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10.1: Introduction to lipids

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    14976
  • Introduction to Lipids

    (Thanks to Rebecca Roston for providing a cohesive organizational framework and image templates)

    Lipids are organic molecule molecules that are soluble in organic solvents, such as chloroform/methanol, but sparingly soluble in aqueous solutions. These solubility properties arise since lipids are mostly hydrophobic.  One type, triglycerols, are used for energy storage, since they are highly reduced and get oxidized to release energy.  Their hydrophobic nature allows them to pack efficiently through self-association in an aqueous environments.  Triglycerols are also used for insulation since they conduct heat poorly, which is good if you live in cold climate but bad if you wish to dissipate heat in a hot one. Triglycerols also offer padding and mechanical protection from shocks (think walruses).  Another type of lipid forms membrane bilayers, which separate cellular contents from the outside environment, or separate intracellular compartments (organelles) from the cytoplasm.  Some lipids are released from cells to signal other cells to change to specific stimuli in a process called cell signaling.  From a more molecular perspective, lipids can act as cofactors for enzymes, pigments, antioxidants and water repellents.   As we saw with proteins, lipid structure mediates their function.  So let's probe their structures.

    Lipids can be split into structural classes in a variety of ways.  An earlier classification divided them into those that release fatty acids on based-catalyzed hydrolysis to form soaps in a saponifcation reaction, and those that don't.    A much better and broader classification is based on if the lipids contain fatty acids or isoprenoids, as shown in the figure below.

    StructClassLipidsFA_Isoprenoids.svg

     

    The nonpolar chains of the fatty acid are drawn in the figure above in the lowest energy zig-zag fashion as we saw when we discussed the main chain conformation of proteins (Chapter 4.1).  In that chapter we started with the an exploration of a long 12 C chain carboxylic acid, dodecanoic acid. In the lowest energy conformation, the dihedral angles are all + 180to minimize torsional strain in the molecule.  Rotation around one C-C bond can produce a gauche form, which introduces a kink into the chain.

     

    dodecanoicacid_trans-gauche.svg

    Fatty Acids

    Fatty acids can be free or covalently linked by ester or amide link to a base molecule like triglycerides or membrane lipids.  The key principle that we learned with our study of proteins, that structure determines function, also applies to lipids.  The figure below shows three different types of molecules, a free fatty acid, a wax with an esterified fatty acid, and a glycolipid with a fatty acid connected by an amide link in another type of lipid (glycosphingolipid). Each has different properties leading to different functions.  Waxes for instance are very nonpolar and water-insoluble.  They are amorphous solids at room temperature but, depending on their structure, can easily melt to form a high viscosity liquids.  They are used as coating on the surfaces of leaves to help prevent water loss.  The glycolipid (glyco- as it contains a monosaccharide group) are constituents of membrane bilayers.

    fattyacidwaxesglycerosphingo.svg

    Fatty acids vary in length, usually contain an even number of carbon atoms, and can be saturated (contain no double bonds in the acyl chain), or unsaturated (with either one -monounsaturated - or multiple - polyunsaturated - cis double bond(s)).  The double bonds are NOT conjugated as they are separated by a methylene (-CH2-) spacer.   Fatty acids can be named in many ways.

    • symbolic name: given as x:y Δ a,b,c where x is the number of carbon atoms in the chain, y is the number of double bonds, and a, b, and c are the positions of the start of the double bonds counting from C1 - the carboxyl carbon. Double bonds are usual cis (Z). 
    • systematic name using IUPAC nomenclature. The systematic name gives the number of carbon atoms in the chain (e.g. hexadecanoic acid for 16:0). If the fatty acid is unsaturated, the base name reflects the number of double bonds (e.g. octadecenoic acid for 18:1 Δ 9 and octadecatrienoic acid for 18:3Δ 9,12,15).
    • common name: (e.g. oleic acid, 18:1Δ9), which is found in high concentration in olive oil)

    They can be named most easily with a symbolic name 

    FattyAcidNomenclature.svg

    There is an alternative to the symbolic representation of fatty acids, in which the carbon atoms are numbered from the distal end (the n or ω end) of the acyl chain (the opposite end from the alpha carbon). Hence 18:3 Δ 9,12,15 could be written as 18:3 (ω -3) or 18:3 (n -3), where the terminal C is numbered one and the first double bond starts at C3. 

    The most common saturated fatty acids found in biochemistry textbooks are listed in the table below.  Note how the melting point increases with the length of the hydrocarbon chain. This arises from increasing noncovlalent induced dipole-induced dipole attractions between the long chains.  Heat must be added to lessen these attraction to allow melting.

    Symbolic

    common name

    systematic name

    structure

    mp(C)

    12:0

    Lauric acid

    dodecanoic acid

    CH3(CH2)10COOH

    44.2

    14:0

    Myristic acid

    tetradecanoic acid

    CH3(CH2)12COOH

    52

    16:0

    Palmitic acid

    Hexadecanoic acid

    CH3(CH2)14COOH

    63.1

    18:0

    Stearic acid

    Octadecanoic acid

    CH3(CH2)16COOH

    69.6

    20:0

    Arachidic aicd

    Eicosanoic acid

    CH3(CH2)18COOH

    75.4

     

    The table below shown common unsaturated fatty acids. Arachidonic acid is an (ω -6) fatty acid while docosahexaenoic acid is an (ω -3) fatty acid. Note the decreasing melting point for the 18:X series with increasing number of double bonds.

    Symbol

    common name

    systematic name

    structure

    mp(C)

    16:1Δ9

    Palmitoleic acid

    Hexadecenoic acid

    CH3(CH2)5CH=CH-(CH2)7COOH

    -0.5

    18:1Δ9

    Oleic acid

    9-Octadecenoic acid

    CH3(CH2)7CH=CH-(CH2)7COOH

    13.4

    18:2Δ9,12

    Linoleic acid

    9,12 -Octadecadienoic acid

    CH3(CH2)4(CH=CHCH2)2(CH2)6COOH

    -9

    18:3Δ9,12,15

    α-Linolenic acid

    9,12,15 -Octadecatrienoic acid

    CH3CH2(CH=CHCH2)3(CH2)6COOH

    -17

    20:4Δ5,8,11,14

    arachidonic acid

    5,8,11,14- Eicosatetraenoic acid

    CH3(CH2)4(CH=CHCH2)4(CH2)2COOH

    -49

    20:5Δ5,8,11,14,17

    EPA

    5,8,11,14,17-Eicosapentaenoic- acid

    CH3CH2(CH=CHCH2)5(CH2)2COOH

    -54

    22:6Δ4,7,10,13,16,19

    DHA

    Docosohexaenoic acid

    22:6w3

     

     Let's consider how  the presence of double bonds in fatty acids influences their melting points.  The figures below shows common variants of fatty acids each with 18 carbon atoms.  Compare the Lewis structure and spacefill models below. What a difference a cis double bond makes!

    The double bonds in fatty acids are cis (Z), which introduces a "permanent" kink into the chain, similar to the"temporary" kink in the saturated doecanoic acid carboxylic acid with a single gauche bond (Figure x.x).  The kink is permanent since there is no rotation around the double bond unless it is broken (which can happen through photoisomerization reactions).  The more double bonds, the greater the kinking.  The more kinks, the less chance for van der Waals contacts between the acyl chains, and reduces induced-dipole-induced dipole interactions between the chains, leading to lowered melting points. 

     

    fattyacid18colonsattopoly.svg

    Now in your mind, replace the cis double bond in oleic acid with a trans.  You should now see a long "zig-zag" shaped molecule with no kinks.  Trans fatty acids are rare in biology but are produced in the industrial partial hydrogenation of fats, which is done to decrease the number of double bonds and make the fats more solid like and tastier while decreasing rancidity.  These trans fatty acids would pack closer together and clearly affect the structure and function of the lipid in a given environment (such as a membrane bilayer). Increased consumption of trans fatty acids is associated with increased risk of cardiovascular disease.  

    This table shows the percentages of fatty acids in different oils/fats

    FAT

    <16:0

    16:1

    18:0

    18:1

    18:2

    18:3

    20:0

    22:1

    22:2

    .

    Coconut

    87

    .

    3

    7

    2

    .

    .

    .

    .

    .

    Canola

    3

    .

     

    11

    13

    10

    .

    7

    50

    2

    Olive Oil

    11

    .

    4

    71

    11

    1

    .

    .

    .

    .

    Butter-fat

    50

    4

    12

    26

    4

    1

    2

    .

    .

    .


     

    Fatty acid composition differs in different organisms:

    • animals have 5-7% of fatty acids with 20-22 carbons, while fish have 25-30%
    • animals have <1% of their fatty acids with 5-6 double bonds, while plants have 5-6% and fish 15-30%

    As there are essential amino acids that cannot be synthesized by human, there are also essential fatty acids that must be supplied by the diet.  There are only two, one each in the n-6 and n-3 classes:

    • n-6 class: α-linoleic acid (18:2 n-6, or 18:2Δ9,12) is a biosynthetic precursor of arachidonic acid (20:4 n-6 or 20:4Δ5,8,11,14)
    • n-3 class:  linolenic acid (18:3 n-3, or 18:3Δ9,12,15) is a biosynthetic precursor of eicosapentaenoic acid (EPA, 20:5 n-3 or 20:5Δ5,8,11,14,17) and to a much smaller extent, docosahexaenoic acid (DHA, 22:6 n-3 or 22:6Δ4,7,10,13,16,19).

    These two fatty acids are essential since mammals cannot introduce double bonds in fatty acids beyond carbon 9. These essential precursor fatty acids are substrates for intracelluar enzymes such as elongases and desaturases (to produce 20:4 n-6, 20:5 n-3 and 22:6 n-3 fatty acids), and beta-oxidation type enzymes in the endoplasmic reticulum and in another organelle, the peroxisome.  The peroxisome is involved in oxidative metabolism of straight chain and branched fatty acids, peroxide metabolism, and cholesterol/bile salt synthesis. Animals fed diets high in plant 18:2(n-6) fats accumulate 20:4(n-6) fatty acids in their tissues while those fed diets high in plant 18:3(n-3) accumulate 22:6(n-3). Animals fed diets high in fish oils accumulate 20:5 (EPA) and 22:6 (DHA) at the expense of 20:4(n-6).

    Many studies support the claim the diets high in fish that contain abundant ω-3 fatty acids, in particular EPA and DHA, reduce inflammation and cardiovascular disease. ω-3 fatty acids are abundant in high oil fish (salmon, tuna, sardines), and lower in cod, flounder, snapper, shark, and tilapia.

    Some suggest that contrary to images of early hominids as hunters and scavengers of meat, human brain development might have required the consumption of fish which is highly enriched in arachidonic and docosahexaenoic acids. A large percent of the brain consists of lipids, which are highly enriched in these two fatty acids. These fatty acids are necessary for the proper development of the human brain and in adults.  Deficiencies in these might contribute to ADHD, dementia, and dyslexia. These fatty acids are essential in the diet, and probably could not have been derived in high enough amounts from the eating of brains of other animals. The mechanism for the protective effects of n-3 fatty acids in health will be explored later in the course when we discuss prostaglandins synthesis and signal transduction.

    Aggregates of Fatty Acids in Aqueous Solution: Micelles

    Structure determines both properties and function.  It should be obvious that free, unesterified fatty acid are very (but not completely) insoluble in water.  When added to water, they saturate the solution at very low concentration and then phase separate out into aggregates called micelles.  The structure of a micelle formed from dodecylsulfate, a common detergent with a sulfate instead of a carboxylate head group, is shown below.  Note all of the nonpolar Cs and Hs of the long alkyl chains are "buried" and are not exposed to water, whereas the sulfate head groups are solvent exposed.

    sdsmicelealone.png

    ​Here is an iCn3D for SDS

    Fatty acids (carboxylates and sulfates) are amphiphilic, with a larger polar/charged head group tha ttapers down to a hydrophobic tail, forming a cone-like structure.  This cone structure allows packing of many of these single chains amphiphiles into a micelle, as shown in the figure below.

     

    LipidGeometric3D_FA_micelleONLY.svg

     

    ​Free fatty acids are transported in the cell and in the blood not in micelles but by fatty acid binding proteins.  The most abundant protein in blood, albumin, binds and transports fatty acids, as shown in the iCn3D model below.  The fatty acids are shown in colored spacefilled rendering. 

     

    https://structure.ncbi.nlm.nih.gov/i...CGUdMj11vNevF6 

    Waxes

    You are familiar with ear wax and also the waxy surface of plants.  Ear wax contains long chain fatty acids (saturated and unsaturated) and alcohols derived from them.  (They also contains isoprenoids derivatives like squalene and cholesterol).  The waxy cuticle surface layers of plants contain very-long-chain fatty acids ( C20–C34) and their derivatives including alkanes, aldehydes, primary and secondary alcohols, ketones, and esters, (They also contain isoprenoid derivatives as well).   We will consider waxes as very long chain fatty acids and their derivatives, as shown in the figure below.

    Waxes2.svg

    These molecules are extremely nonpolar and as such makes great barriers preventing water loss through leaves and water penetration into the ear.  This group of molecules clearly shows that the properties (insolubility, high melting point) and function (hydrophobic barrier/protection) arises from structure (very long chain carbon molecules, few electronegative atoms, and lack of C=C double bonds).  

    Fatty Acid-Containing Lipids

    We can categorize these lipids based on function or structure (even though these are related).  

    Function

    • storage lipids - triacylglycerols
    • membrane lipids - many different lipids

    Structure

    • glycerolipids, which use glycerol as a backbone for fatty acid attachment
    • sphinolipids, which use sphinogosine as a backbone

    The structures of glycerol and sphingosine are shown below.  Fatty acids are connected to these two "backbone" structures by either ester (mostly) or amide links.

    glycerolAndsphingosine.svg

    Let's explore the classes of fatty acid-containing lipids that use these two "backbone" structures.

    Storage Lipids - Triacylglycerols 

    Triacylglycerol contain the majority of fatty acids in species that store fatty acids for energy.  The schematic diagram below shows the glycerol backbone and with three fatty acids esterified to it.   They are glycerolipids as they contain a glycerol base.

    FattyAcidContainingLipids_TAGs.svg

    Glycerol is not chiral but given the incredible diversity of fatty acids, glycerols likely have three different fatty acids esterified to them, making them chiral.  If triglycerols contain predominately saturated fatty acids, they are solids at room temperature and are called fats.  Those with multiple double bonds in the fatty acids are likely liquids at room temperature.  These care called oils. Triglycerols are even more insoluble than fatty acids, which contain a polar and mostly charged carboyxlate.  

    The image below shows a triacylglycerol containing all 16:0 saturated fatty acids (left) and one containing all 16:2Δ9,12 polyunsaturated fatty acids.  The figures were constructed with a specific set of dihedral angles to illustrate a point, that polyunsaturated fats in a triacylglycerol don't pack as tightly and have lower induced dipole-induced dipole attractions between the acyl chains that is possible with saturated fatty acyl chains.  Hence the melting point of triacylglycerols containing polyunsaturated fatty acids is higher than for those with saturated ones.

    16colon0all_16colon2all.svg

     

    Let's repeat the key mantra:  the structure of lipids determines their function. Consider the very insoluble triacylglycerols which are used as the predominant storage form of chemical energy in the body. In contrast to polysaccharides such as glycogen (a polymer of glucose), the Cs in the acyl-chains of the triacylglyceride are in a highly reduced state. The main source of energy to drive not only our bodies but also our society is obtained through oxidizing carbon-based molecules to carbon dioxide and water, in a reaction which is highly exergonic and exothermic. Sugars are already part way down the free energy "hill" since each carbon is partially oxidized. 9 kcal/mol can be derived from the complete oxidation of fats, in contrast to 4.5 kcal/mol from that of proteins or carbohydrates.

    In addition, glycogen is highly hydrated. For every 1 g of glycogen, 2 grams of water is H-bonded to it. Hence it would take 3 times more weight to store the equivalent mass of carbohydrates compared to triacylglyceride, which are stored in anhydrous lipid "droplets" within cells. In addition, fats are more flexible, given the large number of conformations availably to the acyl chain C-C bonds by simple rotation around the C-C bonds.  Polysacahrides have monomeric cyclohexane-like chair structures and are much more rigid.

    Another interesting point is that glucose and glycogen are found in cells, and they can be mobilized quickly for energy needs.  Yes, fats are present in all cells as well (for example all cells have interior and exterior cell membranes).  However, the major storage form of fat, triacylglycerols, is stored in special cells called adipocytes, which comprise adipose or fat tissue,  and must be mobilized by signaling agents and transported in the form of fatty acids to cells for utilization.  Again, triacylglycerols don't form membranes, which separate an outside and inside aqueous world.  They are simply so insoluble that they phase-separate into lipid dropletss.   Their formation and structure is a bit more complex than that, though, and we will discuss lipid droplets  more in the next section. 

    Membrane Lipids -

    Membranes are bilayers of amphiphlic lipids that separate the outside and inside (cytoplasm) aqueous environments in cells and the cytoplasm and interior contents of organelles within cells.  In general, single chain lipid amphiphiles form micelles.  Amphiphilic membrane lipids typically have two nonpolar tails connected to a polar head, giving them a less conical and more cylindrical shape that disallows micelle formation while favoring bilayer formation.  The image below shows a short section of a bilayer membrane made from lipids with a polar (and charged) head group (phosphocholine) and two 16:0 chains.  The red and blue spheres represent the O and N atoms of the head groups, which are clearly sequestered to the exterior parts of the bilayer, where they would interact with water.  The nonpolar 16:0 tails are shown in cyan, clearly illustrating the nonpolar nature of the interior of the bilayer.

    jcp-68nowater.svg

    The model below shows a hydrated bilayer of the di16:0 phosphatidycholine bilayer.  

    We will consider two general types of fatty acid-containing membrane lipids, glycerolipids, with two fatty acids esterified to a glycerol base, and sphingolipids with one fatty acid in amide link to a different base, sphingosine.  Sphingosine comes with its own built-in long alkyl chain that provides the "second" nonpolar chain.  There are many different polar/charged head groups for these membrane lipids.

    Now let's look at more detail at the double chain amphiphiles comprising these membrane bilayers.  

    Glycerolipids

    There two main types of glycerolipids, glycerophospholipids and glyceroglyolipids, which are the most common lipids in membranes.

    Glycerophospholipids

    The figure below shows the structural features and nomenclature for glycerophospholipids.

    FattyAcidContainingLipids_GlycerolPhospholipids.svg

    These lipids have enormous structural variability given the large number of different fatty acids (both saturated and unsaturated) and head groups that can be attached to a phosphate attached to the carbon 3 of glycerol.  The structures of the most common glycerophospholipids are shown below. 

    Structure_Glycerophospholipids copy.svg

    Phosphatidylcholine (PC) has the common name lecithin while phosphatidylserine (PS) is called cephalin.

    Note that the head groups all have charges since they all have a negatively charged phosphate.  PS has two additional charged atoms which would effectively cancel out.  PE has a charged amine but could become uncharged at pH values approaching its pKa. PC has a quaternary amine which is charged independent of pH, which would give PC at net 0 charge but with two discrete charges.

    Glyceroglycolipids

    These do not have a phosphate group attached to the oxygen on C3 of glycerol.  Rather they have a mono- or oligosaccharide or, more loosely, a betaine group, each attached by an ether linkage to the glycerol C3 carbon.  The figure below shows the structural features and nomenclature for glyceroglycolipids.

    FattyAcidContainingLipids_Glycerolglycolipids.svg

    Here are some examples of glycoglyerolipids.

    Structure_Glycoglycerolipids copy-01.svg

    Again there are an enormous number of different glycoglycerolipids, owing to the diversity of head groups and fatty acids esterifed to glycerol at C1 and C2.

    The above figure (right) show an example that has no phosphate but also doesn't have a mono- or polysaccharide for a head group.  Rather it has a betaine group.  Betaine is the common name for trimethylglycine but is used for any N-trimethylated amino acids.  Betaine glycerolipids are found in lower eukaryotic organisms (algae, fungi and some protozoa), in photosynthetic bacteria and in some spore-producing plants like ferns.  Some would called these lipoaminoacids.   

    Membrane Lipids - Sphingolipids

    Phosphosphingolipids and glycosphingolipids

    Let's consider these together.   These groups do not use glycerol as a base for attachment of fatty acids and head group.  Rather they use molecule sphingosine. The figure below shows the structural features and nomenclature for sphingolipids.  The 

    FattyAcidContainingLipids_sphingolipids.svg

    Examples of both classes are shown in the diagram below.  Note the base sphingosine (in red) provides an amine to attached a fatty acid through an amide bond and an OH for attachment of the head group.  

     

    Structure_sphingolipids copy-01.svg

    Sugar-containing glycosphingolipids are found largely in the outer face of plasma membranes. The primary lipid of myelin, which coats neuronal axons and insulate them form loss of electrical signaling down the axon, is galactocerebroside

    The figure below shows a summary of all of the different types of fatty acid-containing lipids

    FattyAcidContainingLipids_FullFlowChartAlone.svg

    Over a 1000 different lipids are found in eukaryotic cells. This complexity has led to the development of an even more comprehensive classification system for lipids. In this system, lipids are given a very detailed as well as all-encompassing definition: "hydrophobic or amphipathic small molecules that may originate entirely or in part by carbanion-based condensations of thioesters (fatty acyl, glycerolipids, glycerophospholipids, sphingolipds, saccharolipds and polyketides) and/or by carbocation-based condensations of isoprene units (prenol lipids and sterol lipids)." Eight different categories of lipids are listed in the parentheses above.  We will stick the definition used throughout this chapter.

    Shapes of membrane lipids

    Let's look at the general shape of the double-chain amphiphiles that make bilayers.  We saw the long chain fatty or sulfate acids form conical structures which fit nicely together when they self-aggregate to form micelles.  In contrast, membrane-forming double chain amphiphiles have more cylindrical shapes that can't be fitted together in micelles but rather form less curved bilayer structure, as shown in the figure below.  We will consider the variety of membrane structures in the next section.

     

    LipidGeometric3DShapes_MembraneDoubleChainAmpLipidsOnly.svg

    Another nomenclature for fatty acid containing lipids but with a twist (actually a mirror): Triacylglyceride/Phospholipid Stereochemistry

    Glycerol is an achiral molecule, since C2 has two identical substituents, -CH2OH. Glycerol in the body can be chemically converted to triglycerols and phospholipids (PL) which are chiral, which exist in one enantiomeric form. How can this be possible if the two CH2OH groups on C2 of glycerol are identical? It turns out that even though these groups are stereochemically equivalent, we can differentiate them as described in the figure below.   Let's replace the -CH2OH in one of the end carbons with -CH2OD. With this simple change, the glycerol is now chiral. Look at the top half of the figure below. 

    snPLs_A.svg

    Glycerol is oriented with the OH on C2 (the middle carbon) pointing to the left. The OH of the top carbon in this orientation, C1, is replaced with OD, where D is deuterium to make the molecule chiral (four different groups attached to C2).  By rotating the molecule such that the H on C2 points to the back, and assigning priorities to the other substituents on C2 (OH =1, DOCH2 =2, and CH2OH = 3), it can be seen that the resulting molecule is in the S configuration. We simply name the C1 carbon which we modified with deuterium as the proS carbon. Likewise, if we replaced the OH on C3 with OD, we will form the R enantiomer. Hence C3 is the proR carbon. This shows that in reality we can differentiate between the two identical CH2OH substituents. We say that glycerol is not chiral, but prochiral. (Think of this as glycerol has the potential to become chiral by modifying one of two identical substituents.)

    In the bottom half of the figure above, we can relate the configuation of glycerol above, (when OH on C2 is pointing to the left) to the absolute configuration of L-glyceraldehyde, a simple sugar (a polyhydroxyaldehyde or ketone), another 3C glycerol derivative. This molecule is chiral with the OH on C2 (the only chiral carbon) pointing to the left. It is easy to remember that any L sugar has the OH on the Last chiral carbon pointing to the Left. The enantiomer (mirror image isomer) of L-glyceraldehyde is D-glyeraldehyde, in which the OH on C2 points to the right. Biochemists use L and D for lipid, sugar, and amino acid stereochemistry, instead of the R,S nomenclature you used in organic chemistry. The stereochemical designation of all the sugars, amino acids, and glycerolipids can be determined from the absolute configuration of L- and D-glyceraldehyde.

    Now lets see how an enzyme can take a prochiral molecule like glycerol and phosphorylate only one of the -CH2OHs to make one specific isomer, glycerol-3-phophate, a key intermediate in the biosynthesis of phosphatidic acid (PA), a glycerophospholipid, as well as chiral triglycerols, shown in the figure below.  The far left part of the pathway shows how the proR CH2OH of glycerol is phosphorylated to produce one specific enantiomer, L-glycerol-3-phosphate.  (The top part of the figure shows another way to make this molecule from glucose through the glycolytic pathway we will encounter in Chapter XX.

     

    TAGsynthsisSNisomers.svg

    The first step (above figure) involves the phosphorylation of the OH on C3 by ATP (a phosphoanhydride similar in structure to acetic anhydride, an excellent acetylating agent) to produce the chiral molecule glycerol phosphate. Based on the absolute configuration of L-glyceraldehyde, and using this to draw glycerol (with the OH on C2 pointing to the left), we can see that the phosphorylated molecule can be named L-glycerol-3-phosphate. However, by rotating this molecule 180 degrees, without changing the stereochemistry of the molecule, we don't change the molecule at all, but using the D/L nomenclature above, we would name the rotated molecule as D-glycerol-1-phosphate. This is illustrated in the figure below.

    snPLs_B.svg

    We can’t give the same molecule two different names. Hence biochemists have developed the stereospecific numbering system (sn), which assigns the 1-position of a prochiral molecule to the group occupying the proS position. Using this nomenclature, we can see that the chiral molecule described above, glycerol-phosphate, can be unambiguously named as sn-glycerol-3-phosphate. The hydroxyl substituent on the proR carbon was phosphorylated.

    It is interesting to note that archaea use isoprenoid chains linked by ether bonds to sn-glycerol 1-phosphate in their synthetic pathways.  As noted above, bacteria and eukaryotes use fatty acids attached by ester bonds to sn-glycerol 3-phosphate

    The enzymatic phosphorylation of the proR CH2OH of glycerol to form sn-glycerol-3-phosphate is illustrated in the figure below. As we were able to differentiate the 2 identical CH2OH substitutents as containing either the proS or proR carbons, so can the enzyme. The enzyme can differentiate identical substituents on a prochiral molecule if the prochiral molecule interacts with the enzyme at three points. Another example of a prochiral reactants/enzyme system involves the oxidation of the prochiral molecule ethanol by the enzyme alcohol dehydrogenase, in which only the proR H of the 2 H’s on C2 is removed. (We will discuss this later.)

     

    3pointBindingGlycerol3P.svg

    Isoprenoid-containing lipids

    This is the last class of lipids we will consider.  They do not contain fatty acids.  Rather they contain isoprene, a small branched alkadiene, which can polymerize into larger molecules containing isoprene monomer to form isoprenoids, often called terpenes.  Instead of using isoprene as the polymerization monomer, either dimethylally pyrophosphate (DMAPP) or isopentenylpyrophosphate (IPP) are used biologically.

    The figure below shows how DMAPP and IPP (both containing 5Cs) are used in a polymerization reaction to form geranyl-pyrophosphate (C10), farnesyl pyrophosphate (C15) and geranyl-geranyl pyrophosphate (C20). 

    IsoprenoidSyn1.svg

    Many isoprenoid lipids are made from farnesyl pyrophosphate.  For membrane purposes, the most important of these is cholesterol.   The figure below shows an overview of the synthesis of cholesterol from two farnesyl pyrophosphates linking together in a "tail to tail" reaction to form squalene, a precursor of cholesterol.  Each isoprene unit (5Cs) is shown in different colors to make it easier to see.

     

    squalene_lanosterol_cholesterol.svg

    Other biologically important isoprenoid-containing vitamins are shown in the figure below.

    OtherIsoprenoidContainingLipids_Vitamins.svg

    One last looks at lipid structure and shapes

    With the exclusion of waxes and triglycerols, the other lipids we have discussed, including the mostly planar molecule cholesterol, are amphiphilic.  We have seen that the single chain fatty acids form micelles while lipids with two nonpolar chains and a polar/charged headgroup form bilayers.  Given the relative size of the head group and the degree of unsaturation of the double bonds in fatty acids, the overall shapes of the membrane-forming lipids differ as illustrated below.  They are arranged like dominos in the membrane based on the their geometric volumes.  Preferential clustering of identical types can cause local and extended changes in prototypical bilayer structure.  

    Membranes and their components must by dynamics to enable all the functions and activities of a membrane.  Ligands bind to membrane receptors (usually proteins), which can invaginate and pinch off to form an intracellular vesicle containing the receptor for processing.  Likewise, vesicles can pinch off into the extracellular space.  Cells must divide.  Think of the membrane changes necessary for that!  Also consider that the length of cholesterol is half that of a typical double chain amphiphile so it fitrs into just one of the bilayer lipid leaflets where it modulates lipid bilayer property.

    LipidGeometric3DShapes.svg

    We will consider membranes in greater detail in section 10.3.  Next, however, we will explore in more detail the properties of micelle and lipid droplet systems before addressing the more structurally complicated lipid bilayers.

    Summary

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    End-of Chapter Questions

     

    Exercise \(\PageIndex{1}\)

    x) A cell membrane has the ability to remodel in response to stress to promote membrane integrity. In the situations below, how could the membrane be remodeled to prevent damage? (I.e. what types of lipids could be added/removed to ensure homeostasis)

    a) Increase in temperature

    b)

    x) What are the three classes of lipids? Explain their similarities and differences. 

    x) For each lipid below, name the type of lipid (membrane lipid, triacylglycerol, storage lipid, sphingolipid, wax, sterol, membrane glycerolipid, none of these), if it could be found in membrane, and if it is fatty acid or isoprene derived.

    (Insert pics of lipids)

     

    Answer

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