Reginald H. Garrett Charles M.

Grisham

Chapter 8 Lipids

Outline
What are the structures and chemistry of fatty acids ? What are the structures and chemistry of triacylglycerols ? What are the structures and chemistry of glycerophospholipids ? What are sphingolipids, and how are they important for higher animals ? What are waxes, and how are they used ?

Outline
What are terpenes, and what is their relevance to biological systems ? What are steroids, and what are their cellular functions ? How do lipids and their metabolites act as biological signals ? What can lipidomics tell us about cell, tissue, and organ physiology ?

Classes of Lipids
All biological lipids are amphipathic (have both polar and nonpolar parts)
Fatty acids Triacylglycerols Glycerophospholipids Sphingolipids Waxes Isoprene-based lipids (including steroids)

8.1 What Are the Structures and Chemistry of Fatty acids?

Know the common names and structures for fatty acids up to 20 carbons long
Saturated fatty acids (common names): Lauric acid (12 C) Myristic acid (14 C) Palmitic acid (16 C) Stearic acid (18 C) Arachidic acid (20 C) Most fatty acids have an even number of carbons

8.1 What Are the Structures and Chemistry of Fatty acids?

Unsaturated fatty acids (common names): Palmitoleic acid (16:1), 9 Oleic acid (18:1), 9 Linoleic acid (18:2), 9,12 -Linolenic acid (18:3), 9,12,15 -Linolenic acid (18:3), 6,9,12 Arachidonic acid (20:4), 5,8,11,14 Most naturally occuring double bonds in lipids are cis.

8.1 What Are the Structures and Chemistry of Fatty acids?

8.1 What Are the Structures and Chemistry of Fatty acids?

Fatty acids are comprised of alkyl chains terminated by carboxylic acid groups. Shown here is palmitic acid, a 16-carbon saturated fatty acid. The term saturated indicates that the acyl chain is fully reduced, i.e., saturated with hydrogens and electrons.
Figure 8.1

8.1 What Are the Structures and Chemistry of Fatty acids?

Figure 8.1 The structures of typical saturated fatty acids.

8.1 What Are the Structures and Chemistry of Fatty acids?

Figure 8.1 The structures of typical unsaturated fatty acids.

8.1 What Are the Structures and Chemistry of Fatty acids?

Figure 8.1 The structures of typical unsaturated fatty acids.

8.1 What Are the Structures and Chemistry of Fatty acids?

Structural consequences of unsaturation
Saturated chains pack tightly and form more rigid, organized aggregates (i.e., membranes). Unsaturated chains bend and pack in a less ordered way due to the cis double bonds. Thus intermolecular forces are not as great and there is greater potential for motion within a membrane.

Fats in the human diet vary widely in their composition

Saturated

Unsaturated

Diets high in trans fatty acids raise plasma LDL cholesterol levels
Trans fatty acids are present at low levels in dairy and meat products from ruminant animals. Partially hydrogenated fats in foods contain much higher amounts.

Figure 8.2 Structures of elaidic acid and vaccenic acid, two trans fatty acids (18:2).

8.2 What Are the Structures and Chemistry of Triacylglycerols (TAG) ?

Triacylglycerols are also called triglycerides
TAGs have three fatty acids esterified to glycerol. TAGs are fats or oils depending the state at 25o. They are a major energy source for many organisms. These have the most reduced form of carbon in nature which means that more energy is available on oxidation. They are stored in adipose tissue until metabolized for energy. They also have a role in insulation and act to cushion vital organs (liver, kidney,etc.).

8.2 What Are the Structures and Chemistry of Triacylglycerols?

Triacylglycerols are the storage form of fatty acids in plants and animals. If all three fatty acids are the same, the molecule is called a simple triacylglycerol (uncommon). Figure 8.3 Triacylglycerols are formed from glycerol and fatty acids.

8.2 What Are the Structures and Chemistry of Triacylglycerols?

Mixed triacylglycerols contain two or three different fatty acids (typical). TAGs with saturated acyl groups are solids at room temp. The m.p. decreases with decreasing chain length and increasing unsaturation. Figure 8.3 Triacylglycerols are formed from glycerol and fatty acids.

Polar Bears Prefer Nonpolar Food

Polar bears face an ironic dilemma. They are surrounded by water they cannot use. Ice and snow are too cold and seawater is too salty. They produce all the water they need from metabolism of fat:

(CH2) + 1.5 O2 CO2 + H2O

Adult polar bears consume only fat (from seals they catch). By not consuming protein (and merely recycling their own proteins into new ones), they have no need to urinate or defecate and go for months without doing so, saving precious body water.

8.3 Phosphatidic acid: The parent of Glycerophospholipids

Glycerophospholipids are essential components of cell membranes and are also found in other parts of cells. They have a diacylglycerol core.

Figure 8.4 Phosphatidic acid, the parent compound for glycerophospholipids.

8.3 What Are the Structures and Chemistry of Glycerophospholipids

A glycerophospholipid is a 1,2-diacylglycerol that has a phosphate group esterified both to carbon 3 of the glycerol backbone and to another alcohol. Glycerophospholipids are phospholipids but the reverse is not necessarily true. The parent structure is phosphatidic acid. Know the names and structures in Figure 8.6. Understand the prochirality of glycerol. Remember, if a phospholipid contains an unsaturation, it is most likely at the 2-position.

The sn-Numbering System is Used to Name the Glycerophospholipids

A prochiral structure

Figure 8.5 The two identical CH2OH groups on the central carbon of glycerol may be distiguished be imagining a slight increase in priority for one of them (by replacement of an H by a D) as shown. The molecule may then be named using the (R,S) or Cahn, Ingold, Prelog naming system.

The sn-Numbering System is Used to Name the Glycerophospholipids

Fischer Projections

Figure 8.5 The absolute configuration of sn-glycerol-3phosphate is shown. The pro-R and pro-S positions of the parent glycerol are indicated. The stereochemical numbering system (sn) assigns C1 to the pro-S carbon.

8.3 A Glycerophospholipid
Tail Head

(Lecithin)

Within membrane

Inside or outside of membrane

Figure 8.6 The structure of phosphatidylcholine. The core of the structure (diacylglycerol) is shown here with a blue background. In the rest of Figure 8.6, the core is displayed using this blue motif. Other common head pieces are ethanolamine, serine, inositol and some glycerol.

8.3 What Are the Structures and Chemistry of Glycerophospholipids

(Cephalin)

Figure 8.6 Structures of several glycerophospholipids and a space-filling model of phosphatidylglycerol.

8.3 What Are the Structures and Chemistry of Glycerophospholipids

Figure 8.6 Structures of several glycerophospholipids and a space-filling model of phosphatidylinositol.

Phosphatides Exist in Many Varieties

Unsaturated fatty acids are found typically at the 2position of the glycerol backbone. It is rare to find unsaturated fatty acids at the 1-position.

Figure 8.7 A space-filling model of 1-stearoyl-2-oleoylphosphatidylcholine.

Ether Glycerophospholipids
Ether containing glycerophospholipids possess an ether linkage instead of an acyl group at the C-1 position of glycerol.
There are two common types: plasmalogens and platelet activating factors (PAF). Plasmalogens are ether glycerophospholipids in which the alkyl chain is unsaturated, see Figure 8.8.

Ether Glycerophospholipids: Plasmalogens

Figure 8.8 The plasmalogen, 1-alkyl-2-acylphosphatidylethanol amine, is typically called phosphatidal ethanolamine.

R1 is unsaturated

Ether Glycerophospholipids
Figure 8.9 The structure of a choline plasmalogen called phosphatidal choline. Other common head groups are ethanolamine and serine. Plasmalogens are sometimes called enol ethers.
Unsaturated and cis

Ether Glycerophospholipids
Platelet activating factor (PAF) is also an ether glycerophospholipid. PAF is a potent biochemical signal molecule. PAF is involved in reducing inflammation, lowering blood pressure and platelet aggregation. Note the short (acetate) fatty acyl chain at the C-2 position in PAF which makes it more soluble. Phospholipids, in general, are major membrane components.

Ether Glycerophospholipids: PAF

Figure 8.8 The structure of 1alkyl-2-acetylphosphatidylcholine, a platelet activating factor (PAF). Active at 10-11 M.

acetyl

Phospholipids
There are two general types of phospholipids. A major function of both is to serve as biological membrane components. Glycerol based phospholipids including phosphatidyl choline, phosphatidyl serine, etc. as well as the phosphatidal derivatives. Sphingosine based, phospholipids are the other group. The membrane structures are called sphingomyelins.

8.4 Sphingolipids: Most are Phospholipids

Sphingolipids include both phosphorylated and
nonphosphorylated compounds Sphingosine, an 18-carbon alcohol, forms the backbone of these lipids rather than glycerol. A fatty acid joined to sphingosine in an amide linkage forms a ceramide. Sphingomyelins are ceramides with mostly P-choline at C1, a few have P-ethanolamine. Glycosphingolipids are ceramides with one or more sugars in beta-glycosidic linkage to the 1hydroxyl group and no phosphate.

8.4 What Are Sphingolipids and How Are They Important for Higher Animals?
Figure 8.10 Sphingolipids are based on the structure of sphingosine. Note the trans double bond.

Sphingosine is an 18-carbon alcohol. The carbons are derived from palmitoylCoA and serine. Fatty acids joined in amide linkage at the highlighted nitrogen form ceramides.

8.4 What Are Sphingolipids and How Are They Important for Higher Animals?
Figure 8.10 A ceramide is formed by joining a fatty acid in amide linkage to a sphingosine. A phosphate esterified at C1 forms ceramide phosphate. A head group esterified to ceramide phosphate yields a sphingolipid. (Choline and ethanolamine are common head groups).

8.4 What Are Sphingolipids and How Are They Important for Higher Animals?

Figure 8.10 A ceramide with a phosphocholine head group is a choline sphingomyelin. Sphingomyelins are components of the myelin sheath.

Sphingolipids having no Phosphate

Glycosphingolipids are not phospholipids. Cerebrosides are ceramides with one sugar attached (usually glucose or galactose). These are called glucocerebrosides or galactocerebrosides. They are components of nerve and muscle cell membrane. Gangliosides are ceramides with 3 or more sugars, one or more of which is a sialic acid. They have imputed involvement in signal transduction and immunology.

8.4 What Are Sphingolipids and How Are They Important for Higher Animals?
Figure 8.10 A ceramide with a single sugar is a cerebroside. Note the -glycosidic bond to ceramide and the lack of phosphate.

8.4 What Are Sphingolipids and How Are They Important for Higher Animals?
Gangliosides are important components of muscle and nerve membranes. More than 50 are known. Note the -link to ceramide here also.

Figure 8.10 Gangliosides are ceramides with three or more sugars esterified, one of which is a sialic acid.

8.5 What Are Waxes, and How Are They Used?

Waxes are esters of long-chain alcohols with long-chain fatty acids
Waxes are insoluble in water, due to their mostly hydrocarbon composition. Animal skin and fur are wax-coated and are water-repellant. Leaves of many plants and bird feathers are similarly water-repellant. Carnauba wax, from a palm tree in Brazil, is a hard wax used for high-gloss finishes for automobiles, boats, floors, and shoes. Lanolin is a wool wax used in cosmetics, such as Oil of Olay, named for its lanolin content.

8.5 What Are Waxes, and How Are They Used?

Figure 8.11 Waxes consist of long-chain alcohols esterified to long-chain fatty acids. Triacontanol palmitate is the principal component of beeswax.

8.6 What Are Terpenes, and What is Their Relevance to Biological Systems?
Terpenes are a class of lipids formed from combinations of isoprene units
Isoprene is 2-methyl-1,3-butadiene. Monoterpenes have two isoprene units (C10). Sesquiterpenes have three isoprene units (C15). A diterpene have four isoprene units (C20). All steroids (including cholesterol and the steroid hormones) are terpene-derived molecules. The biological precursors of these lipids are isopentenyl pyrophosphate and dimethylallyl pyrophosphate rather than isoprene.

8.6 What Are Terpenes, and What is Their Relevance to Biological Systems?
Note there are two possible linkage modes: head-to-tail tail-to-tail
Tail

Head

Figure 8.12 The structure of isoprene (2-methyl-1,3-butadiene) and the structure of head-to-tail and tail-to-tail linkages. Isoprene itself can be formed by distillation of natural rubber, a linear head-to-tail polymer of isoprene units.

8.6 What Are Terpenes, and What is Their Relevance to Biological Systems?

Figure 8.13 Many monoterpenes are readily recognized by their characteristic flavors or odors (limonene in lemons; citronellal in roses and perfumes; menthol used in cough drops.

8.6 What Are Terpenes, and What is Their Relevance to Biological Systems?
Figure 8.13 Diterpenes include retinal (the visual pigment in rhodopsin), and phytol (found in chlorophyll. Gibberellic acid is a plant hormone.

8.6 What Are Terpenes, and What is Their Relevance to Biological Systems?
Figure 8.13 The triterpene lanosterol is a constituent of wool fat and is also a precursor to cholesterol and the other steroids. Lycopene is a carotenoid found in ripe fruit, especially tomatoes.

Why Do Plants Emit Isoprene?

The haze that gave the Blue Ridge Mountains of Virginia their name is composed in part of isoprene This isoprene is produced and emitted by the plants and trees of the mountains Global emission of isoprene is 3x1014 grams/year Isoprene acts as a blanket for vegetation, to protect trees and plants from high temperatures in summer

Long-chain polyisoprenoid molecules serve several functions in various organisms

Figure 8.14 Dolichol phosphate is an initiation point for synthesis of carbohydrate polymers in animals. In bacteria, undecaprenol (aka bactoprenol) delivers sugars for synthesis of cell wall components.

8.7 What Are Steroids, and What Are Their Cellular Functions?
Steroids are polyprenyl (isoprene-based) molecules built on a core structure of three 6membered rings and one 5-membered ring, all fused together 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

8.7 What Are Steroids, and What Are Their Cellular Functions?

Know structure and numbering

Figure 8.16 The structure of cholesterol, C27, shown with steroid ring designations and numbering.

Cholesterol is the parent of other steriod related structures.

8.7 What Are Steroids, and What Are Their Cellular Functions?
The bile acids, C24, a family including cholic acid and deoxycholic acid, are detergent molecules secreted in bile from the gallbladder that assist in the absorption of dietary lipids in the intestine.

Figure 8.17 The structures of several important sterols derived from cholesterol.

8.7 What Are Steroids, and What Are Their Cellular Functions?
Cortisol, C21, an adrenocortical hormone provides control of carbohydrate, protein, and lipid metabolism. Progesterone, C21, is a precursor of testosterone and estradiol. Testosterone, C19, is the primary male sex steroid hormone. Estradiol, C18, is the primary female sex steroid hormone.

Figure 8.17 The structures of several important sterols derived from cholesterol.

8.8 How Do Lipids and Their Metabolites Act as Biological Signals?

Glycerophospholipids and sphingolipids play important roles as chemical signals in and on cells. Lipid signals act locally, either within the cell where they are made or on nearby cells. These signals typically initiate a cascade of reactions with multiple effects. The lifetimes of these signals are usually very short. The creation and breakdown of lipid signals is carefully regulated and timed. Some of the reactions that produce these signals are shown on the next slide.

Hydrolysis by Phospholipases
Figure 8.18 Phospholipases A1 and A2 cleave fatty acids from a glycerophospholipid, producing lysophospholipids. Phospholipases C and D hydrolyze on either side of the phosphate in the polar head group.

8.8 How Do Lipids and Their Metabolites Act as Biological Signals?

Glycerophospholipid breakdown produces a variety of signal products: Arachidonic acid Lysophosphatidic acid Diacylglycerol Inositol phosphates, including inositol-1,4,5OH HO trisphosphate (PIP2). O
-

O -P=O
4
=

OPO3
5

O-

O3 P O OH

8.8 How Do Lipids and Their Metabolites Act as Biological Signals?

Figure 8.19 Modification and breakdown of glycerophospholipids produce a variety of signals and regulatory effects.

Eicosanoids
These are derived from unsaturated C20 fatty acids.

Functions:
Lower blood pressure Smooth muscle contraction Prevent contraception Produce fever Water retention Electrolyte balance Inhibit FA breakdown

Sphingolipids can be modified or broken down to produce chemical signals

Sphingosine can be phosphorylated to produce sphingosine-1-phosphate (S1P) inside cells. S1P may either exert a variety of intracellular effects or may be excreted from the cell, where it can bind to membrane receptor proteins, either on adjacent cells or on the cell from which it was released.

8.9 What Can Lipidomics Tell Us about Cell, Tissue, and Organ Physiology?
Many human diseases involve the disruption of lipid metabolic enzymes and pathways. New techniques have made possible the global analysis of lipids and their interacting protein partners in organs, cells, and organelles an approach termed lipidomics. Typical cells contain over a thousand different lipids. Complete understanding of lipid function will require the determination of which lipids are present and in what concentrations. Cellular lipidomics provides a framework for understanding the myriad roles of lipids.

End Chapter 8 Lipids