Lipids

Key Concepts

• Major functions: energy storage, major membrane components
• Other functions: signals, electron carriers, emulsifying agents....
  
• Membrane lipids (amphipathic)
  
  • Glycerophospholipids: glycerol backbone + 2 fatty acyl "tails" in ester linkage + a polar "head group"= a phosphate ester of another alcohol like choline, ethanolamine, serine, inositol, etc.
    
  • Sphingolipids: sphingosine backbone (1 "tail") + fatty acid chain in amide linkage (another "tail") + either carbohydrate (glycosidic bond to sphingosine) or phosphate ester of another alcohol like choline or ethanolamine (ester bond to sphingosine)
    • glycosphingolipids (cerebrosides, gangliosides)
    • phosphosphingolipids (sphingomyelins)
      
  • Cholesterol
    
• Other lipids: eicosanoids, cholesterol and steroid hormones, vitamins A, D, E, and K, electron carriers, sugar carriers (dolichols)
  • Eicosanoids (prostaglandins, thromboxanes, and leukotrienes) are all synthesized starting from arachidonic acid.
  • Cholesterol and other steroids, fat-soluble vitamins, ubiquinone and plastoquinone, and dolichols are all isoprenoid lipids -- synthesized by condensation of isoprene units.
    

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Lipids

• NOT polymers composed of monomers with similar properties like amino acids, nucleotides, or monosaccharides
• "Lipids" defined based on a common physical property - they're insoluble in water and soluble in organic solvents
• FUNCTIONS
  • Two of the major functions of lipids:
    • major form of energy storage in the body
    • basic structural unit of cellular membranes
  • Other important functions of lipids (smaller quantities present in cell): electron carriers, enzyme cofactors (fat-soluble vitamins or their metabolic products), light-absorbing pigments, hydrophobic anchors, hormones, intracellular messengers, emulsifying agents....
• extremely diverse chemically
  • Many are amphipathic (contain a polar head group and a nonpolar tail) --> "internal schizophrenia" that dictates biological properties of lipids
• Lipids associate in aqueous environment by noncovalent interactions to form supramolecular structures, e.g., monolayers, micelles, bilayers or vesicles. (Figure below was in "Water and Noncovalent Interactions" notes.)
• driving force for formation is entropic - removal of nonpolar tails from contact with water ("hydrophobic effect")
• structures (micelles, bilayers, etc.) also stabilized by
  • van der Waals interactions between hydrocarbon chains of nonpolar tails, and
  • electrostatic interactions (hydrogen bonding & solvation of charged groups) of polar head groups with H₂O

Fatty Acids

• the simplest lipids that exhibit the above properties
• carboxylic acids with long hydrocarbon tail (fatty acids).
• usually contain an even number of carbons
• If double bonds are present (unsaturation), they're usually cis.
• pK_a of fatty acids' carboxyl groups about 4.5
  • At physiological pH, what's the predominant form?
  • In this form they can form monolayers at the air-water interface or micelles in water.

Fig. 11-1 (Nelson & Cox, Lehninger Principles of Biochemistry, 3rd ed., 2000): Packing of fatty acids into stable aggregates (a) Stearic acid (stearate at pH 7), a fully saturated 18-C fatty acid (no double bonds), in its usual extended conformation (b) Oleic acid (oleate at pH 7), an 18-C fatty acid with 1 cis double bond. Double bond doesn't permit rotation, and introduces "kink" (rigid bend) in hydrocarbon tail

(c) Fully saturated fatty acid chains in the extended form pack into nearly crystalline arrays, stabilized by many van der Waals interactions (textbook misstates this as "many hydrophobic interactions") (d) Presence of 1 or more double bonds interferes with this tight packing and results in less stable aggregates. Which type of aggregate would require input of more heat energy to "melt" it, the saturated fatty acid array, or the less ordered array with a mixture of unsaturated chains? So which has the higher melting point?

• Fatty acid nomenclature ("shorthand"):
  • CHAINLENGTH : Number of double bonds
  • positions of any double bonds indicated as D^{#,# etc.} where the superscript numbers indicate FIRST C atom participating in that double bond.
    WHERE DO YOU START WITH C ATOM NUMBERING IN A CARBOXYLIC ACID?
    
  • EXAMPLE: fatty acid with 18 carbon atoms and 2 double bonds, from C9 to C10, and from C12 to C13, is:
    18:2(D^9,12) (also known as linoleic acid)
    CH₃(CH₂)₄CH=CHCH₂CH=CH(CH₂)₇COOH
    

Waxes: esters of fatty acids and long chain alcohols

Triacylglycerols: triesters of glycerol and fatty acids

a major storage form of energy animal fats and vegetable oils are triacylglycerols (differ in content of unsaturated fatty acids) Soaps (K+ or Na+ salts of fatty acids) produced by hydrolysis (saponification) of fats with NaOH or KOH form micelles in water hydrophobic core of a soap micelle can solubilize greasy dirt

• Lipids vs. carbohydrates for energy storage:

Membrane Lipids

• Lipids = the major constituent of all biological membranes
• predominant lipids in membranes contain a polar head group and two hydrocarbon tails
  • glycerophospholipids
  • phosphosphingolipids
  • glycosphingolipids
    

• Fig. 11-6 (Nelson & Cox, Lehninger Principles of Biochemistry, 3rd ed., 2000): Principal classes of storage and membrane lipids
  

Glycerophospholipids

• fatty acyl derivatives of glycerol-3-phosphate (phosphatidic acid, phosphatidate at pH 7).
• fatty acyl groups in ester linkages to 1st and 2nd OH groups of glycerol-phosphate backbone
  • 2 hydrophobic tails = the nonpolar/hydrophobic portion of these amphipathic molecules
• phosphate group esterified to another alcohol to produce the different phospholipids
• phosphate group and the specific alcohol substituent = polar "head" group of the lipid

• (Phospholipid)

Fig. 11-10 (Nelson & Cox, Lehninger Principles of Biochemistry, 3rd ed., 2000): Glycerophospholipids Parent compound = phosphatidic acid, a phosphomonoester Different derivatives have different alcohol compounds in a second phosphoester linkage to phosphatidate --> phosphodiesters Derivatives named for the second alcohol substituent, e.g., choline, ethanolamine, serine, inositol, etc. What's the polar head group on a glycerophospholipid?

Sphingolipids

• Derivatives of sphingosine (a longchain amino alcohol) which is structurally similar to glycerol (SEE FIG. 11-11 in text), except
  • the #2 position has amino group (-NH₂) instead of OH, and
  • sphingosine has an extra 15-C chain with 1 double bond on its C#3 (a "built-in" tail, where the analogous C#1 on glycerol would need a fatty acyl ester for a tail)
• All sphingolipid classes have fatty acyl chain linked by amide linkage to amino substituent at position 2 of sphingosine --> parent compound called a ceramide.
• A second hydrophobic "tail" on sphingolipids is the rest of the sphingosine molecule itself (carbons 4-18).

Fig. 11-10 (Nelson & Cox, Lehninger Principles of Biochemistry, 3rd ed., 2000): Sphingolipids 2 main classes of sphingolipids, phosphosphingolipids and glycosphingolipids Both phosphosphingolipids and glycosphingolipids are derivatives of ceramide, with different substitutents at C1 of sphingosine. phosphosphingolipids: sphingomyelins: ceramide esterified via C1-OH to phosphocholine or phosphoethanolamine What's the polar head group on a sphinomyelin? glycosphingolipids: one or several carbohydrate units attached to C1-OH of ceramide by an O-glycosidic bond to form polar head group. Sphingomyelin.

• Membrane lipids constantly synthesized and degraded (metabolic turnover)
  • degradation via a collection of a lot of specific hydrolases stored in lysosomes
  • Enzyme deficiencies (genetic) can --> inability to degrade specific glycosphingolipids --> sometimes lethal consequences (see carbohydrate function notes and BOX 11-2, p. 375, in Nelson & Cox, Principles of Biochemistry, 3rd ed., 2000) --- examples:
    • Tay-Sachs disease, resulting from lack of hexoseaminidase A, needed to hydrolyze glycosidic bond attaching terminal N-acetylgalactosamine residue in ganglioside GM2
    • Niemann-Pick disease, resulting from lack of sphingomyelinase, needed to hydrolyze phosphate ester linkage of phosphocholine to ceramide
      
      
• Fig. 11-12 (Nelson & Cox, Lehninger Principles of Biochemistry, 3rd ed., 2000): Glycosphingolipids as blood group determinants

(See also carbohydrate function notes, under glycoproteins.) Immune system of a person early in development "learns" to recognize oligosaccharides on their own glycoproteins and glycolipids as "self", and doesn't make antibodies to those. Antigenic determinants (epitopes) that are LACKING on person's own glycoproteins and glycolipids are treated as "foreign", and if immune system encounters those it makes antibodies against the "non-self" antigens. Thus a blood transfusion containing "non-self" antigens causes an immune response, rejection of the "foreign" blood. Look at the structures of the oligosaccharide blood group antigens to the left -- Why would individuals who are type AB (have both type A and type B oligosaccharides themselves) be called "universal acceptors", able to accept blood transfusions of ANY blood type? Why would type O individuals be called "universal donors", able to donate blood to people of any blood type (A, B, AB, or O)?

• Fig. 11-13 (Nelson & Cox, Lehninger Principles of Biochemistry, 3rd ed., 2000): Phospholipase specificities (phospholipid hydrolases)
  • important not only in degradation of membrane lipids, but also in various signaling cascades

EXAMPLES: a hormone-sensitive PLC in the plasma membrane, when activated by an appropriate signal, generates diacyl glycerol (DAG) + inositol trisphosphate (IP3), both of which act as "second messengers" in regulatory processes inside cells. PLA2 needed for removal of arachidonic acid from membrane glycerophospholipids to use in synthesis of eicosanoid lipids like prostaglandins, local (paracrine) hormones involved in inflammation and other processes (see below)

• Eicosanoid lipids -- 3 classes
  • prostaglandins (lots of functions, including involvement in inflammation, smooth muscle contraction, e.g. in uterus during menstruation and labor, etc.)
  • thromboxanes (produced by platelets -- act in formation of blood clots and reduction of blood flow to site of a clot)
  • leukotrienes (involved in smooth muscle contraction in allergic reactions in anaphylactic shock, and in smooth muscle contraction of airways to lungs, so overproduction --> asthmatic attacks)
  • Steroid drugs like prednisone inhibit phospholipase A₂, so reduce production of ALL the eicosanoids.
• Fig. 11-16 (Nelson & Cox, Lehninger Principles of Biochemistry, 3rd ed., 2000): Arachidonic acid and some eicosanoid derivatives (Greek eikosi = 20)
  • Arachidonic acid 20:4^(D5,8,11,14) = precursor generated by PLA₂ (itself under hormonal control) from membrane phospholipids

What is the enzyme that's needed for cyclization and oxidation (inhibited by nonsteroidal antiinflammatory drugs like ibuprofen)? (Hint: see problem set #9 and/or Box 21-2, p. 786 in textbook.

• Cholesterol
  • another major membrane lipid
  • modulates properties of the bilayer formed by the two-tailed lipids (glycerophospholipids and sphingolipids)

  synthesized from isoprene units, so referred to as an isoprenoid lipid

Cholesterol only weakly amphipathic most of molecule is hydrophobic OH substituent at position 3 = polar head group Cholesterol also = precursor of other important lipids: bile acids (emulsifying agents) steroid hormones (important signaling molecules) (Cholesterol).

Other isoprenoid lipids:

• fat-soluble vitamins
  • vitamin A (vision)
  • viamin D (Ca²⁺ uptake, bone Ca²⁺ and phosphate)
  • vitamin E (tocopherols) (antioxidant)
  • vitamin K (cofactor for posttranslational modification of blood clotting proteins -- formation of g-carboxyglutamate, Gla)
    • rat poison, warfarin, an analog of vitamin K (potent anticoagulant -- rats die of internal bleeding)
    • dicoumarol used in humans as a "blood thinner" (anticoagulant to help prevent heart attacks and strokes due to blood clotting)
      
      
• electron carriers
  • ubiquinone (in mitochondrial membranes, electron transport system)
  • plastoquinone (in chloroplast membranes, photosynthetic electron transport)
    
    
• sugar carriers = dolichols
  • activate sugars for transfer to glycoproteins (eukaryotes) or to cell wall components (bacteria)
  • hydrophobic carriers -- anchor sugar to membrane where transfer reaction occurs