acids Double bonds are generally cis Position of double bonds indicated by  n, where n indicates lower numbered carbon of each pair Shorthand notation example: 20:4  5,8,11,14 ( total # carbons : # double bonds,  double bond positions )

8. Structure and nomenclature of fatty acids

9. Fatty acids are stored as triglycerols (triglycerides)

10. Glycerophospholipids The most abundant lipids in membranes Possess a glycerol backbone A phosphate is esterified to both glycerol and another compound bearing an -OH group Phosphatidates are glycerophospholipids with two fatty acid groups esterified to C-1 and C-2 of glycerol 3-phosphate

11. (a) Glycerol 3-P and (b) phosphatidate

12. Structures of glycerophospholipids (a) Phosphatidyl ethanolamine (b) Phosphatidyl serine (c) Phosphatidylcholine

14. Phospholipases hydrolyze phospholipids

15. Structure of an ethanolamine plasmalogen Plasmalogens - C-1 hydrocarbon substituent attached by a vinyl ether linkage (not ester linkage)

16. Sphingolipids Sphingolipids - sphingosine (trans-4-sphingenine) is the backbone (abundant in central nervous system tissues ) Ceramides - fatty acyl group linked to C-2 of sphingosine by an amide bond Sphingomyelins - phosphocholine attached to C-1 of ceramide

17. Cerebrosides - glycosphingolipids with one monosaccharide residue attached via a glycosidic linkage to C-1 of ceramide Galactosylcerebrosides (galactosylceramides) - a single  -D-galactose as a polar head group Gangliosides - contain oligosaccharide chains with N-acetyl-neuraminic acid (NeuNAc) attached to a ceramide

18. Structure of a galactocerebroside

19. Ganglioside G M2 (NeuNAc in blue)

20. Steroids Classified as isoprenoids - related to 5- carbon isoprene (found in membranes of eukaryotes) Steroids contain four fused ring systems: 3- six carbon rings (A,B,C) and a 5-carbon D ring Ring system is nearly planar Substituents point either down (  ) or up (  )

21. Cholesteryl ester

22. Other Biologically Important Lipids Waxes are nonpolar esters of long-chain fatty acids and long chain monohydroxylic alcohols Waxes are very water insoluble and high melting They are widely distributed in nature as protective waterproof coatings on leaves, fruits, animal skin, fur, feathers and exoskeletons

23. Myricyl palmitate, a wax

24. Eicosanoids Eicosanoids are oxygenated derivatives of C 20 polyunsaturated fatty acids (e.g. arachidonic acid) Prostaglandins - eicosanoids having a cyclopentane ring Aspirin alleviates pain, fever, and inflammation by inhibiting the synthesis of prostaglandins

25. Prostaglandins Prostaglandins are involved in many biological processes. Are biosynthesized from linoleic acid (C 18 ) via arachidonic acid (C 20 ).

28. Examples: PGE 1 and PGF 1  O HOOOH OH HO HO OHOOH PGE 1 PGF 1 

30. Aspirin Inhibits the Synthesis of Prostaglandins

31. Biological Membranes Are Composed of Lipid Bilayers and Proteins Biological membranes define the external boundaries of cells and separate cellular compartments A biological membrane consists of proteins embedded in or associated with a lipid bilayer

32. Several important functions of membranes Some membranes contain protein pumps for ions or small molecules Some membranes generate proton gradients for ATP production Membrane receptors respond to extracellular signals and communicate them to the cell interior

33. Lipid Bilayers Lipid bilayers are the structural basis for all biological membranes Noncovalent interactions among lipid molecules make them flexible and self-sealing Polar head groups contact aqueous medium Nonpolar tails point toward the interior

34. Membrane lipid and bilayer

35. Fluid Mosaic Model of Biological Membranes Fluid mosaic model - membrane proteins and lipids can rapidly diffuse laterally or rotate within the bilayer (proteins “float” in a lipid-bilayer sea) Membranes: ~25-50% lipid and 50-75% proteins Lipids include phospholipids, glycosphingolipids, cholesterol (in some eukaryotes) Compositions of biological membranes vary considerably among species and cell types

36. Structure of a typical eukaryotic plasma membrane

37. Lipid Bilayers and Membranes Are Dynamic Structures (a)Lateral diffusion is very rapid (b) Transverse diffusion (flip-flop) is very slow

38. Phase transition of a lipid bilayer Fluid properties of bilayers depend upon the flexibility of their fatty acid chains

39. Three Classes of Membrane Proteins (1) Integral membrane proteins (or intrinsic proteins or trans-membrane proteins) (2) Peripheral membrane proteins (3) Lipid-anchored membrane proteins

40. Lipid-anchored membrane proteins

41. Membrane Transport Three types of integral membrane protein transport: (1) Channels and pores (2) Passive transporters (3) Active transporters

42. Table 9.3 Characteristics of membrane transport

43. A. Pores and Channels Pores and channels are transmembrane proteins with a central passage for ions and small molecules Solutes of appropriate size, charge, and molecular structure can diffuse down a concentration gradient Process requires no energy Rate may approach diffusion-controlled limit

44. Membrane transport through a pore or channel Central passage allows molecules and ions of certain size, charge and geometry to transverse the membrane

45. B. Passive Transport Passive transport (facilitated diffusion) does not require an energy source Protein binds solutes and transports them down a concentration gradient

46. Types of passive transport systems Uniport - transporter carries only a single type of solute Some transporters carry out cotransport of two solutes, either in the same direction (symport) or in opposite directions (antiport)

47. Kinetics of passive transport Initial rate of transport increases until a maximum is reached (site is saturated)

48. The erythrocyte membrane contains channels that function to exchange anions, such as chloride (Cl - ) and bicarbonate (HCO 3 - ), across the membrane bilayer. From the following data, describe the effect that exogenous sulfate (SO 4 - ) has on (Cl - ) influx in erythroyctes.

49. C. Active Transport Transport requires energy to move a solute up its concentration gradient Transport of charged molecules or ions may result in a charge gradient across the membrane

50. Types of active transport Primary active transport is powered by a direct source of energy as ATP, light or electron transport Secondary active transport is driven by an ion concentration gradient

51. Primary active transport protein function Protein binds specific substrate, conformational change allows molecule or ion to be released on the other side of the membrane

52. Secondary active transport in E. coli Oxidation of S red generates a transmembrane proton gradient Movement of H + down its gradient drives lactose transport (lactose permease)

53. Secondary active transport in animals: Na + -K + ATPase Na + gradient (Na + -K + ATPase) drives glucose transport

55. Transduction of Extracellular Signals Specific receptors in plasma membranes respond to external chemicals (ligands) that cannot cross the membrane: hormones, neurotransmitters, growth factors Signal is passed through membrane protein transducer to a membrane-bound effector enzyme Effector enzyme generates a second messenger which diffuses to intracellular target

56. General mechanism of signal transduction across a membrane

57. G Proteins are Signal Transducers Many hormone receptors rely on guanine nucleotide-binding proteins (G proteins) as transducers G proteins have GTPase activity: they slowly hydrolyze the bound GTP to GDP and P i Two interconvertible forms of G proteins: an inactive GDP-bound form and an active GTP- bound form

58. Composition of G-proteins G proteins consist of ,  and  subunits The G  -GTP complex interacts with the effector enzyme Hydrolysis of GTP by the G  -GTP complex deactivates the G protein and permits assembly of the inactive G  complex

59. Hydrolysis of GTP to GDP and P i

60. G-protein cycle G proteins are activated by binding to a receptor-ligand complex G-proteins are inactivated slowly by their own GTPase activity

61. B. The Adenylyl Cyclase Signaling Pathway cAMP and cGMP are second messengers They transmit information from extracellular hormones to intracellular enzymes Many hormones that regulate intracellular metabolism exert effects on target cells by activating cAMP pathway

62. cAMP response to hormones cAMP response to hormones Hormones active the G protein G s G s activates adenylyl cyclase enzyme to produce cAMP cAMP activates protein kinases to phosphorylate cellular enzymes and affect metabolic pathway processes

63. Production,inactivation of cAMP

65. Activation of protein kinase A by cAMP

66. Caffeine, theophylline inhibit cAMP phosphodiesterase Inhibition of cAMP phosphodiesterases prolongs the effects of cAMP This increases the intensity and duration of stimulatory hormones

67. Summary of the adenyl cyclase signaling pathway

68. The Inositol-Phospholipid Signaling Pathway A major signal-transduction pathway for some hormones, growth factors (2 second messengers) Diacylglycerol and IP 3 (inositol 1,4,5 triphosphate) are produced from the membrane phospholipid PIP 2 (phosphatidylinositol 4,5-bisphosphate) IP 3 activates a calcium channel Diacylglycerol activates protein kinase C

69. Phosphatidylinositol 4,5-bisphosphate (PIP 2 ) produces IP 3 and diacylglycerol

71. Inositol- phospholipid signaling pathway

72. D. Receptor Tyrosine Kinases (TK) Many growth factors operate by a signaling pathway involving a tyrosine kinase TK is a multifunctional transmembrane protein containing a receptor, a transducer, and an effector Binding of a ligand to the extracellular receptor domain activates tyrosine kinase (intracellular)

73. Activation of receptor tyrosine kinases by ligand-induced dimerization

74. Phosphorylated dimer phosphorylates cellular target proteins

75. Each domain catalyzes phosphorylation of its partner

76. Insulin receptor and tyrosine kinase activity Insulin binds to 2 extracellular  -chains Transmembrane  -chains then autophosphorylate Tyrosine kinase domains then phosphorylate insulin- receptor substrates (IRSs) (which are proteins)

77. Insulin-stimulated formation of PIP 3