The solubility of lipids in nonpolar organic solvents results from their significanthydrocarbon component. The hydrocarbon portion of the compound is responsiblefor its “oiliness” or “fattiness.” The word lipid comes from the Greek lipos, whichmeans “fat.”

26 Lipids

001

stearic acid

linoleic acid

L ipids are organic compounds, found in living organisms, that aresoluble in nonpolar organic solvents. Because compounds are classified as lipids on the basis of a physical property—

their solubility in an organic solvent—rather than as a result of theirstructures, lipids have a variety of structures and functions, as thefollowing examples illustrate:

COOH

CH2OH

OH

H

CH3

CH3

CH2

CH2

CH

CH3

CH3

CH2OH

PGE1a vasodilator

cortisonea hormone

vitamin Aa vitamin

tristearina fat

limonenein orange and

lemon oils

HO H

HO

H

OH

HH3C H3C

O

C OO

O

O

OO

O

O

CH3

002 C H A P T E R 2 6 Lipids

MeltingNumber point

of carbons Common name Systematic name Structure °C

Saturatedlauric acid dodecanoic acid 44

myristic acid tetradecanoic acid 58

palmitic acid hexadecanoic acid 63

stearic acid octadecanoic acid 69

arachidic acid eicosanoic acid 77

Unsaturated

palmitoleic acid (9Z )-hexadecenoic acid 0

oleic acid (9Z )-octadecenoic acid 13

linoleic acid (9Z,12Z )-octadecadienoic acid −5

linolenic acid (9Z,12Z,15Z )-octadecatrienoic acid −11

arachidonic acid (5Z,8Z,11Z,14Z )-eicosatetraenoic acid −50

EPA (5Z,8Z,11Z,14Z,17Z )-eicosapentaenoic acid −50

COOH

COOH

COOH

COOH

COOH

COOH

COOH

COOH

COOH

COOH

COOH

12

14

16

18

20

16

18

18

18

20

20

Table 26.1 Common Naturally Occurring Fatty Acids

26.1 Fatty Acids

Fatty acids are carboxylic acids with long hydrocarbon chains. The fatty acids mostfrequently found in nature are shown in Table 26.1. Because they are synthesized fromacetate, a compound with two carbon atoms, most naturally occurring fatty acids con-tain an even number of carbon atoms and are unbranched. The mechanism for thebiosynthesis of fatty acids is discussed in Section 19.21. Fatty acids can be saturatedwith hydrogen (and therefore have no carbon–carbon double bonds) or unsaturated(have carbon–carbon double bonds). Fatty acids with more than one double bond arecalled polyunsaturated fatty acids. Double bonds in naturally occurring unsaturatedfatty acids are never conjugated—they are always separated by one methylene group.

The physical properties of a fatty acid depend on the length of the hydrocarbonchain and the degree of unsaturation. As expected, the melting points of saturated fattyacids increase with increasing molecular weight because of increased van der Waalsinteractions between the molecules (Section 2.9).

The double bonds in unsaturated fatty acids generally have the cis configuration. Thisconfiguration produces a bend in the molecules, which prevents them from packingtogether as tightly as fully saturated fatty acids. As a result, unsaturated fatty acids have

3-D Molecules:Stearic acid; Oleic acid;Linoleic acid; Linolenic acid

Section 26.1 Fatty Acids 003

OMEGA FATTY ACIDSOmega is a term used to indicate the position ofthe first double bond—from the methyl end—in an

unsaturated fatty acid. For example, linoleic acid is calledomega-6 fatty acid because its first double bond is after the sixthcarbon, and linolenic acid is called omega-3 fatty acid becauseits first double bond is after the third carbon. Mammals lack theenzyme that introduces a double bond beyond C-9 (the carboxylcarbon is C-1). Linoleic acid and linolenic acids, therefore, areessential fatty acids for mammals. In other words, the acids mustbe included in the diet because, although they cannot be synthe-sized, they are required for normal body function.

linoleic acid linolenic acid

COOH

omega-3fatty acid

COOH

omega-6fatty acid

missing art 26PYB02

fewer intermolecular interactions and, therefore, lower melting points than saturatedfatty acids with comparable molecular weights (Table 26.1). The melting points of theunsaturated fatty acids decrease as the number of double bonds increases. For example,an 18-carbon fatty acid melts at 69 °C if it is saturated, at 13 °C if it has one double bond,at if it has two double bonds, and at if it has three double bonds.-11 °C-5 °C

oleic acid

an 18-carbon fatty acidwith one double bond

stearic acid an 18-carbon fatty acidwith one double bond

linoleic acid

an 18-carbon fatty acidwith three double bonds

linolenic acid an 18-carbon fatty acidwith three double bonds

PROBLEM 1

Explain the difference in the melting points of the following fatty acids:

a. palmitic acid and stearic acid c. oleic acid and linoleic acid

b. palmitic acid and palmitoleic acid

PROBLEM 2

What products are formed when arachidonic acid reacts with excess ozone followed bytreatment with (Hint: See Section 20.8.)H2O2?

Art to be fixed

26.2 Waxes

Waxes are esters formed from long-chain carboxylic acids and long-chain alcohols.For example, beeswax, the structural material of beehives, has a 16-carbon carboxylicacid component and a 30-carbon alcohol component. The word wax comes from theOld English weax, meaning “material of the honeycomb.” Carnauba wax is a par-ticularly hard wax because of its relatively high molecular weight, arising from a32-carbon carboxylic acid component and a 34-carbon alcohol component. Carnaubawax is widely used as a car wax and in floor polishes.

Waxes are common in living organisms. The feathers of birds are coated with wax tomake them water repellent. Some vertebrates secrete wax in order to keep their fur lubri-cated and water repellent. Insects secrete a waterproof, waxy layer on the outside of theirexoskeletons. Wax is also found on the surfaces of certain leaves and fruits, where itserves as a protectant against parasites and minimizes the evaporation of water.

26.3 Fats and Oils

Triacylglycerols, also called triglycerides, are compounds in which the three OHgroups of glycerol are esterified with fatty acids. If the three fatty acid components of atriacylglycerol are the same, the compound is called a simple triacylglycerol. Mixedtriacylglycerols, on the other hand, contain two or three different fatty acid compo-nents and are more common than simple triacylglycerols. Not all triacylglycerol mole-cules from a single source are necessarily identical; substances such as lard and oliveoil, for example, are mixtures of several different triacylglycerols (Table 26.2).

▲ Raindrops on a feather

004 C H A P T E R 2 6 Lipids

Table 26.2 Approximate Percentage of Fatty Acids in Some Common Fats and Oils

Saturated fatty acids Unsaturated fatty acids

mp lauric myristic palmitic stearic oleic linoleic linolenic(°C)

Animal fats

Butter 32 2 11 29 9 27 4 —

Lard 30 — 1 28 12 48 6 —

Human fat 15 1 3 25 8 46 10 —

Whale blubber 24 — 8 12 3 35 10 —

Plant oils

Corn 20 — 1 10 3 50 34 —

Cottonseed 1 — 1 23 1 23 48 —

Linseed 24 — — 6 3 19 24 47

Olive 6 — — 7 2 84 5 —

Peanut 3 — — 8 3 56 26 —

Safflower 15 — — 3 3 19 70 3

Sesame 6 — — 10 4 45 40 —

Soybean 16 — — 10 2 29 51 7--

-

---

C18C18C18C18C16C14C12

a major component ofbeeswax

structural material of beehives

CH3(CH2)24CO(CH2)29CH3

O

a major component ofcarnauba wax

coating on the leavesof a Brazilian palm

CH3(CH2)30CO(CH2)33CH3

O

a major component ofspermaceti wax

from the heads ofsperm whales

CH3(CH2)14CO(CH2)15CH3

O▲ Layers of honeycomb in a beehive

Section 26.3 Fats and Oils 005

Triacylglycerols that are solids or semisolids at room temperature are called fats.Fats are usually obtained from animals and are composed largely of triacylglycerolswith either saturated fatty acids or fatty acids with only one double bond. The saturat-ed fatty acid tails pack closely together, giving the triacylglycerols relatively highmelting points, causing them to be solids at room temperature.

Liquid triacylglycerols are called oils. Oils typically come from plant products suchas corn, soybeans, olives, and peanuts. They are composed primarily of triacylglycerolswith unsaturated fatty acids that cannot pack tightly together. Consequently, they haverelatively low melting points, causing them to be liquids at room temperature. Theapproximate fatty acid compositions of some common fats and oils are shown inTable 26.2.

Some or all of the double bonds of polyunsaturated oils can be reduced by catalytichydrogenation (Section 4.11). Margarine and shortening are prepared by hydrogenat-ing vegetable oils such as soybean oil and safflower oil until they have the desired con-sistency. This process is called “hardening of oils.” The hydrogenation reaction mustbe carefully controlled, however, because reducing all the carbon–carbon doublebonds would produce a hard fat with the consistency of beef tallow.

Vegetable oils have become popular in food preparation because some studies havelinked the consumption of saturated fats with heart disease. Recent studies have shownthat unsaturated fats may also be implicated in heart disease. However, oneunsaturated fatty acid—a 20-carbon fatty acid with five double bonds, known as EPAand found in high concentrations in fish oils—is thought to lower the chance of devel-oping certain forms of heart disease. Once consumed, dietary fat is hydrolyzed in theintestine, regenerating glycerol and fatty acids. We have seen that the hydrolysis of fatsunder basic conditions forms glycerol and salts of fatty acids that are commonlyknown as soap (Section 17.13).

H2

PtRCH CHCH2CH CHCH2CH CH RCH2CH2CH2CH CHCH2CH2CH2

an oila fat

glycerol

O

O

O

CH2 OH

CH2 OH

CH OH

CH2 O

CH2 O

CH O

fatty acids

R1 C OH

R3 C OH

R2 C OH

O

O

O

a triacylglycerola fat or an oil

C R1

C R3

C R2

▲ This puffin’s diet is high in fish oil.

PROBLEM 3

Do all triacylglycerols have the same number of asymmetric carbons?

PROBLEM 4

Which has a higher melting point, glyceryl tripalmitoleate or glyceryl tripalmitate?

Organisms store energy in the form of triacylglycerols. A fat provides about sixtimes as much metabolic energy as an equal weight of hydrated glycogen because fatsare less oxidized than carbohydrates and, since fats are nonpolar, they do not bindwater. In contrast, two-thirds of the weight of stored glycogen is water (Section 22.18).

Animals have a subcutaneous layer of fat cells that serves as both an energy sourceand an insulator. The fat content of the average man is about 21%, whereas the fat con-tent of the average woman is about 25%. Humans can store sufficient fat to provide forthe body’s metabolic needs for two to three months, but can store only enough carbo-hydrate to provide for its metabolic needs for less than 24 hours. Carbohydrates, there-fore, are used primarily as a quick, short-term energy source.

Polyunsaturated fats and oils are easily oxidized by by means of a radical chainreaction. In the initiation step, a radical removes a hydrogen from a methylene groupthat is flanked by two double bonds. This hydrogen is the most easily removed one

O2

006 C H A P T E R 2 6 Lipids

OLESTRA: NONFAT WITH FLAVORChemists have been searching for ways to reducethe caloric content of foods without decreasing

their flavor. Many people who believe that “no fat” is synony-mous with “no flavor” can understand this problem. The federalFood and Drug Administration (Section 30.13) approved thelimited use of Olestra as a substitute for dietary fat in snackfoods. Procter and Gamble spent 30 years and more than $2billion to develop this compound. Its approval was based on theresults of more than 150 studies.

Olestra is a semisynthetic compound. That is, Olestra doesnot exist in nature, but its components do. Developing a com-pound that can be made from units that are a normal part of ourdiet decreases the potential toxic effects of the new compound.Olestra is made by esterifying all the OH groups of sucrosewith fatty acids obtained from cottonseed oil and soybean oil.Therefore, its component parts are table sugar and vegetable

oil. Olestra works as a fat substitute because its ester linkagesare too hindered to be hydrolyzed by digestive enzymes. As aresult, Olestra tastes like fat, but it has no caloric value since itcannot be digested.

CO

CO

CO

OC

COCH2

CH2OC

CH2

O

O

O

2

1

OC

O

O

O

O

O

O

O

OC

O

olestra

3-D Molecule:Olestra

because the resulting radical is resonance stabilized by both double bonds. This radicalreacts with forming a peroxy radical with conjugated double bonds. The peroxyradical removes a hydrogen from a methylene group of another molecule of fatty acid,forming an alkyl hydroperoxide. The two propagating steps are repeated over and over.

The reaction of fatty acids with causes them to become rancid. The unpleasanttaste and smell associated with rancidity are the results of further oxidation of the alkylhydroperoxide to shorter chain carboxylic acids such as butyric acid that have strongodors. The same process contributes to the odor associated with sour milk.

PROBLEM 5

Draw the resonance contributors for the radical formed when a hydrogen atom is removedfrom C-10 of arachidonic acid.

O2

O2,

Section 26.3 Fats and Oils 007

resonance contributor with isolated double bonds

resonance contributor with conjugated double bonds

initiation

propagation

propagation

a peroxy radical

RCH CH CH

H

CH CH X+ RCH CH CH CH CH HX+

RCH CH CH

O O

CH CH

RCH CH CH2 CH CH

RCH CH CH CH CH

O O

an alkyl hydroperoxide

RCH+ CH CH CH CHRCH CH CH CH CH

O OH

WHALES AND ECHOLOCATIONWhales have enormous heads, accounting for 33%of their total weight. They have large deposits of

fat in their heads and lower jaws. This fat is very different fromboth the whale’s normal body fat and its dietary fat. Becausemajor anatomical modifications were necessary to accommo-date this fat, it must have some important function for theanimal. It is now believed that the fat is used for echolocation—emitting sounds in pulses and gaining information by analyzingthe returning echoes. The fat in the whale’s head focuses theemitted sound waves in a directional beam, and the echoes arereceived by the fat organ in the lower jaw. This organ transmitsthe sound to the brain for processing and interpretation, provid-ing the whale with information about the depth of the water,changes in the seafloor, and the position of the coastline. Thefat deposits in the whale’s head and jaw therefore give the ani-mal a unique acoustic sensory system and allow it to competesuccessfully for survival with the shark, which also has a well-developed sense of sound direction. Humpback whale in Alaska

phosphatidylserine

008 C H A P T E R 2 6 Lipids

26.4 Membranes

For biological systems to operate, some parts of organisms must be separated fromother parts. On a cellular level, the outside of the cell must be separated from the in-side. “Greasy” lipid membranes serve as the barrier. In addition to isolating the cell’scontents, these membranes allow the selective transport of ions and organic moleculesinto and out of the cell.

PhospholipidsPhosphoacylglycerols (also called phosphoglycerides) are the major componentsof cell membranes. They are similar to triacylglycerols except that a terminal OHgroup of glycerol is esterified with phosphoric acid rather than with a fatty acid,forming a phosphatidic acid. Because phosphoacylglycerols are lipids that containa phosphate group, they are classified as phospholipids. The C-2 carbon of glycerolin phosphoacylglycerols has the R configuration.

Phosphatidic acids are the simplest phosphoacylglycerols and are present only insmall amounts in membranes. The most common phosphoacylglycerols in membraneshave a second phosphate ester linkage. The alcohols most commonly used to form thissecond ester group are ethanolamine, choline, and serine. Phosphatidylethanolaminesare also called cephalins, and phosphatidylcholines are called lecithins. Used asemulsifying agents, lecithins are added to foods such as mayonnaise to prevent theaqueous and fat components from separating.

Phosphoacylglycerols form membranes by arranging themselves in a lipid bilayer.The polar heads of the phosphoacylglycerols are on the outside of the bilayer, and thefatty acid chains form the interior of the bilayer. Cholesterol—a membrane lipid dis-cussed in Section 26.9—is also found in the interior of the bilayer (Figure 26.1). Atypical bilayer is about 50 Å thick. [Compare the bilayer with the micelles formed bysoap in aqueous solution (Section 17.13).]

CH2 O

CH2 O

O−

CH O

O

O

O

R configurationC R1

P OH

C R2

a phosphatidic acid

3-D Molecule:Phosphatidic acid

CH2 O

CH2 O

O−

CH O

O

O

O

a phosphatidylethanolaminea cephalin

C R1

P OCH2CH2NH3

C R2

CH2 O

CH2

CH3

CH3

O

O−

CH O

O

O

O

a phosphatidylcholinea lecithin

C R1

P OCH2CH2NCH3

C R2

++

CH2 O

CH2

NH3

O

O−

CH O

O

O

O

a phosphatidylserine

C R1

P OCH2CHCOO−

C R2

+

Section 26.4 Membranes 009

polarhead

CH2O R1

R2

C

O

CCHO=

nonpolarfatty acidchains

O

O−

PCH2O

O

O(CH2)2NH3

+cholesterolmolecule

enlargement of aphosphoacylglycerol

▲ Figure 26.1A lipid bilayer.

IS CHOCOLATE A HEALTH FOOD?We have long been told that our diets should in-clude lots of fruits and vegetables because they are

good sources of antioxidants. Antioxidants protect against car-diovascular disease, cancer, and cataracts, and they slow the ef-fects of aging. Recent studies show that chocolate has high levelsof antioxidants—complex mixtures of phenolic compounds(Section 9.8). On a weight basis, the concentration of antioxi-dants in chocolate is higher than the concentration in red wine orgreen tea and 20 times higher than the concentration in tomatoes.Dark chocolate contains more than twice the level of antioxi-dants as milk chocolate. Unfortunately, white chocolate containsno antioxidants. Another piece of good news is that stearic acid,the main fatty acid in chocolate, does not appear to raise bloodcholesterol levels the way other saturated fatty acids do.

The fluidity of a membrane is controlled by the fatty acid components of the phos-phoacylglycerols. Saturated fatty acids decrease membrane fluidity because theirhydrocarbon chains can pack closely together. Unsaturated fatty acids increase fluiditybecause they pack less closely together. Cholesterol also decreases fluidity (Sec-tion 26.9). Only animal membranes contain cholesterol, so they are more rigid thanplant membranes.

The unsaturated fatty acid chains of phosphoacylglycerols are susceptible to reac-tion with similar to the reaction described on p. 7 for fats and oils. Oxidation ofphosphoacylglycerols can lead to the degradation of membranes. Vitamin E is an im-portant antioxidant that protects fatty acid chains from degradation via oxidation. Vit-amin E, also called is classified as a lipid because it is soluble innonpolar organic solvents. Because vitamin E reacts more rapidly with oxygen thantriacylglycerols do, the vitamin prevents biological membranes from reacting withoxygen (Section 9.8). There are some who believe that vitamin E slows the agingprocess. Because vitamin E also reacts with oxygen more rapidly than fats do, it isadded to many foods to prevent spoilage.

-tocopherolvitamin E

CH3

CH3

H3C

HO

O

a-tocopherol,

O2,

3-D Molecule:Vitamin E

AU: Sentence above is not definite,

whereas sentence in box

is quite definite. Want to be consistent?

Pg number to be fixed

PROBLEM 8

a. Draw the structures of three different sphingomyelins.b. Draw the structure of a galactocerebroside.

PROBLEM 9

The membrane phospholipids in animals such as deer and elk have a higher degree of un-saturation in cells closer to the hoof than in cells closer to the body. Explain how this traitcan be important for survival.

010 C H A P T E R 2 6 Lipids

MULTIPLE SCLEROSISAND THE MYELIN SHEATHThe myelin sheath is a lipid-rich material that is

wrapped around the axons of nerve cells. Composed largely ofsphingomyelins and cerebrosides, the sheath functions so as to

increase the velocity of nerve impulses. Multiple sclerosis is adisease characterized by loss of the myelin sheath, a consequentslowing of nerve impulses, and eventual paralysis.

PROBLEM 6

Membranes contain proteins. Integral membrane proteins extend partly or completelythrough the membrane, whereas peripheral membrane proteins are found on the inner orouter surfaces of the membrane. What is the likely difference in the overall amino acidcomposition of integral and peripheral membrane proteins?

PROBLEM 7

A colony of bacteria accustomed to an environment at 25 °C was moved to an identical en-vironment, at 35 °C. The higher temperature increased the fluidity of the bacterial mem-branes. What could the bacteria do to regain their original membrane fluidity?

SphingolipidsSphingolipids are also found in membranes. They are the major lipid components inthe myelin sheaths of nerve fibers. Sphingolipids contain sphingosine instead of glyc-erol. In sphingolipids, the amino group of sphingosine is bonded to the acyl group ofa fatty acid. Both asymmetric carbons in sphingosine have the S configuration.

Two of the most common kinds of sphingolipids are sphingomyelins andcerebrosides. In sphingomyelins, the primary OH group of sphingosine is bondedto phosphocholine or phosphoethanolamine, similar to the bonding in lecithins andcephalins. In cerebrosides, the primary OH group of sphingosine is bonded to asugar residue through a linkage (Section 22.13). Sphingomyelins arephospholipids because they contain a phosphate group. Cerebrosides, on the otherhand, are not phospholipids.

a sphingomyelina glucocerebroside

CH

CH OH

CH(CH2)12CH3

CH2 O P OCH2CH2NCH3

CH NH C

O

O

O− CH3

CH3

R

CH

CH OH

CH(CH2)12CH3

CH2

O

CH NH C

O

R

HOHO

CH2OH

HH

H

OHHH

+ O

b-glycosidic3-D Molecule:Sphingosine

sphingosine

CH

CH OH

CH(CH2)12CH3

CH2 OH

CH NH2

s configuration

Ulf Svante von Euler (1905–1983)first identified prostaglandins—fromsemen—in the early 1930s. Henamed them for their source, theprostate gland. By the time it wasrealized that all cells except redblood cells synthesize prostaglandins,their name had become entrenched.Von Euler was born in Stockholm andreceived an M.D. from the KarolinskaInstitute, where he remained as amember of the faculty. He discoverednoradrenaline and identified itsfunction as a chemical intermediatein nerve transmission. For this work,he shared the 1970 Nobel Prize inphysiology or medicine with JuliusAxelrod and Sir Bernard Katz.

Section 26.5 Prostaglandins 011

26.5 Prostaglandins

Prostaglandins are found in all body tissues and are responsible for regulating a vari-ety of physiological responses, such as inflammation, blood pressure, blood clotting,fever, pain, the induction of labor, and the sleep–wake cycle. All prostaglandins havea five-membered ring with a seven-carbon carboxylic acid substituent and an eight-carbon hydrocarbon substituent. The two substituents are trans to each other.

Prostaglandins are named in accordance with the format PGX, where X designatesthe functional groups of the five-membered ring. PGAs, PGBs, and PGCs all contain acarbonyl group and a double bond in the five-membered ring. The location of the dou-ble bond determines whether a prostaglandin is a PGA, PGB, or PGC. PGDs andPGEs are ketones, and PGFs are 1,3-diols. A subscript indicates the totalnumber of double bonds in the side chains, and and indicate the configurationof the two OH groups in a PGF: indicates a cis diol and indicates a trans diol.

Prostaglandins are synthesized from arachidonic acid, a 20-carbon fatty acid with fourcis double bonds. In the cell, arachidonic acid is found esterified to the 2-position ofglycerol in many phospholipids. Arachidonic acid is synthesized from linoleic acid.Because linoleic acid cannot be synthesized by mammals, it must be included in the diet.

An enzyme called prostaglandin endoperoxide synthase catalyzes the conversion ofarachidonic acid to the precursor of all prostaglandins. There are two forms ofthis enzyme; one carries out the normal physiological production of prostaglandin,and the other synthesizes additional prostaglandin in response to inflammation. Theenzyme has two activities: a cyclooxygenase activity and a hydroperoxidase activity. Ituses its cyclooxygenase activity to form the five-membered ring. In the first step ofthis transformation, a hydrogen atom is removed from a carbon flanked by two doublebonds. This hydrogen is removed relatively easily because the resulting radical is

PGH2,

HO

PGF2

HO H

COOH

HOH

PGE1

O OH COOH

HHO OHPGE2

H

COOH

HHO OH

O

R1

R2

H

R1

H

R1

H

H

OR1

R2

O

R2

HO

O

R2

HPGAs PGBs PGCs PGDs

“b”“a”“b”“a”

b-hydroxy

prostaglandin skeleton

COOHH

H

For their work on prostaglandins,Sune Bergström, Bengt IngemarSamuelsson, and John Robert Vaneshared the 1982 Nobel Prize inphysiology or medicine. Bergströmand Samuelsson were born inSweden—Bergström in 1916 andSamuelsson in 1934. They are both atthe Karolinska Institute. Vane wasborn in England in 1927 and is at theWellcome Foundation in Beckenham,England.

012 C H A P T E R 2 6 Lipids

stabilized by electron delocalization. The radical reacts with oxygen to form a peroxyradical. Notice that these two steps are the same as the first two steps in the reactionthat causes fats to become rancid (Section 26.3). The peroxy radical rearranges and re-acts with a second molecule of oxygen. The enzyme then uses its hydroperoxidase ac-tivity to convert the OOH group into an OH group, forming which rearrangesto form a prostaglandin.

In addition to serving as a precursor for the synthesis of prostaglandins, is aprecursor for the synthesis of thromboxanes and prostacyclins. Thromboxanes con-strict blood vessels and stimulate the aggregation of platelets, the first step in bloodclotting. Prostacyclins have the opposite effect, dilating blood vessels and inhibiting

PGH2

PGE2,PGH2,

COOH

arachidonic acid

H H

COOHH

O

O

COOH

COOH

O

O

O

OH

OH

O

O

COOH

HO

O

OH

COOH

COOH

OH

OH

COOH

O

HO

HO

OH

OOH

HO H

H

H

H

H

H

H

H

H

H

O

O

cyclooxygenase

biosynthesis of prostaglandins, thromboxanes, and prostacyclins

a peroxy radical

hydroperoxidaseseveralsteps

severalsteps

PGH2

a thromboxane

PGE2a prostaglandin

a prostacyclin

Section 26.5 Prostaglandins 013

the aggregation of platelets. The levels of these two compounds must be carefully con-trolled to maintain the proper balance in the blood.

Aspirin (acetylsalicylic acid) inhibits the cyclooxygenase activity of prostaglandinendoperoxide synthase. It does this by transferring an acetyl group to a serine hydrox-yl group of the enzyme (Section 17.10). Aspirin, therefore, inhibits the synthesis ofprostaglandins and, in that way, decreases the inflammation produced by these com-pounds. Aspirin also inhibits the synthesis of thromboxanes and prostacyclins. Over-all, this causes a slight decrease in the rate of blood clotting, which is why somedoctors recommend one aspirin tablet every other day to reduce the chance of a heartattack or stroke caused by clotting in blood vessels.

Other anti-inflammatory drugs, such as ibuprofen (the active ingredient in and ) and naproxen (the active ingredient in ), also inhibit

the synthesis of prostaglandins. They compete with either arachidonic acid or theperoxy radical for the enzyme’s binding site.

Both aspirin and these other nonsteroidal anti-inflammatory drugs (NSAIDs) inhibitthe synthesis of all prostaglandins—those produced under normal physiological condi-tions and those produced in response to inflammation. The production of acid in thestomach is regulated by a prostaglandin. When prostaglandin synthesis stops, therefore,the acidity of the stomach can rise above normal levels. New drugs— and

—that recently have become available inhibit only the enzyme that producesprostaglandin in response to stress. Thus, inflammatory conditions now can be treatedwithout some of the harmful side effects.

Vioxx

CH3

O

O

O

O

S

Celebrex

CH3

F3C

CH3

O

NN

O

S

Vioxx®Celebrex®

Aleve®Nuprin®Motrin®,Advil®,

O +CH3C HOCH2 + HO

HOOC

acetylsalicylic acidaspirin

cyclooxygenase

active enzyme

serine hydroxylgroup

acetylgroup

cyclooxygenase

inactive enzyme

O

OCH2CH3C

O

HOOC

COOH

OCCH3

Oaspirin

CHCOOHCH3CHCH2

CH3 CH3

CHCOOH

CH3

CH3Oibuprofen

naproxen

Leopold Stephen Ru i ka(1887–1976) was the first torecognize that many organiccompounds contain multiples of fivecarbons. A Croatian, Ru i kaattended college in Switzerland and became a Swiss citizen in 1917.He was a professor of chemistry atthe University of Utrecht in theNetherlands and later at the FederalInstitute of Technology in Zürich.For his work on terpenes, he sharedthe 1939 Nobel Prize in chemistrywith Adolph Butenandt (p. 25).

cMzM

cMzM

014 C H A P T E R 2 6 Lipids

Arachidonic acid can also be converted into a leukotriene. Because they inducecontraction of the muscle that lines the airways to the lungs, leukotrienes are implicat-ed in allergic reactions, inflammatory reactions, and heart attacks. Leukotrienes alsobring on the symptoms of asthma and are implicated in anaphylactic shock, a poten-tially fatal allergic reaction. There are several antileukotriene agents available for thetreatment of asthma.

PROBLEM 10

Treating with a strong base such as sodium tert-butoxide followed by addition ofacid converts it to Propose a mechanism for this reaction.

26.6 Terpenes

Terpenes are a diverse class of lipids. More than 20,000 terpenes are known. Theycan be hydrocarbons, or they can contain oxygen and be alcohols, ketones, oraldehydes. Oxygen-containing terpenes are sometimes called terpenoids. Certainterpenes and terpenoids have been used as spices, perfumes, and medicines for manythousands of years.

After analyzing a large number of terpenes, organic chemists realized that theycontained carbon atoms in multiples of 5. These naturally occurring compounds con-tain 10, 15, 20, 25, 30, and 40 carbon atoms, which suggests that there is a compoundwith five carbon atoms that serves as their building block. Further investigationshowed that their structures are consistent with the assumption that they were made byjoining together isoprene units, usually in a head-to-tail fashion. (The branched end ofisoprene is called the head, and the unbranched end is called the tail.) Isoprene is thecommon name for 2-methyl-1,3-butadiene, a compound containing five carbon atoms.

That isoprene units are linked in a head-to-tail fashion to form terpenes is known asthe isoprene rule.

head

tailtail

carbon skeleton of two isoprene units with a bondbetween the tail of one and the head of another

head

OH

HO

mentholpeppermint oil

geraniolgeranium oil

zingibereneoil of ginger

-selineneoil of celery

PGC2.PGA2

OH OH

arachidonic acid a leukotriene

COOH COOH

Pg number to be fixed

Section 26.6 Terpenes 015

In the case of cyclic compounds, the linkage of the head of one isoprene unit to the tailof another is followed by an additional linkage to form the ring. The second linkage isnot necessarily head-to-tail, but is whatever is necessary to form a stable five- or six-membered ring.

In Section 26.8, we will see that the compound actually used in the biosynthesis ofterpenes is not isoprene, but isopentenyl pyrophosphate, a compound that has the samecarbon skeleton as isoprene. We will also look at the mechanism by which isopentenylpyrophosphate units are joined together in a head-to-tail fashion.

Terpenes are classified according to the number of carbons they contain (Table 26.3).Monoterpenes are composed of two isoprene units, so they have 10 carbons.Sesquiterpenes, with 15 carbons, are composed of three isoprene units. Many fra-grances and flavorings found in plants are monoterpenes and sesquiterpenes. Thesecompounds are known as essential oils.

head

tail

OO

carvonespearmint oil

a monoterpene

head

tail -farnesene

a sesquiterpene found in thewaxy coating on apple skins

head

tail

Table 26.3 Classification of Terpenes

Carbon atoms Classification Carbon atoms Classification

10 monoterpenes 25 sesterterpenes

15 sesquiterpenes 30 triterpenes

20 diterpenes 40 tetraterpenes

Triterpenes (six isoprene units) and tetraterpenes (eight isoprene units) have im-portant biological roles. For example, squalene, a triterpene, is a precursor of steroidmolecules (Section 26.9).

Carotenoids are tetraterpenes. Lycopene, the compound responsible for the red col-oring of tomatoes and watermelon, and the compound that causes carrotsand apricots to be orange, are examples of carotenoids. is also the coloringb-Carotene

b-carotene,

squalene

agent used in margarine. and other colored compounds are found in theleaves of trees, but their characteristic colors are usually obscured by the green color ofchlorophyll. In the fall, when chlorophyll degrades, the colors become apparent. Themany conjugated double bonds in lycopene and cause the compounds to becolored (Section 8.13).

PROBLEM 11 SOLVED

Mark off the isoprene units in menthol, zingiberene, and squalene.

SOLUTION For zingiberene, we have

PROBLEM 12

One of the linkages in squalene is tail-to-tail, not head-to-tail. What does this suggestabout how squalene is synthesized in nature? (Hint: Locate the position of the tail-to-taillinkage.)

PROBLEM 13

Mark off the isoprene units in lycopene and Can you detect a similarity in theway in which squalene, lycopene, and are biosynthesized?

26.7 Vitamin A

Vitamins A, D, E, and K are lipids (Sections 25.9 and 29.6). Vitamin A is the onlywater-insoluble vitamin we have not already discussed. which is cleavedto form two molecules of vitamin A, is the major dietary source of the vitamin. Vita-min A, also called retinol, plays an important role in vision.

The retina of the eye contains cone cells and rod cells. The cone cells are responsi-ble for color vision and for vision in bright light. The rod cells are responsible for vi-sion in dim light. In rod cells, vitamin A is oxidized to an aldehyde and the transdouble bond at C-11 is isomerized to a cis double bond. The mechanism for the en-zyme-catalyzed interconversion of cis and trans double bonds is discussed inSection 18.15. The protein opsin uses a lysine side chain (Lys 216) to form an iminewith (11Z)-retinal, resulting in a complex known as rhodopsin. When rhodopsin

b-Carotene,

b-caroteneb-carotene.

b-selinene,

-carotene

lycopene

b-carotene

b-Carotene

016 C H A P T E R 2 6 Lipids

Tutorial:Isoprene units in terpenes

Section 26.8 Biosynthesis of Terpenes 017

absorbs visible light, it isomerizes to the trans isomer. This change in molecular geom-etry causes an electrical signal to be sent to the brain, where it is perceived as a visualimage. The trans isomer of rhodopsin is not stable and is hydrolyzed to (11E)-retinaland opsin in a reaction referred to as bleaching of the visual pigment. (11E)-Retinal isthen converted back to (11Z)-retinal to complete the vision cycle.

The details of how the foregoing sequence of reactions creates a visual image arenot clearly understood. The fact that a simple change in configuration can be responsi-ble for initiating a process as complicated as vision, though, is remarkable.

26.8 Biosynthesis of Terpenes

Biosynthesis of Isopentenyl PyrophosphateThe five-carbon compound used for the biosynthesis of terpenes is 3-methyl-3-butenylpyrophosphate, loosely called isopentenyl pyrophosphate by biochemists.Each step in its biosynthesis is catalyzed by a different enzyme. The first step is thesame Claisen condensation that occurs in the first step of the biosynthesis of fattyacids, except that the acetyl and malonyl groups remain attached to coenzyme A ratherthan being transferred to the acyl carrier protein (Section 19.21). The Claisen conden-sation is followed by an aldol addition with a second molecule of malonyl-CoA. Theresulting thioester is reduced with two equivalents of NADPH to form mevalonic acid(Section 25.2). A pyrophosphate group is added by means of two successive phospho-rylations with ATP. Decarboxylation and loss of the OH group result in isopentenylpyrophosphate.

910

11

1213

14

11

12

15

retinolvitamin A

CH2OH

oxidation

(isomerization)

H O(11Z)-retinal

H2N opsin

the chemistry of vision

11

12

activated rhodopsin

visible light

(isomerization)11

12

H NH2OH+

H

N

11

12

(11E)-retinal

H

O + H2N

rhodopsin

opsin

opsin

opsin

018 C H A P T E R 2 6 Lipids

The mechanism for converting mevalonic acid into mevalonyl phosphate is essen-tially an reaction with an adenosyl pyrophosphate leaving group (Section 27.3). Asecond reaction converts mevalonyl phosphate to mevalonyl pyrophosphate. ATPis an excellent phosphorylating reagent for nucleophiles because its phosphoanhydridebonds are easily broken. The reason that phosphoanhydride bonds are so easily brokenis discussed in Section 27.4.

SN2SN2

O

−O

O O

SCoA

−O

OH O

OH

+

+

+

+

acetyl-CoA malonyl-CoA acetoacetyl-CoA

hydroxymethylglutaryl-CoA

Claisencondensation

biosynthesis of isopentenyl pyrophosphate

1.

2.

CoASH CO2

H2O

2 NADP+ 2 NADPHADP ATP

mevalonic acidmevalonyl phosphate

OOH

COO−

CO2

OHO

P

O−O−

SCoA

O O

SCoA

O O

SCoA

SCoA

COO−COO−

+ CoASH

+ +CO2

ADP

ADP

ATP

ATP

O O− HO

mevalonyl pyrophosphateisopentenyl pyrophosphate

O

OHO

P

O−

O

P

O−O O−O

O

P

O−

O

P

O−O−

O

P

O−COO−

OH

OH

COO−

−O

O

OP

O−+

mevalonic acid

adenosine

ATP

O

OP

O−

O

OP

O−

O +

+

−

mevalonyl pyrophosphate

−O

−O

ADP

OH

O

O

P

O–

O

OH

O

O

P

O−

O

P

O−O−

O

O

P

O−O

O

P

O−

O

O

P

O−O

O

P

O−

adenosine

−O

ADP

O

O

P

O−O

O

P

O−

adenosine

O

O

P

O−

adenosine

COO−

COO−

+ H +

Section 26.8 Biosynthesis of Terpenes 019

PROBLEM 14 SOLVED

Give the mechanism for the last step in the biosynthesis of isopentenyl pyrophosphate,showing why ATP is required.

SOLUTION In the last step of the biosynthesis of isopentenyl pyrophosphate, elimina-tion of is accompanied by elimination of an group, which is a strong base andtherefore a poor leaving group. ATP is used to convert the OH group into a phosphategroup, which is easily eliminated because it is a weak base.

PROBLEM 15

Give the mechanisms for the Claisen condensation and aldol addition that occur in the firsttwo steps of the biosynthesis of isopentenyl pyrophosphate.

Biosynthesis of Dimethylallyl PyrophosphateBoth isopentenyl pyrophosphate and dimethylallyl pyrophosphate are needed forthe biosynthesis of terpenes. Therefore, some isopentenyl pyrophosphate is convertedto dimethylallyl pyrophosphate by an enzyme-catalyzed isomerization reaction. Theisomerization involves addition of a proton to the carbon of isopentenyl py-rophosphate that is bonded to the greater number of hydrogens (Section 4.4) and elim-ination of a proton from the carbocation intermediate in accordance with Zaitsev’srule (Section 11.2).

sp2

C

O +

+ +

ADP

O

O

O

P

O−

O

O−P

O−

O

O

OP

O−

O

O− CO2P

O−HO

O

O−P

O−

O

O

O−P

O−O

O

P

O−−O O

O

P

O−

adenosine

O−

+ H+

OH

C

O + O

ATP

O

O

O

P

O−

O

O−P

O−O

O

P

O−−O

O

P

O−O

O

P

O−

adenosine

O−

-OHCO2

AU: Add here?- H +?

isopentenyl pyrophosphate dimethylallyl pyrophosphate

O

O

OP

O−

O

O−P

O−O

O

OP

O−

O

O− H++P

O−O

O

OP

O−

O

O−P

O−

H++

020 C H A P T E R 2 6 Lipids

Terpene BiosynthesisThe reaction of dimethylallyl pyrophosphate with isopentenyl pyrophosphate formsgeranyl pyrophosphate, a 10-carbon compound. In the first step of the reaction,isopentenyl pyrophosphate acts as a nucleophile and displaces a pyrophosphate groupfrom dimethylallyl pyrophosphate. Pyrophosphate is an excellent leaving group: Itsfour OH groups have values of 0.9, 2.0, 6.6, and 9.4. Therefore, three of the fourgroups will be primarily in their basic forms at physiological pH A pro-ton is removed in the next step, resulting in the formation of geranyl pyrophosphate.

The following scheme shows how some of the many monoterpenes could be syn-thesized from geranyl pyrophosphate:

1pH = 7.32.pKa

dimethylallyl pyrophosphate

geranyl pyrophosphatepyrophosphate

isopentenyl pyrophosphate

O

O

OP

O−

O

O−P

O−O

O

OP

O−

O

O−P

O−

O

O

OP

O−

O

O−P

O−−O

O

OP

O−

O

O−P

O−

+ H+

+O

O

OP

O−

O

O−P

O−

+

+

geranyl pyrophosphate

-terpineolin juniper oil

OO

geraniolin rose and

geranium oils

OH

citronellolin rose and

geranium oils

mentholin peppermint oil

OH

citronellalin lemon oil

CH

O

OP

O−

O

O−P

O−

H2O H+

H2O

H2O

OH OH

O

OH

reduction

reduction

oxidation

oxidation

+

OH

terpin hydratea common constituent

of cough medicine

limonenein orange and

lemon oils

Section 26.8 Biosynthesis of Terpenes 021

PROBLEM 16

Propose a mechanism for the conversion of the E isomer of geranyl pyrophosphate to the Zisomer.

PROBLEM 17

Propose mechanisms for the formation of and limonene from geranylpyrophosphate.

Geranyl pyrophosphate can react with another molecule of isopentenyl pyrophos-phate to form farnesyl pyrophosphate, a 15-carbon compound.

Two molecules of farnesyl pyrophosphate form squalene, a 30-carbon compound.The reaction is catalyzed by the enzyme squalene synthase, which joins the two mole-cules in a tail-to-tail linkage. Squalene is the precursor of cholesterol, and cholesterolis the precursor of all other steroids.

geranyl pyrophosphate isopentenyl pyrophosphate

farnesyl pyrophosphate

O

O

OP

O−

O

O−P

O−

O

O

OP

O−

O

O−P

O−−O

O

OP

O−

O

O−P

O−

H+

+

O

O

OP

O−

O

O−P

O−

O

O

OP

O−

O

O−P

O−+

+

+

a-terpineol

E isomerZ isomer

O

O O O−P P

O

O− O−

O

O O O−P P

O

O− O−

Farnesyl pyrophosphate can react with another molecule of isopentenyl pyrophos-phate to form geranylgeranyl pyrophosphate, a 20-carbon compound. Two geranylger-anyl pyrophosphates can join to form phytoene, a 40-carbon compound. Phytoene isthe precursor of the carotenoid (tetraterpene) pigments in plants.

PROBLEM 18

In aqueous acidic solution, farnesyl pyrophosphate forms the following sesquiterpene:

Propose a mechanism for this reaction.

PROBLEM 19 SOLVED

If squalene were synthesized in a medium containing acetate whose carbonyl carbon werelabeled with radioactive which carbons in squalene would be labeled?

SOLUTION Acetate reacts with ATP to form acetyl adenylate, which then reacts withCoASH to form acetyl-CoA (Section 17.20). Because malonyl-CoA is prepared fromacetyl-CoA, the thioester carbonyl carbon of malonyl-CoA will also be labeled. Examin-ing each step of the mechanism for the biosynthesis of isopentenyl pyrophosphate fromacetyl-CoA and malonyl-CoA allows you to determine the locations of the radioactivelylabeled carbons in isopentenyl pyrophosphate. Similarly, the locations of the radioac-tively labeled carbons in geranyl pyrophosphate can be determined from the mechanismfor its biosynthesis from isopentenyl pyrophosphate. And the locations of the radioac-tively labeled carbons in farnesyl pyrophosphate can be determined from the mechanismfor its biosynthesis from geranyl pyrophosphate. Knowing that squalene is obtainedfrom a tail-to-tail linkage of two farnesyl pyrophosphates tells you which carbons insqualene will be labeled.

14C,

022 C H A P T E R 2 6 Lipids

O− + AMP

O

SCoA

O

SCoA

OO

SCoA

CoASH

−O

O

O

adenosine

+ pyrophosphate

P

O−

−O O

O

P

O−O

O

P

O−O

adenosine

O

P

O−

CH3

O

CCH3

O

C

acetyl-CoA

acetyl-CoA malonyl-CoA

14

14 14

1414

farnesyl pyrophosphate

tail to tail

O

O

OP

O−

O

O−P

O−O

O

OP

O−

O

−OP

O−

squalene synthase

farnesyl pyrophosphate

squalene

+

Section 26.9 Steroids 023

26.9 Steroids

Hormones are chemical messengers—organic compounds synthesized in glands anddelivered by the bloodstream to target tissues in order to stimulate or inhibit someprocess. Many hormones are steroids. Because steroids are nonpolar compounds, theyare lipids. Their nonpolar character allows them to cross cell membranes, so they canleave the cells in which they are synthesized and enter their target cells.

All steroids contain a tetracyclic ring system. The four rings are designated A, B,C, and D. A, B, and C are six-membered rings and D is a five-membered ring. Thecarbons in the steroid ring system are numbered as shown.

We have seen that rings can be trans fused or cis fused and that trans fused ringsare more stable (Section 2.15). In steroids, the B, C, and D rings are all trans fused. Inmost naturally occurring steroids, the A and B rings are also trans fused.

2. H2O3. NADPH4. ATP5. ATP

OO

SCoA

OO

SCoA

OH

C

O

O

O

O

P

O−

O

O−P

O−

−O

O−

1.

mevalonyl pyrophosphate

acetoacetyl-CoA

1414

1414

14

14

O

O

OP

O−

O

O−P

O−O

O

OP

O−

O

O−P

O−

O

O

OP

O−

O

O−P

O−O

O

OP

O−

O

O−P

O−

1414

1414

1414

14

14

1414

1414

1414

1414

1414

1414

14

14

14

14

14

14

isopentenyl pyrophosphatedimethylallyl pyrophosphate

geranyl pyrophosphate

squalene

farnesyl pyrophosphate

CH3 and Hare trans

H

R

H3C

H3C

CH3 and Hare cis

angular methylgroups

H

H

H

H

R

H3C

H3C

HH

H

H

H

the steroid ring system

A B

C1

45

10

6

2

3 7

814

1312

11

9

15

17

16D

024 C H A P T E R 2 6 Lipids

Two German chemists, HeinrichOtto Wieland (1877–1957) andAdolf Windaus (1876–1959), eachreceived a Nobel Prize in chemistry(Wieland in 1927 and Windaus in 1928) for work that led to thedetermination of the structure ofcholesterol.

Heinrich Wieland, the son of achemist, was a professor at theUniversity of Munich, where heshowed that bile acids were steroidsand determined their individualstructures. During World War II, heremained in Germany but was openlyanti-Nazi.

Many steroids have methyl groups at the 10- and 13-positions. These are calledangular methyl groups. When steroids are drawn, both angular methyl groups areshown to be above the plane of the steroid ring system. Substituents on the same sideof the steroid ring system as the angular methyl groups are designated (indicated by a solid wedge). Those on the opposite side of the plane of the ringsystem are (indicated by a hatched wedge).

PROBLEM 20

A at C-5 means that the A and B rings are _____ fused; an at C-5means that they are _____ fused.

The most abundant member of the steroid family in animals is cholesterol, the pre-cursor of all other steroids. Cholesterol is biosynthesized from squalene, a triterpene(Section 26.6). Cholesterol is an important component of cell membranes(Figure 26.1). Its ring structure makes it more rigid than other membrane lipids. Be-cause cholesterol has eight asymmetric carbons, 256 stereoisomers are possible, butonly one exists in nature (Chapter 5, Problem 20).

The steroid hormones can be divided into five classes: glucocorticoids, mineralo-corticoids, androgens, estrogens, and progestins. Glucocorticoids and mineralocorti-coids are synthesized in the adrenal cortex and are collectively known as adrenalcortical steroids. All adrenal cortical steroids have an oxygen at C-11.

Glucocorticoids, as their name suggests, are involved in glucose metabolism, aswell as in the metabolism of proteins and fatty acids. Cortisone is an example of aglucocorticoid. Because of its anti-inflammatory effect, it is used clinically to treatarthritis and other inflammatory conditions.

Mineralocorticoids cause increased reabsorption of and by thekidneys, leading to an increase in blood pressure. Aldosterone is an example of amineralocorticoid.

HCO3-Na+, Cl-,

HHHH

H

HC

O

H3CH

HOCH3

CH2OH

O

H3C

C OOH

CH2OH

C O

O

O

aldosteronecortisone

H3C

H3C

H

H H

HOcholesterol

a-hydrogenb-hydrogen

A-substituents

B-substituents

Adolf Windaus originally intendedto be a physician, but the experienceof working with Emil Fischer for ayear changed his mind. Hediscovered that vitamin D was asteroid, and he was the first torecognize that vitamin containedsulfur.

B1

HH H

RH

RH

CH3CH3

A and B rings are trans fused

CH3CH3

H

A and B rings are cis fused

CH3 and Hare trans

CH3 and Hare cis

Section 26.9 Steroids 025

Adolf Friedrich Johann Butenandt(1903–1995) was born in Germany.He shared the 1939 Nobel Prize inchemistry (with Ru i ka; see p. 14)for isolating and determining thestructures of estrone, androsterone,and progesterone. Forced by the Nazigovernment to refuse the prize, heaccepted it after World War II. Hewas the director of the KaiserWilhelm Institute in Berlin and laterwas a professor at the Universities ofTübingen and Munich.

cMzM

PROBLEM 21

Is the OH substituent of the A ring of cholesterol an or a

PROBLEM 22

Aldosterone is in equilibrium with its cyclic hemiacetal. Draw the hemiacetal form ofaldosterone.

The male sex hormones, known as androgens, are secreted by the testes. They areresponsible for the development of male secondary sex characteristics during puberty.They also promote muscle growth. Testosterone and areandrogens.

Estradiol and estrone are female sex hormones known as estrogens. They are se-creted by the ovaries and are responsible for the development of female secondary sexcharacteristics. They also regulate the menstrual cycle. Progesterone is the hormonethat prepares the lining of the uterus for implantation of an ovum and is essential forthe maintenance of pregnancy. It also prevents ovulation during pregnancy.

Although the various steroid hormones have remarkably different physiological ef-fects, their structures are quite similar. For example, the only difference betweentestosterone and progesterone is the substituent at C-17, and the only difference be-tween and estradiol is one carbon and six hydrogens, but thesecompounds make the difference between being male and being female. These exam-ples illustrate the extreme specificity of biochemical reactions.

PROBLEM 23

The acid component of a cholesterol ester is a fatty acid such as linoleic acid. Draw thestructure of a cholesterol ester.

In addition to being the precursor of all the steroid hormones in animals, cholesterolis the precursor of the bile acids. In fact, the word cholesterol is derived from theGreek words chole meaning “bile” and stereos meaning “solid.” The bile acids—cholic acid and chenodeoxycholic acid—are synthesized in the liver, stored in the gall-bladder, and secreted into the small intestine, where they act as emulsifying agents sothat fats and oils can be digested by water-soluble digestive enzymes. Cholesterol isalso the precursor of vitamin D (Section 29.6).

5a-dihydrotestosterone

HHHHHH

H3C

CH3

HO

H

C O

CH3

O CH3

O

H

CH3

HO

H

OH

estrone progesteroneestradiol

HH

H

H

CH3

O

H3C

OH

5 -dihydrotestosterone

HH

H

CH3

O

H3C

OH

testosterone

5a-dihydrotestosterone

b-substituent?a-substituent

Michael S. Brown and JosephLeonard Goldstein shared the 1985Nobel Prize in physiology ormedicine for their work on theregulation of cholesterol metabolismand the treatment of disease causedby elevated cholesterol levels in theblood. Brown was born in New Yorkin 1941; Goldstein, in South Carolinain 1940. They are both professors ofmedicine at the University of TexasSouthwestern Medical Center.

Pg number to be fixed

026 C H A P T E R 2 6 Lipids

CHOLESTEROL ANDHEART DISEASECholesterol is probably the best-known lipid be-

cause of the correlation between cholesterol levels in the bloodand heart disease. Cholesterol is synthesized in the liver and isalso found in almost all body tissues. Cholesterol is also foundin many foods, but we do not require it in our diet because thebody can synthesize all we need. A diet high in cholesterol canlead to high levels of cholesterol in the bloodstream, and the ex-cess can accumulate on the walls of arteries, restricting the flowof blood. This disease of the circulatory system is known asatherosclerosis and is a primary cause of heart disease. Choles-terol travels through the bloodstream packaged in particles thatalso contain cholesterol esters, phospholipids, and proteins. The

particles are classified according to their density. LDL (low-density lipoprotein) particles transport cholesterol from the liverto other tissues. Receptors on the surfaces of cells bind LDL par-ticles, allowing them to be brought into the cell so that it can usethe cholesterol. HDL (high-density lipoprotein) is a cholesterolscavenger, removing cholesterol from the surfaces of mem-branes and delivering it back to the liver, where it is convertedinto bile acids. LDL is the so-called bad cholesterol, whereasHDL is the “good” cholesterol. The more cholesterol we eat, theless the body synthesizes. But this does not mean that the pres-ence of dietary cholesterol has no effect on the total amount ofcholesterol in the bloodstream, because dietary cholesterol alsoinhibits the synthesis of the LDL receptors. So the more choles-terol we eat, the less the body synthesizes, but also, the less thebody can get rid of by bringing it into target cells.

CLINICAL TREATMENT OFHIGH CHOLESTEROLStatins are the newest class of cholesterol-reduc-

ing drugs. Statins reduce serum cholesterol levels by inhibitingthe enzyme that catalyzes the reduction of hydroxymethylglu-taryl-CoA to mevalonic acid (Section 26.8). Decreasing themevalonic acid concentration decreases the isopentenyl py-rophosphate concentration, so the biosynthesis of all terpenes,including cholesterol, is diminished. As a consequence of di-minished cholesterol synthesis in the liver, the liver expressesmore LDL receptors—the receptors that help clear LDL fromthe bloodstream. Studies show that for every 10% that choles-

terol is reduced, deaths from coronary heart disease are reducedby 15% and total death risk is reduced by 11%.

Compactin and lovastatin are natural statins used clinicallyunder the trade names and Atorvastatin

a synthetic statin, is now the most popular statin.has greater potency and a longer half-life than natural

statins have, because its metabolites are as active as the parentdrug in reducing cholesterol levels. Therefore, smaller doses ofthe drug may be administered. The required dose is reducedfurther because is marketed as a single enantiomer. Inaddition, it is more lipophilic than compactin and lovastatin, soit has a greater tendency to remain in the endoplasmic reticu-lum of the liver cells, where it is needed.

Lipitor®

Lipitor®(Lipitor)®,

Mevacor®.Zocor ®

(CH3)2CH

OH OHO

O

OO

H3C H3CCH3 CH3

F

H3C H3C

OHO HOHOC

O

CNHO

OO

CH3H3CCH3

O

N

lovastatin simvastatinMevacor Zocor

atorvastatinLipitor

PROBLEM 24

Are the three OH groups of cholic acid axial or equatorial?

CH3

HO

HO

OH

COOH

HH3C

HH

cholic acidH

H3C

HO OH

COOH

HH3C

HH

chenodeoxycholic acidH

Tutorial:

Steroids

Section 26.10 Biosynthesis of Cholesterol 027

Konrad Bloch and Feodor Lynenshared the 1964 Nobel Prize inphysiology or medicine. Blochshowed how fatty acids andcholesterol are biosynthesized fromacetate. Lynen showed that the two-carbon acetate unit is actually acetyl-CoA, and he determined the structureof coenzyme A.

Konrad Emil Bloch (1912–2000)was born in Upper Silesia (then apart of Germany), left Nazi Germanyfor Switzerland in 1934, and came tothe United States in 1936, becominga U.S. citizen in 1944. He received aPh.D. from Columbia in 1938, taughtat the University of Chicago, andbecame a professor of biochemistryat Harvard in 1954.

Feodor Lynen (1911–1979) wasborn in Germany, received a Ph.D.under Heinrich Wieland, and marriedWieland’s daughter. He was head ofthe Institute of Cell Chemistry at theUniversity of Munich.

26.10 Biosynthesis of Cholesterol

How is cholesterol, the precursor of all the steroid hormones, biosynthesized? Thestarting material for the biosynthesis is the triterpene squalene, which must first beconverted to lanosterol. Lanosterol is converted to cholesterol in a series of 19 steps.

The first step in the conversion of squalene to lanosterol is epoxidation of the2,3-double bond of squalene. Acid-catalyzed opening of the epoxide initiates a seriesof cyclizations resulting in the protosterol cation. Elimination of a C-9 proton from thecation initiates a series of 1,2-hydride and 1,2-methyl shifts, resulting in lanosterol.

Converting lanosterol to cholesterol requires removing three methyl groups fromlanosterol (in addition to reducing two double bonds and creating a new double bond).Removing methyl groups from carbon atoms is not easy: Many different enzymes are re-quired to carry out the 19 steps. So why does nature bother? Why not just use lanosterolinstead of cholesterol? Konrad Bloch answered that question when he found that mem-branes containing lanosterol instead of cholesterol are much more permeable. Small mol-ecules are able to pass easily through lanosterol-containing membranes. As each methylgroup is removed from lanosterol, the membrane becomes less and less permeable.

PROBLEM 25

Draw the individual 1,2-hydride and 1,2-methyl shifts responsible for conversion of the proto-sterol cation to lanosterol. How many hydride shifts are involved? How many methyl shifts?

cholesterol

H

H

H

HO

H3C H

H3C

biosynthesis of lanosterol and cholesterol

CH3

H

HO

H3C

H3C

CH3

H

HO

H3C

H

H

H+O

+

squaleneepoxidase

O2

+ H+

lanosterol

squalene

protosterol cation

19 steps

squalene oxide

CH3

028 C H A P T E R 2 6 Lipids

26.11 Synthetic Steroids

The potent physiological effects of steroids led scientists, in their search for newdrugs, to synthesize steroids that are not available in nature and to investigate theirphysiological effects. Stanozolol and Dianabol are drugs developed in this way. Theyhave the same muscle-building effect as testosterone. Steroids that aid in the develop-ment of muscle are called anabolic steroids. These drugs are available by prescriptionand are used to treat people suffering from traumas accompanied by muscle deteriora-tion. The same drugs have been administered to athletes and racehorses to increasetheir muscle mass. Stanozolol was the drug detected in several athletes in the 1988Olympics. Anabolic steroids, when taken in relatively high dosages, have been foundto cause liver tumors, personality disorders, and testicular atrophy.

Many synthetic steroids have been found to be much more potent than naturalsteroids. Norethindrone, for example, is better than progesterone in arresting ovula-tion. Another synthetic steroid, RU 486, when taken along with prostaglandins, termi-nates pregnancy within the first nine weeks of gestation. Notice that these oralcontraceptives have structures similar to that of progesterone.

norethindrone

H

H3C

O

H

RU 486

H

H

H3C

O

OHC CCH3

CH3N

CH3

H

OHC CH

H

stanozolol

H3C

H3C

H

Dianabol

H

H

H3C

O

H3C

OHCH3

HH

OHCH3

H

H

HNN

Summary

Lipids are organic compounds, found in living organisms,that are soluble in nonpolar organic solvents. Fatty acidsare carboxylic acids with long hydrocarbon chains. Doublebonds in fatty acids have the cis configuration. Fatty acidswith more than one double bond are called polyunsatu-rated fatty acids. Double bonds in naturally occurring un-saturated fatty acids are separated by one methylene group.Waxes are esters formed from long-chain carboxylic acidsand long-chain alcohols. Prostaglandins are synthesizedfrom arachidonic acid and are responsible for regulating avariety of physiological responses.

Triacylglycerols (triglycerides) are compounds in whichthe three OH groups of glycerol are esterified with fatty acids.Triacylglycerols that are solids or semisolids at room temper-

ature are called fats. Liquid triacylglycerols are called oils.Some or all of the double bonds of polyunsaturated oils can bereduced by catalytic hydrogenation. Phosphoacylglycerolsdiffer from triacylglycerols in that the terminal OH group ofglycerol is esterified with phosphoric acid instead of a fattyacid. Phosphoacylglycerols form membranes by arrangingthemselves in a lipid bilayer. Phospholipids are lipids thatcontain a phosphate group. Sphingolipids, also found inmembranes, contain sphingosine instead of glycerol.

Terpenes contain carbon atoms in multiples of 5. Theyare made by joining together five-carbon isoprene units,usually in a head-to-tail fashion—the isoprene rule.Monoterpenes—terpenes with two isoprene units—have10 carbons; sesquiterpenes have 15. Squalene, a triterpene

Problems 029

Key Terms

adrenal cortical steroids (p. 024)anabolic steroids (p. 028)androgens (p. 025)angular methyl group (p. 024)bile acids (p. 025)carotenoid (p. 015)cephalins (p. 008)cerebroside (p. 010)cholesterol (p. 024)cis fused (p. 023)dymethyl allyl pyrophosphate (p. 019)essential oils (p. 015)estrogens (p. 025)fat (p. 005)fatty acid (p. 002hormone (p. 023)isopentenyl pyrophosphate (p. 019)

isoprene rule (p. 014)lecithins (p. 008)lipid (p. 001)lipid bilayer (p. 008)leukotriene (p. 014)membrane (p. 008)mixed triacylglycerol (p. 004)monoterpene (p. 015)oil (p. 005)phosphatidic acid (p. 008)phosphoacylglycerol (p. 008)phosphoglycerides (p. 008)phospholipid (p. 008)polyunsaturated fatty acid (p. 002)prostacyclins (p. 012)prostaglandin (p. 011)sesquiterpene (p. 015)

simple triacylglycerol (p. 004)sphingomyelins (p. 010)sphingolipid (p. 010)squalene (p. 015)steroid (p. 023)

(p. 024)(p. 024)

terpene (p. 014)terpenoid (p. 014)tetraterpene (p. 015)thromboxanes (p. 012)trans fused (p. 023)triacylglycerol (p. 004)triterpene (p. 015)wax (p. 004)

b-substituenta-substituent

(a terpene with six isoprene units), is a precursor of steroidmolecules. Lycopene and are tetraterpenescalled carotenoids. is cleaved to form twomolecules of vitamin A.

The five-carbon compound used for the synthesis of ter-penes is isopentenyl pyrophosphate. The reaction ofdimethylallyl pyrophosphate (formed from isopentenylpyrophosphate) with isopentenyl pyrophosphate formsgeranyl pyrophosphate, a 10-carbon compound. Geranylpyrophosphate can react with another molecule of isopen-tenyl pyrophosphate to form farnesyl pyrophosphate, a15-carbon compound. Two molecules of farnesyl pyrophos-phate form squalene, a 30-carbon compound. Squalene isthe precursor of cholesterol. Farnesyl pyrophosphate canreact with another molecule of isopentenyl pyrophosphateto form geranylgeranyl pyrophosphate, a 20-carboncompound. Two geranylgeranyl pyrophosphates join to

b-Caroteneb-carotene

form phytoene, a 40-carbon compound. Phytoene is theprecursor of the carotenoids.

Hormones are chemical messengers. Many hormonesare steroids. All steroids contain a tetracyclic ring system.The B, C, and D rings are trans fused. In most naturallyoccurring steroids, the A and B rings are also trans fused.Methyl groups at C-10 and C-13 are called angular methylgroups. -Substituents are on the same side of the steroidring system as the angular methyl groups; -substituentsare on the opposite side. Synthetic steroids are steroids thatare not found in nature.

The most abundant member of the steroid family inanimals is cholesterol, the precursor of all other steroids.Cholesterol is an important component of cell membranes;its ring structure causes it to be more rigid than other mem-brane lipids. In the biosynthesis of cholesterol, squalene isconverted to lanosterol, which is converted to cholesterol.

AB

Problems

26. An optically active fat, when completely hydrolyzed, yields twice as much stearic acid as palmitic acid. Draw the structure of the fat.

27. a. How many different triacylglycerols are there in which one of the fatty acid components is lauric acid and two are myristic acid?b. How many different triacylglycerols are there in which one of the fatty acid components is lauric acid, one is myristic acid, and

one is palmitic acid?

28. Cardiolipins are found in heart muscles. Give the products formed when a cardiolipin undergoes complete acid-catalyzed hydrolysis.

CH2O

CHO CR2

O−

OCH2CHCH2O

OHa cardiolipin

OCH2P

OCHR4C

O−

O

OO

O

P

OCH2R3C

O

CH2O CR1

O

AU: Insert boldface

terms in Key Terms?

(boxed) Or make

lightface in text?

030 C H A P T E R 2 6 Lipids

29. Nutmeg contains a simple, fully saturated triacylglycerol with a molecular weight of 722. Draw its structure.

30. Give the product that would be obtained from the reaction of cholesterol with each of the following reagents: (Hint: Because ofsteric hindrance from the angular methyl groups, the is more susceptible to attack by reagents than the .)a.b. in THF, followed by c. Pd Cd.e. peroxyacetic acidf. the product of part

31. Dr. Cole S. Terol synthesized the following samples of mevalonic acid and fed them to a group of lemon trees:

Which carbons in citronellal, which is isolated from lemon oil, will be labeled in trees that were fed the following?a. sample A b. sample B c. sample C

32. An optically active monoterpene (compound A) with molecular formula undergoes catalytic hydrogenation to form anoptically inactive compound with molecular formula (compound B). When compound B is heated with acid, followed byreaction with and workup under reducing conditions one of the products obtained is 4-methylcyclohexanone. Givepossible structures for compound A.

33. If junipers were allowed to grow in a medium containing acetate in which the methyl carbon was labeled with which carbonsin would be labeled?

34. a. Propose a mechanism for the following reaction:

b. To what class of terpene does the starting material belong? Mark off the isoprene units in the starting material.

35. 5-Androstene-3,17-dione is isomerized to 4-androstene-3,17-dione by hydroxide ion. Propose a mechanism for this reaction.

5-androstene-3,17-dione

H3C

H3C

O

HO−

H2O

O

4-androstene-3,17-dione

H3C

H3C

O

O

CH3CH3

CH3 CH3

H3C

H3C

HO

H+

CH3

CH3 H3C CH3

CH3H3C

+ H3O+CH3

CH3H3C

CH3

a-terpineol

14C,

1Zn, H2O2,O3,C10H20O

C10H18O

CH2CO−

CH3CCH2CH2OH

OH

Osample A

CH2CO−

CH3CCH2CH2OH

OH

Osample B

CH2CO−

CH3CCH2CH2OH

OH

Osample C

14

14 14

cholesterol

H3C H

HH

H3C

HO

e + CH3O-

Br2 + H2O>H2,

H2O2 + HO-BH3

H2O, H+b-facea-face

Problems 031

36. Both OH groups of one of the following steroid diols react with excess ethyl chloroformate, but only one OH group of the othersteroid diol reacts under the same conditions:

Explain the difference in reactivity.

37. The acid-catalyzed dehydration of an alcohol to a rearranged alkene is known as a Wagner–Meerwein rearrangement. Propose amechanism for the following Wagner–Meerwein rearrangement:

38. Diethylstilbestrol (DES) was given to pregnant women to prevent miscarriage, until it was found that the drug caused cancer inboth the mothers and their female children. DES has estradiol activity even though it is not a steroid. Draw DES in a way thatshows that it is structurally similar to estradiol.

HOOH

CH3CH2

CH2CH3

diethylstilbestrolDES

+ H3O+

OH

isoborneol camphene

H+

CH3CH2OCOCH3CH2OCCl

O

O

OH

H3C

HO

H3C

5 -cholestane-3 ,7 H H

OH

-diol

CH3CH2OCOCH3CH2OCCl

O

O OH

OCOCH2CH3

H3C

HO OH

H3C

H5 -cholestane-3 ,7 -diol