Chapter 8 Flashcards

Lipids

• Heterogeneous class of naturally occurring organic compounds.

• Classified based on common solubility properties.

• Examples: Fats and oils

• Insoluble in water.

• Soluble in aprotic organic solvents (diethyl ether, chloroform, methylene chloride, and acetone).

• Amphipathic in nature.

  • Amphipathic: Molecule with a polar, water-soluble group at one end and a nonpolar hydrocarbon group at the other end.

Fatty Acids

• Water-insoluble hydrocarbons used for cellular energy storage.

• Highly reduced, providing a rich source of stored chemical energy.

• Stored as triacylglycerols, which is efficient because water is not needed for hydration.

• Hydrocarbon derivatives.

• Oxidation is highly exergonic (to CO2 and H2O).

• Properties depend on:

  • Length

  • Degree of unsaturation

Types of Fatty Acids

• Unbranched chain carboxylic acids.

• 12–20 carbons long.

• Derived from hydrolysis of animal fats, vegetable oils, or phosphodiacylglycerols of biological membranes.

• Amphipathic compounds.

• Types:

  • Unsaturated: Contain carbon–carbon double bonds.

  • Saturated: Contain only single bonds.

Nomenclature for Unbranched Fatty Acids

• Chain length and number of bonds, separated by a colon (e.g., 18:1).

• Numbering begins at the carboxyl carbon.

• Positions of double bonds indicated by ∆ and a superscript number.

Classification of Lipids

• Open-chain compounds:

  • Fatty acids

  • Triacylglycerols

  • Sphingolipids

  • Phosphoacylglycerols

  • Glycolipids

• Fused-ring compounds:

  • Cholesterol

  • Steroid hormones

  • Bile acids

Structures of Some Typical Fatty Acids

• Includes:

  • Palmitic acid

  • Stearic acid

  • Oleic acid

  • Linoleic acid

  • α-Linolenic acid

  • Arachidonic acid

Typical Naturally Occurring Saturated Fatty Acids

• Lauric acid (12 carbons)

  • Formula: CH3(CH2){10}CO2H

  • Melting Point: 44°C

• Myristic acid (14 carbons)

  • Formula: CH3(CH2){12}CO2H

  • Melting Point: 58°C

• Palmitic acid (16 carbons)

  • Formula: CH3(CH2){14}CO2H

  • Melting Point: 63°C

• Stearic acid (18 carbons)

  • Formula: CH3(CH2){16}CO2H

  • Melting Point: 71°C

• Arachidic acid (20 carbons)

  • Formula: CH3(CH2){18}CO2H

  • Melting Point: 77°C

Typical Naturally Occurring Unsaturated Fatty Acids

• Palmitoleic acid (16 carbons, 1 double bond)

  • Formula: CH3(CH2)5CH=CH(CH2)7CO2H

  • Melting Point: -0.5°C

• Oleic acid (18 carbons, 1 double bond)

  • Formula: CH3(CH2)7CH=CH(CH2)7CO2H

  • Melting Point: 16°C

• Linoleic acid (18 carbons, 2 double bonds)

  • Formula: CH3(CH2)4CH=CH(CH2)CH=CH(CH2)7CO_2H

  • Melting Point: -5°C

• Linolenic acid (18 carbons, 3 double bonds)

  • Formula: CH3(CH2CH=CH)3(CH2)7CO2H

  • Melting Point: -11°C

• Arachidonic acid (20 carbons, 4 double bonds)

  • Formula: CH3(CH2)4CH=CH(CH2)4(CH2)2CO2H

  • Melting Point: -50°C
    *Degree of unsaturation refers to the number of double bonds.
    *The superscript indicates the position of double bonds.
    *For example, ∆9 refers to a double bond at the ninth carbon atom from the carboxyl end of the molecule.

Unsaturated Fatty Acids

• cis isomer predominates, trans isomer is rare.

• cis double bond puts a kink in the long-chain hydrocarbon tail.

• Shape of a trans fatty acid resembles that of a saturated fatty acid in its fully extended conformation.

• Double bonds are isolated by several singly bonded carbons.

• Lower melting points than their saturated counterparts.

• Greater the degree of unsaturation, lower the melting point.

Melting Points of Fatty Acids

• Strongly influenced by length and degree of unsaturation.

  • Saturated fatty acids: waxy consistency.

  • Unsaturated fatty acids: oily liquids.

• Extent of packing depends on degree of saturation.

• Less thermal energy is needed to disorder poorly ordered arrays of unsaturated fatty acids, resulting in lower melting points compared to saturated fatty acids of the same chain length.

Fatty Acid Notation

• Indicates the number of carbon atoms and the number of double bonds separated by a colon.

• Examples:

  • 18:0: 18-carbon saturated fatty acid with no double bonds.

  • 18:1: 18-carbon fatty acid with one double bond.

Fatty Acid Notation (cont’d)

• Unsaturated Fatty Acids are often named based on the location of the double bond starting at the methyl (CH_3) terminus.

• Since it starts at the end we use the last letter of the Greek alphabet omega ω hence we take about “ω fatty acids”

• Example: α-Linolenic Acid (an ω-3 fatty acid)

Example 8.1

• Denoting fatty acids in terms of carbons and double bonds, and identifying ω fatty acid types.

Example 8.1 Answer

• 9:1 omega-6

• 11:3 omega-4

• 14:0

Triacylglycerols (Triglycerides)

• Lipids formed by esterification of three fatty acids to glycerol.

• Ester groups form polar part, tails are nonpolar.

• Accumulated in adipose tissues for storing fatty acids.

• Ester linkages hydrolyzed by lipases when fatty acids are used.

• Serve as concentrated stores of metabolic energy.

Triacylglycerols are Formed from Glycerol and Fatty Acids

• Tristearin (a simple triacylglycerol) - three stearic acids esterified to glycerol

• Mixed triacylglycerol - myristic, stearic, and palmitoleic acids esterified to glycerol

Saponification

• Reaction of glyceryl ester with NaOH or KOH to produce glycerol and respective Na or K salts (soaps).

• Soaps form water-insoluble salts in hard water, which contains Ca(II), Mg(II), and Fe\left(II\right) ions.

• Glycerol is used in creams and in the manufacture of nitroglycerin.

Phosphatidic Acid

• Compound in which two fatty acids and phosphoric acid are esterified to the three hydroxyl groups of glycerol.

• Phosphoric acid is triprotic in nature.

• Can form ester bonds to glycerol and to some other alcohol to create phosphatidyl esters.

Phosphatidyl Esters

• Classed as phosphoacylglycerols.

• Classification depends on nature of second alcohol esterified to phosphoric acid.

• Nature of fatty acids in a molecule varies widely.

• Structure:

  • Long, nonpolar, hydrophobic tails.

  • Polar, highly hydrophilic head groups.

  • Amphipathic in nature.

Phosphoacylglycerols

• Polar head group is charged.

• Phosphate group is ionized at neutral pH.

• Positively charged amino group contributed by an amino alcohol esterified to the phosphoric acid.

Waxes

• Complex mixtures of esters of long-chain carboxylic acids and long-chain alcohols.

• Serve as protective coatings for plants and animals.

Sphingolipids

• Contain sphingosine, a long-chain amino alcohol.

• Found in plants and animals and are abundant in the nervous system.

• Sphingomyelin

  • Primary alcohol of sphingosine is esterified to phosphoric acid, which is esterified to choline.

Glycolipids

• Lipid to which a sugar moiety is bonded.

• Ceramides

  • Parent compounds for glycolipids.

• Glycosidic bond is formed between the primary alcohol group of the ceramide and a sugar residue (glucose or galactose).

• Resulting compound is called a cerebroside.

Example of Glycolipids: Gangliosides

• Glycolipids with a complex carbohydrate moiety that contains more than three sugars.

• One is always a sialic acid.

• Called acidic glycosphingolipids because of their net negative charge at neutral pH.

Example 8.1

• Looking up information about the Antifungal drug Amphotericin B (AmB).

• Why is AmB toxic to both humans and to fungi?

Solution 8.1

• It binds to Ergosterol, which is structurally very similar to Cholesterol

Steroids

• Lipids with a characteristic fused-ring structure.

  • Three six-membered rings (A, B, and C rings).

  • One five-membered ring (D ring).

• Important steroids include sex hormones and cholesterol.

• Cholesterol:

  • Occurs in cell membranes.

  • Highly hydrophobic.

  • Acts as a precursor of other steroids.

  • Plays a role in the development of atherosclerosis.

Structures of Some Steroids

• Includes:

  • Cholesterol

  • Testosterone

  • Estradiol

  • Progesterone

Biological Membranes

• Every cell has a cell (plasma) membrane.

• Eukaryotic cells also have membrane-enclosed organelles (nuclei and mitochondria).

• Molecular basis of membrane structure lies in its lipid and protein components.

• Separate cells from the external environment and transport specific substances into and out of cells.

• Interaction between lipid bilayers and membrane proteins determines membrane function.

• Contain many important enzymes whose function depends on the membrane environment.

Biological Membranes (continued)

• Major force driving the formation of lipid bilayers is hydrophobic interaction.

• Differ from lipid bilayers as they contain proteins as well as lipids.

Lipid Bilayer

• Aggregate of a lipid molecule in which the polar head groups are in contact with water and the hydrophobic parts are not.

• Polar surface contains charged groups.

• Hydrocarbon interior consists of saturated and unsaturated fatty acid chains and the fused-ring system of cholesterol.

Lipid Bilayer (continued)

• Arrangement is held together by noncovalent interactions.

  • van der Waals and hydrophobic interactions

• Both inner and outer layers contain mixtures of lipids.

• Bulkier molecules tend to occur in the outer layer.

• Smaller molecules tend to occur in the inner layer.

Lipid Composition of Membranes in Rat Liver Cells, in Weight Percent

• Various types of lipids are present in varying percentages in different membranes, including plasma membrane, nuclear membrane, golgi apparatus, mitochondria, and lysosomes

Membrane Fluidity

• Arrangement of hydrocarbon interior of the bilayer can be ordered and rigid or disordered and fluid.

• Depends on composition of the bilayer.

  • Saturated fatty acids

    • Linear arrangement of hydrocarbon chains leads to rigidity.

  • Unsaturated fatty acids

    • Kink in the hydrocarbon chain causes disorder in its packing and leads to greater fluidity.

Effect of Double Bonds on the Conformations of Hydrocarbon Tails of Fatty Acids

• Saturated - linear hydrocarbon tails

• Unsaturated (one double bond) - kink in hydrocarbon tail

• Unsaturated (two double bonds) - more pronounced kink in hydrocarbon tail

Membrane Fluidity and Cholesterol

• Presence of cholesterol can enhance order and rigidity.

• Fused-ring structure of cholesterol is rigid.

• Stabilizes extended straight-chain arrangement of saturated fatty acids by van der Waals interactions.

Membrane Fluidity in Plants and Animals

• Animal membranes are less fluid and more rigid than plant membranes.

• Plant membranes have a higher percentage of unsaturated fatty acids than animal membranes.

• Presence of cholesterol is characteristic of animal, rather than plant, membranes.

• Membranes of prokaryotes are the most fluid.

  • Contain no appreciable amounts of steroids

Phase Transition in Lipid Bilayer

• Ordered bilayers become less ordered in the presence of heat.

• Cooperative transition occurs at a characteristic temperature.

• Transition temperature is higher for more rigid membranes and is lower for less rigid membranes.

• Mobility of the lipid chains increases dramatically
  *Note that the surface area must increase and the thickness must decrease as the membrane goes through a phase transition.
  *The mobility of the lipid chains increases dramatically.

Types of Membrane Proteins

• Peripheral proteins: Loosely bound to the outside of a membrane.

  • Bound by polar interactions, electrostatic interactions, or both and can be removed by raising the ionic strength of the medium.

  • Example - Heterotrimeric G protein

• Integral proteins: Embedded in a membrane.

  • Can be removed by treatment with detergents or extensive sonication, which may lead to denaturation of the protein.

  • Example - Rhodopsin

Membrane Proteins

• Lipid-anchored proteins

• Integral membrane protein

• Peripheral membrane protein

Integral and Peripheral Proteins

• Rhodopsin (integral protein)

• Heterotrimeric G protein (peripheral protein)

Anchoring Proteins to Membranes

• Proteins span across the membrane in the form of an α-helix or a β-sheet.

• Structures minimize the contact of polar parts with the nonpolar lipids

• Proteins can be anchored to the lipids via covalent bonds from cysteines or free amino groups on the protein to one of the several lipid anchors

Anchoring Proteins to Membranes (continued)

• N-myristoyl and S-palmitoyl are the anchoring motifs

• Anchors can be via N-terminal Gly

• Form a thioester linkage with Cys

Certain Proteins Are Anchored to Biological Membranes by Lipid Anchors

• N-Myristoylation

• S-Palmitoylation

Functions of Membrane Proteins

• Mediate the entry of specific substances into a cell

  • Transport proteins

• Contain specific binding sites for extracellular substances

  • Receptor proteins

Fluid-Mosaic Model

• Model in which proteins and a lipid bilayer exist side by side without covalent bonds between them.

• Basic structure of the biological membranes is that of a lipid bilayer, with proteins embedded in the bilayer structure.

• Lipids are sorted into assemblages called rafts, which serve as fundamental building blocks on which membrane specificity is based.

• Fluid mosaic

  • Term that implies that there is lateral motion of components in the membrane

Fluid-Mosaic Model of Membrane Structure

• Shows lipids, integral proteins, peripheral proteins, glycoproteins, and glycolipids in the plasma membrane

Membrane Imaging Methods

• Electron microscopy

  • Depends on scattering a beam of electrons from the surface of the sample

  • Freeze-fracture technique - Membrane is frozen and then fractured along the interface between the layers

• Atomic force microscopy

  • Sample surface is scanned using a cantilever with a sharp tip

  • Electrical measurements determine the force generated between the tip and the surface, which generates the image

Freeze-Fracture Technique

• Protocol: Quick-frozen cells are fractured to split apart lipid bilayers for analysis of the membrane interior.

• The specimen is frozen quickly in liquid nitrogen and then fractured by a sharp blow by a knife edge.

• The fracture may travel over membrane surfaces as it passes through the specimen, or it may split membrane bilayers into inner and outer halves.

• Interpreting the Results: The image of a freeze-fractured plasma membrane is visualized using the electron microscope. The particles visible in the exposed membrane interior are integral membrane proteins.

Membrane Transport: Passive Transport

• Process by which a substance enters a cell without expenditure of cell energy.

• Driven by concentration gradient.

• Categories

  • Simple diffusion: Process by which a molecule or an ion moves through an opening or pore in a membrane without requirement for a carrier or an expenditure of energy.

  • Facilitated diffusion: Process by which substances enter a cell by binding to a carrier protein.

    • Does not require energy

Passive Diffusion

• Passive diffusion of an uncharged species across a membrane depends only on the concentrations (C1 and C2) on the two sides of the membrane.

Example 8.2

• Introducing the "partitioning coefficient" or "LogP value", which is a measure of lipophilicity, defined as: logP = log \frac{[molecule]{lipid mixture}}{[molecule]{water}}.

Example 8.2 Cont’d

Data

• Presenting the IC50 values and lipophilicity data for a set of related drugs.

  • What is the correlation between activity and lipophilicity?

  • Are there any outliers in the data?

Example 8.2 Answer

Graph showing a scatter plot of IC50 (uM) vs logP along with marked data points like 'X 6-CN'

Facilitated Diffusion

• Facilitated diffusion in erythrocytes

• Glucose in blood concentration: 5 mM

• Intracellular glucose concentration: < 5 mM

• Involves glucose permease

Plot for Passive and Facilitated Diffusion

• Simple diffusion

  • Rate of movement is controlled by difference in concentration across the membrane.

• Facilitated diffusion

  • Plotting the rate of transport against S gives a hyperbolic curve similar to that seen in Michaelis–Menten enzyme kinetics.

Membrane Transport: Active Transport

• Substance is moved against a concentration gradient

• Involves a carrier protein and requires an energy source to move solutes against a gradient

• Primary active transport

  • Transport is directly linked to the hydrolysis of a high-energy molecule, such as ATP

  • Sodium–potassium ion pump (Na^+/K^+ ion pump)

• Secondary active transport

  • Driven by H+ gradient

  • Proton pumps: Active transporters that create H+ gradients

Sodium-Potassium lon Pump

• Showing the conformational changes of the protein and the hydrolysis of phosphate bound to the protein, coupled with the transport of Na^+ and K^+ ions

Mechanism for Na^+/K^+ ATPase (the Sodium–Potassium Ion Pump)

• The model assumes two principal conformations, E1 and E2.

• Binding of Na^+ ions to E1 is followed by phosphorylation and release of ADP.

• Na^+ ions are transported and released, and K^+ ions are bound before dephosphorylation of the enzyme.

• Transport and release of K^+ ions complete the cycle.

Example of Secondary Active Transport

• Showing the transport of lactose coupled with the H+ gradient created by a proton pump

The Sodium-Potassium Pump

• Illustrating the cycle of the sodium-potassium pump.

Membrane Receptors

• Large oligomeric proteins with molecular weights on the order of hundreds of thousands

• Examples - Receptors for G proteins, low-density lipoprotein (LDL), and human growth hormone (hGH)

• Binding of a biologically active substance to a receptor initiates an action within the cell

• Requirements

  • Presence of essential functional groups that have the correct 3-D conformation

  • Ability of binding sites to provide a good fit for the substrate

  • Action can be inhibited by an inhibitor or a poison

Low-Density Lipoprotein (LDL)

• Principal carrier of cholesterol in the bloodstream

• Consists of various lipids and a protein

• Cholesterol portion is used by the cell

• A portion of the membrane with LDL receptor and bound LDL is taken into the cell as a vesicle.

• The receptor protein releases LDL and is returned to the cell surface when the vesicle fuses to the membrane.

• LDL releases cholesterol in the cell.

• An oversupply of cholesterol inhibits synthesis of the LDL receptor protein.

• An insufficient number of receptors leads to elevated levels of LDL and cholesterol in the bloodstream. This situation increases the risk of heart attack.

Mechanism of Action of Human Growth Hormone and its Receptor

• Illustrating the interaction between growth hormone and its receptor, leading to activation of protein kinases.