Lipids and Membranes

1. Lipids and Membranes

2. Lipids • Lipids are compounds that are soluble in non-polar organic solvents, but insoluble in water. • Can be hydrophobic or amphipathic

3. Major Lipid Classes • Acyl-lipids - contain fatty acid groups as main non-polar group • Isoprenoids – made up of 5 carbon isoprene units

4. Lipid Subclasses

5. Function of major acyl-lipids • Phospholipids – membrane components • Triacylglycerols – storage fats and oils • Waxes – moisture barrier • Eicosanoids – signaling molecules (prostaglandin) • Sphingomyelins – membrane component (impt. in mylein sheaths) • Glycospingolipids – cell recognition (ABO blood group antigen)

6. Function of major isoprenoid lipids • Steroids (sterols) – membrane component, hormones • Lipid Vitamins – Vitamin A, E, K • Carotenoids - photosynthetic accessory pigments • Chlorophyll – major light harvesting pigment • Plastoquinone/ubiquinone – lipid soluble electron carriers • Essential oils – menthol

7. Fatty acids • Amphipathic molecule • Polar carboxyl group • Non-polar hydrocarbon tail • Diverse structures (>100 different types) • Differ in chain length • Differ in degree of unsaturation • Differ in the position of double bonds • Can contain oxygenated groups

8. Fatty acid nomenclature • Short hand nomenclature describes total number of carbons, number of double bonds and the position of the double bond(s) in the hydrocarbon tail. C18:1 D9 = oleic acid, 18 carbon fatty acid with a double bond positioned at the ninth carbon counting from and including the carboxyl carbon (between carbons 9 and 10)

9. Fatty acid nomenclature • Omega (w) notation – counts carbons from end of hydrocarbon chain. • Omega 3 fatty acids advertised as health promoting • Linoleate = 18:3 D9,12,15 and 18:3w3,6,9

10. Common saturated fatty acids

11. Common unsaturated fatty acids

12. Physical Properties of Fatty acids 18:0 18:1 18:3 • Saturated chains pack tightly and form more rigid, organized aggregates • Unsaturated chains bend and pack in a less ordered way, with greater potential for motion 70o 13o -17o

13. Melting points of fatty acids affect properties of acyl-lipids • Membrane fluidity determined by temperature and the degree of fatty acid unsaturation of phospholipids • Certain bacteria can modulate fatty acid unsaturation in response to temperature • Difference between fats and oils • Cocoa butter – perfect melt in your mouth fat made of triacylglycerol with 18:0-18:1-18:0 fatty acids • Margarine is hydrogenated vegetable oil. Increase saturation of fatty acids. Introduces trans double bonds (thought to be harmful)

14. Unusual fatty acids can function analogously to unsaturated fatty acids

15. Major acyl-lipids • Phospholipids – membrane components • Triacylglycerols – storage fats and oils • Waxes – moisture barrier • Eicosanoids – signaling molecules (prostaglandin) • Sphingomyelins – membrane component (impt. in mylein sheaths) • Glycospingolipids – cell recognition (ABO blood group antigen)

16. Phospholipids • Phospholipids are built on glycerol back bone. • Two fatty acid groups are attached through ester linkages to carbons one and two of glycerol. • Unsaturated fatty acid often attached to carbon 2 • A phosphate group is attached to carbon three • A polar head group is attached to the phosphate (designated as X in figure)

18. Common membrane phospholipids

19. Enzymes used to Dissect Phospholipid Structure

20. Plasmalogens • Plasmalogens have hydrocarbon at carbon 1 attached thru vinyl ether linkage • Polar head group could be ethanolamine or choline • Important component of membranes in central nrevous system

21. Sphingolipids • Sphingolipids named from Sphinx due to mysterious role • Abundant in eukaryotic membranes, but not found in bacteria • Structural backbone made of sphingosine • Unbranched 18 carbon alcohol with a trans double bond between C4 and C5 • Contains an amino group attached to C2 and hydroxyl groups on C1 and C3

22. Ceramides • Sphingosine with fatty acid attached to carbon 2 by amide linkage • Metabolic precursors to sphingolipids

23. Sphingomyelin • has phosphocholine group attached to C1 of ceramide. • Resembles phosphatidylcholine • Major component of myelin sheaths that surround nerve cells

24. Cerebrosides • contains one monosaccharide residue attached to C-1 of ceramide • Glucose and galtactose are common • Can have up to 3 more monosaccharide residues attached to sugar on C1 • Abundant in nerve tissue • Up to 15% of myelin sheath made up of cerebrosides

25. Gangliosides • Gangliosides have oliosaccharide containing N-acetylneuraminic acid attached to C1 of ceramide • Diverse class of sphingolipid due to variety of olgosaccharide species attached • Oligosaccharide moiety present on extracellular surface of membranes • ABO blood group antigens are gangliosides • Impt in cell recognition, cell-cell communication

26. Defects in sphingolipid metabolism lead to disease state • Tay-Saachs disease is a genetic defect in gangliosides degradation. Gangliosides accumulate in spleen and brain. Leads to retardation in development, paralysis, blindness, and early death. • Niemann-Pick disease is a genetic defect in sphingomyelin degradation. Causes Sphingomyelin accumulation in brain, spleen and liver. Causes mental retardation. Children die by age 3 or 4.

27. Triacylglycerols (TAG) • Fats and oils • Impt source of metabolic fuels • Because more reduced than carbos, oxidation of TAG yields more energy (16 kJ/g carbo vs. 37 kJ/g TAG) • Americans obtain between 20 and 30% of their calories from fats and oils. 70% of these calories come from vegetable oils • Insulation – subcutaneous fat is an important thermo insulator for marine mammals

28. Olestra • Olestra is sucrose with fatty acids esterified to –OH groups • digestive enzymes cannot cleave fatty acid groups from sucrose backbone • Problem with Olestra is that it leaches fat soluble vitamins from the body

29. isoprenoids • Isoprenoids are derived from the condensation of 5 carbon isoprene units • Can combine head to head or head to tail • Form molecules of 2 to >20 isoprene units • Form large array of different structures

30. Terprenes

31. Steroids • Based on a core structure consisting of three 6-membered rings and one 5-membered ring, all fused together • Triterpenes – 30 carbons • Cholesterol is the most common steroid in animals and precursor for all other steroids in animals • Steroid hormones serve many functions in animals - including salt balance, metabolic function and sexual function

32. cholesterol • Cholesterol impt membrane component • Only synthesized by animals • Accumulates in lipid deposits on walls of blood vessels – plaques • Plaque formation linked to cardiovascular disease

33. Steroids

34. Many steroids are derived from cholesterol

35. Membranes • Barrier to toxic molecules • Help accumulate nutrients • Carry out energy transduction • Facilitate cell motion • Modulate signal transduction • Mediate cell-cell interactions

36. The Fluid Mosaic Model • The phospholipid bilayer is a fluid matrix • The bilayer is a two-dimensional solvent • Lipids and proteins can undergo rotational and lateral movement • Two classes of proteins: • peripheral proteins (extrinsic proteins) • integral proteins (intrinsic proteins)

37. The Fluid Mosaic Model

38. Motion in the bilayer • Lipid chains can bend, tilt and rotate • Lipids and proteins can migrate ("diffuse") in the bilayer • Frye and Edidin proved this (for proteins), using fluorescent-labelled antibodies • Lipid diffusion has been demonstrated by NMR and EPR (electron paramagnetic resonance) and also by fluorescence measurements • Diffusion of lipids between lipid monolayers is difficult.

39. fusion After 40 minutes

40. Flippases • Lipids can be moved from one monolayer to the other by flippase proteins • Some flippases operate passively and do not require an energy source • Other flippases appear to operate actively and require the energy of hydrolysis of ATP • Active flippases can generate membrane asymmetries

42. Membranes are Asymmetric • In most cell membranes, the composition of the outer monolayer is quite different from that of the inner monolayer

43. Membrane Phase Transitions • Below a certain transition temperature, membrane lipids are rigid and tightly packed • Above the transition temperature, lipids are more flexible and mobile • The transition temperature is characteristic of the lipids in the membrane

44. Phase Transitions • Only pure lipid systems give sharp, well-defined transition temperatures • Red = pure phospholipid • Blue = phopholipid + cholesterol

45. Structure of Membrane Proteins • Integral (intrinsic) proteins • Peripheral (extrinsic) proteins • Lipid-anchored proteins

46. Peripheral Proteins • Peripheral proteins are not strongly bound to the membrane • They can be dissociated with mild detergent treatment or with high salt concentrations

47. Integral Membrane Proteins • Integral proteins are strongly imbedded in the bilayer • They can only be removed from the membrane by denaturing the membrane (organic solvents, or strong detergents) • Often transmembrane but not necessarily • Glycophorin, bacteriorhodopsin are examples

48. Seven membrane-spanning alpha helices, connected by loops, form a bundle that spans the bilayer in bacteriorhodopsin. The light harvesting prosthetic group is shown in yellow. Bacteriorhodopsin has loops at both the inner and outer surface of the membrane. It displays a common membrane-protein motif in that it uses alpha helices to span the membrane.

49. Lipid-Anchored Proteins • Four types have been found: • Amide-linked myristoyl anchors • Thioester-linked fatty acyl anchors • Thioether-linked prenyl anchors • Glycosyl phosphatidylinositol anchors

50. Amide-Linked Myristoyl Anchors • Always myristic acid • Always N-terminal • Always a Gly residue that links