Lipids and Membranes

Lipids

• Unlike proteins, nucleic acids and polysaccharides, lipids are not polymers composed of monomers with similar properties like amino acids, nucleotides, or monosaccharides.
• Rather, lipids share a common physical property - they are insoluble in water and soluble in organic solvents.
• Chemically, lipids are an extremely diverse group of molecules.
• Two of the major functions of lipids are to serve as
  • The major form of energy storage in the body
  • The basic structural unit of cellular membranes.
• Other important functions: lipids (smaller quantities present in cell) serve as electron carriers, enzyme cofactors (fat-soluble vitamins or their metabolic products), light-absorbing pigments, hydrophobic anchors, hormones, intracellular messengers, emulsifying agents....
• Many lipid molecules are amphipathic - they contain a polar head group and a nonpolar tail.
• This internal schizophrenia dictates the biological properties of lipids
  • In an aqueous environment lipid molecules associate by noncovalent interactions to form supramolecular structures such as monolayers, micelles, bilayers or vesicles
  • The driving force is entropic - to remove the nonpolar tails from contact with water - The Hydrophobic Effect.
  • The structures are stabilized by van der Waals interactions between the hydrocarbon chains of the nonpolar tails and interactions of the polar head groups with water.

   

Fatty Acids

• The simplest lipids, which exhibit the above properties, are the fatty acids - carboxylic acids containing a long hydrocarbon tail (fatty acids).
• The fatty acids usually contain an even number of carbons and if double bonds are present (unsaturation), they are usually cis.
• The pK_a of the fatty acids is about 4.5 and at physiological pH they are present as carboxylate ions. In this form they can form monolayers at the air-water interface or micelles in water.

Triacylglycerols

• A major storage form of energy are the triacylglycerols, which are triesters of glycerol and fatty acids.
• Animal fats and vegetable oils are triacylglycerols and different in their content of unsaturated fatty acids.
• Soaps (K⁺ or Na⁺ salts of fatty acids) are produced by hydrolysis (saponification) of fats with NaOH or KOH and form micelles in water.
• The hydrophobic core of a soap micelle can solubilize greasy dirt.
• Waxes are esters of fatty acids and long chain alcohols.

Membrane Lipids

• All biological membranes contain lipids as the major constituent.
• The predominant lipids in membranes - glycerophospholipids, phosphosphingolipids and glycosphingolipids - contain a polar head group and two hydrocarbon tails.

Glycerophospholipids are fatty acyl derivatives of glycerol-3-phosphate,phosphatidic acid (phosphatidate). The acyl groups are in ester linkages to the first and second OH groups of the glycerol-phosphate backbone. The two hydrophobic tails define the nonpolar/hydrophobic portion of these amphipathic molecules. The phosphate group is esterified to another alcohol, such as choline, ethanolamine, etc, to produce the different phospholipids. The phosphate group and the specific alcohol substituent comprise the polar "head" group of the lipid.   (Phospholipid)

In the different classes of sphingolipids, a fatty acyl chain is linked by an amide linkage to the amino substituent at position 2 of the longchain amino alcohol sphingosine; the resulting parent compound is called a ceramide. The second hydrophobic "tail" on sphingolipids is the rest of the sphingosine molecule itself (carbons 4-18). Both phosphosphingolipids and glycosphingolipids are derivatives of ceramide, with different substitutents at C1 of sphingosine. In sphingomyelin, a sphingolipid, the ceramide is esterified to phosphocholine or phosphoethanolamine as the polar head group. In a glycosphingolipid, the ceramide is attached by an O-glycosidic bond to one or several carbohydrate units to form the polar head group. Sphingomyelin.

• Cholesterol, another major membrane lipid, bears little obvious resemblance to the lipids described above, being only a weakly amphipathic molecule; most of the molecule is hydrophobic, the OH substituent at position 3 being the polar head group.
• Cholesterol is an important constituent of membranes and modulates the properties of the bilayer formed by the two-tailed lipids described above. Cholesterol is also the precursor of other important lipids, the bile acids (emulsifying agents) and the steroid hormones.
• (Cholesterol).

Membrane Structure

 Membrane functions

1. selective permeability barrier (regulate molecular & ionic compositions of cells and intracellular organelles)
2. information processing (signal reception and transmission/transduction)
3. organization of reaction sequences (e.g., electron transport)
4. energy conversion
   a) photosynthesis (light energy --> chemical bond energy)
   b) oxidative phosphorylation (oxidation --> chemical bond energy)

• The purpose of a membrane is separate two aqueous compartments, e.g., the cytoplasm of the cell from the external fluid, or the inner mitochondrial space from the cell cytoplasm, etc.
• The phospholipid bilayer forms the physical barrier that allows such compartmentation. (Bilayer).
• But, a cell cannot survive unless it can take up nutrients and excrete waste products - the cell needs to be selectively permeable.
• Proteins within the membrane (integral membrane proteins) or proteins bound to the membrane (peripheral membrane proteins) mediate this permeability (Companion: Membranes/Biological Membranes).
• Thus, the membrane can be considered a two-dimensional fluid composed of lipids and proteins (both often with attached carbohydrates) - the fluid mosaic model.
• The membrane is not a static structure, rather the lipids and proteins are in constant motion with lateral diffusion in the plane of the membrane.
• The rate of movement of the components in the membrane depends on the fluidity, i.e., viscosity, of the membrane (dynamic).
• The fluidity is primarily determined by the nature of the lipids in the membrane - unsaturated fatty acids increase the fluidity of the membrane, as do fatty acids with shorter chainlengths.
• The nature of the polar head group of the phospholipids can also influence the fluidity - phosphatidylcholine increases fluidity, whereas phosphatidylethanolamine decreases fluidity.
• Cholesterol serves to "buffer" extreme fluidity changes.
• Motion within the plane of the membrane is rapid (diffusion).
• Movement from one side of the bilayer to the other, "flip-flop", is very slow (flip-flop).

• The slow rate of exchange of components from one side of the membrane to the other leads to asymmetry of membranes.
• The protein and lipid compositions of the two halves of the bilayer are different.

Membrane Proteins

• Peripheral membrane proteins can be removed from the membrane by washing the cells in media of different ionic strength or pH.
• Integral membrane proteins can only be removed by extraction with detergents, which disrupt the bilayer structure.
• Integral membrane proteins often have hydrophobic a-helices, which serve as the membrane spanning domains (membrane_protein). .
• Here is a more detailed look at the interaction of a membrane protein with lipids (transmembrane_protein). .
• Amphiphilic b-sheets are another way to insert a protein in a membrane (porin).  
• Some proteins are anchored to the membrane via a covalently attached lipid. 

   

• Prenylated proteins have farnesyl or geranylgeranyl residues attached to a Cys.

   

• Fatty acylated proteins have either myristic acid attached via an amide linkage to an N-terminal Gly, or palmitate esterified to a Cys.

  (Oops -- the structure of the Cys R group in the palmitoyl derivative shown here is missing the methylene group between the S and the a-carbon. Sorry!)