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Chapter 24Chapter 24LipidsLipids

Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.

Lipids

Lipids are naturally occurring substances grouped together on the basis of a common property—solubility. They are extracted from cellular material using a nonpolar solvent.

Some of the most important of them—the ones in this chapter—are related in that they have acetic acid (acetate) as their biosynthetic origin.

In many biosynthetic pathways a substance called acetyl coenzyme A serves as a carrier of acetate.

Lipids

Since lipids are defined by solubility rather than structure, they include a variety of molecules having different structures. Some are:

1. Fats & Oils (Triacylglycerols)

2. Fatty acids

3. Phospholipids - glycerol based - sphinogsine based

4. Waxes

5. Prostaglandins

6. Terpenes - Cholesterol

24.124.1Acetyl Coenzyme A:Acetyl Coenzyme A:

Not a lipid, it is a coenzyme Not a lipid, it is a coenzyme used in fatty acid metabolismused in fatty acid metabolism

Structure of Coenzyme A P

OP

ON N

SR

H3C CH3

OH

O O

H H

O

HO O O OH

O

HO

OPHO

HO

O

NN

NN

NH2

R = H; Coenzyme A

R = CCH3; Acetyl coenzyme A

O

Reactivity of Coenzyme A

Nucleophilic acyl substitution

CH3CSCoA

OHY ••

CH3C

O

Y •• + HSCoA

Acetyl coenzyme A is a source of an acetyl group toward biological nucleophiles; it is an acetyl transfer agent.

Reactivity of Coenzyme A

can react via enol

CH3CSCoA

O

Acetyl coenzyme A reacts with biological electrophiles at its carbon atom.

CSCoA

OH

H2C

E+

CH2CSCoA

O

E

24.224.2Fats, Oils, and Fatty AcidsFats, Oils, and Fatty Acids

Fats and Oils

Fats and oils are naturally occurring mixture of triacylglycerols (also called triglycerides).

Fats are solids; oils are liquids.

RCOCH

CH2OCR'O

CH2OCR"

O

O

CH3(CH2)16COCH

CH2OC(CH2)16CH3O

CH2OC(CH2)16CH3

O

O

Fats and Oils

Tristearin; mp 72°C

Fats and Oils

2-Oleyl-1,3-distearylglycerol; mp 43°C

CH2OC(CH2)16CH3

CH2OC(CH2)16CH3

O

O

CH2(CH2)6COCH

O

C

H

C

H

CH3(CH2)6CH2

Fats and Oils

2-Oleyl-1,3-distearylglycerolmp 43°C

H2, Pt

Tristearinmp 72°C

Fatty Acids

Acids obtained by the hydrolysis of fats and oils are called fatty acids.

Fatty acids usually have an unbranched chain with an even number of carbon atoms.

If double bonds are present, they are almost always cis.

H2OHOCH

CH2OH

CH2OH

O

R'COCH

CH2OCRO

CH2OCR"

O

O

R'COH

O

HOCR

O

HOCR"

Table 24.1

O

CH3(CH2)10COH Dodecanoic acid Lauric acid

Systematic name Common name

O

CH3(CH2)12COH Tetradecanoic acid Myristic acid

O

CH3(CH2)14COH Hexadecanoic acid Palmitic acid

Table 24.1

O

CH3(CH2)16COH Octadecanoic acid Stearic acid

O

CH3(CH2)18COH Eicosanoic acid Arachidic acid

Systematic name Common name

Table 24.1

O

C

H

C

H

CH3(CH2)7 (CH2)7COH

Systematic name: (Z)-9-Octadecenoic acid

Common name: Oleic acid

Table 24.1

Systematic name: (9Z, 12Z)-9,12-Octadecadienoic acid

Common name: Linoleic acid

C

H

C

H

CH3(CH2)4

O

(CH2)7COHCH2

C

H

C

H

Table 24.1

Systematic name: (9Z, 12Z, 15Z)-9,12,15-Octadecatrienoic acid

Common name: Linolenic acid

C

H

C

H

O

(CH2)7COHCH2

C

H

C

H

CH3CH2

C

H

C

H

CH2

Table 24.1

Systematic name: (5Z, 8Z, 11Z, 14Z)-5,8,11,14-Icosatetraenoic acid

Common name: Arachidonic acid

H

H H

H

H HH

H

OH

O

trans-Fatty Acids

Are formed by isomerization that can occur when esters of cis-fatty acids are hydrogenated. O

OR

H O

ORH

H2, cat

O

OR

H O

ORH

H

O

OR

H

H2, cat

24.424.4PhospholipidsPhospholipids

A major component of cell A major component of cell membranes.membranes.

Phospholipids

Phospholipids may be glycerol based or sphingosine based.

Sphingosine itself is derived from serine and palmitic acid and leads to ceramide-P.

Phosphatidic acid is derived from glycerol, fatty acids and Pi. It is used to form triacylglycerols (TAG) and glycerol based phospholipids.

The starting materials for TAG are L-glycerol 3-phosphate and the appropriate acyl coenzyme A (CoASH is an acyl group carrier).

Phosphatidic Acid

Phosphatidic acid is central to the synthesis of triacylglycerols and glycerol based phospholipids.

Common glycerol based phospholipids are phosphatidylcholine (lecithin), phosphatidylethanolamine (cephalin), phosphatidylserine and phosphatidylinositol.

Phospholipids contain a head group (polar) and a tail section (nonpolar) and are major components of cell membranes.

CH2OPO3H2

CH2OH

HHO + R'CSCoA

O

RCSCoA

O

+

The diacylated species formed in this step is called a phosphatidic acid.

CH2OPO3H2

CH2OCR

HR'CO

O

O

Phosphatidic Acid Synthesis

The phosphatidic acid then undergoes hydrolysis of its phosphate ester function.

H2O

CH2OPO3H2

CH2OCR

HR'CO

O

O

CH2OH

CH2OCR

HR'CO

O

O

TAG Synthesis

Reaction with a third acyl coenzyme A molecule yields a triacylglycerol (TAG).

R"CSCoA

OCH2OH

CH2OCR

HR'CO

O

O

CH2OCR"

CH2OCR

HR'CO

O

O

O

This shows triglyceride (TAG) formation.

TAG is not a phospholipid.

TAG Synthesis

Phosphatidic acids are intermediates in the formation of the phospholipid phosphatidylcholine.

Phosphatidylcholine

CH2OPO3H2

CH2OCR

HR'CO

O

O

CH2OPO2

CH2OCR

HR'CO

O

O

–

(CH3)3NCH2CH2O+

Phosphatidylcholine

Phosphatidylcholine

CH2OPO2

CH2OCR

HR'CO

O

O

–

(CH3)3NCH2CH2O+

polar "head group"

hydrophobic "tail"

hydrophobic "tail"

Phosphatidylcholine

hydrophilic "head group"

hydrophobic(lipophilic) "tails"

Cell Membranes

Cell membranes are "lipid bilayers."

Each layer has an assembly of phospholipid molecules as the main structural component.

water

water

Cell Membranes

The interior of the cell membrane is hydrocarbon-like.

Polar materials cannot pass from one side to the other of the membrane.

water

water

Ceramide Phosphate with a head group attached (usually choline) are sphingomyelins.

Sphingomyelins

CH2OPO3H2

CHCH=CH(CH2)12CH3

HR'CNH

O

CH2OPO2

HR'CNH

O

–

(CH3)3NCH2CH2O+

A sphingomyelin

HO

HO

CHCH=CH(CH2)12CH3

Ceramide phosphate

24.524.5WaxesWaxes

Waxes

Waxes are water-repelling solids that coat the leaves of plants, etc.

Structurally, waxes are mixtures of esters. The esters are derived from fatty acids and long-chain alcohols.

CH3(CH2)14COCH2(CH2)28CH3

O

Triacontyl hexadecanoate: occurs in beeswax

24.624.6ProstaglandinsProstaglandins

Eicosanoids include:prostaglandinsthromboxanesprostacyclinsleukotrienes

Eicosanoids are compounds related to eicosanoic acidCH3(CH2)18CO2H.

Eicosanoids

Prostaglandins are involved in many biological processes.

One group of prostaglandins is made from arachidonic acid (C20) which is derived from linoleic acid (C18). (See Table 24.1)

Prostaglandins

O

HO

O

OH

OH HO

HO OH

O

OH

PGE1

PGF1

Examples: PGE1 and PGF1

PGE2 is biosynthesized from arachidonic acid.

The oxygens come from O2.

The enzyme involved (prostaglandin endoperoxide synthase) has cyclooxygenase (COX) acitivity.

Prostaglandin Biosynthesis

Arachidonic acid

O2

fatty acid cyclooxygenase

CO2H

CH3

PGG2

O

HOO

CO2H

CH3

O

Prostaglandin Biosynthesis

reduction ofhydroperoxide

PGG2

O

HOO

CO2H

CH3

O

PGH2

O

HO

CO2H

CH3

O

Prostaglandin Biosynthesis

OHO HO

CO2H

CH3 PGE2

PGH2

O

HO

CO2H

CH3

O

Prostaglandin Biosynthesis

Cleavage of cyclic peroxide

PGH2

O

HO

CO2H

CH3

O

TXA2

O

OHO

CO2H

CH3

Thromboxane A2 is biosynthesized from PGH2

TXA2 promotes platelet

aggregation and blood clotting

Thromboxane A2 (TXA2)

PGI2

Like thromboxane A2, prostacyclin I2 is

biosynthesized from PGH2.

PGI2 inhibits platelet

aggregation and relaxescoronary arteries.

OH

HO2C

CH3

HO

O

Prostacyclin I2 (PGI2)

Leukotrienes arise from arachidonic acid viaa different biosynthetic pathway.

They are the substances most responsible for constricting bronchial passages during asthma attacks.

Leucotriene C4 (LTC4)

CO2H

OH

CH3

SCH2CHCNHCH2CO2H

O

NH

C OO2CCHCH2CH2

NH3+

–

Leucotriene C4 (LTC4)

24.724.7Terpenes: The Isoprene RuleTerpenes: The Isoprene Rule

Terpenes

Terpenes are natural products that are structurally related to isoprene.

H2C C

CH3

CH CH2

or

Isoprene(2-methyl-1,3-butadiene)

Terpenes

Myrcene (isolated from oil of bayberry) is a typical terpene.

CH2

CH3

CH3C CHCH2CH2CCH

CH2 or

The Isoprene Unit

An isoprene unit is the carbon skeleton of isoprene (ignoring the double bonds). Myrcene contains two isoprene units.

The Isoprene Unit

The isoprene units of myrcene are joined "head-to-tail". head tail

tail head

Table 24.2

Class Number of carbon atoms

Monoterpene 10

Sesquiterpene 15

Diterpene 20

Sesterpene 25

Triterpene 30

Tetraterpene 40

Classification of Terpenes

Figure 24.7

Representative Monoterpenes -Phellandrene

(eucalyptus)Menthol

(peppermint)Citral

(lemon grass)

O

H

OH

Figure 24.7

Locating the isoprene units. -Phellandrene

(eucalyptus)Menthol

(peppermint)Citral

(lemon grass)

OH O

H

Figure 24.7

-Phellandrene(eucalyptus)

Menthol(peppermint)

Citral(lemon grass)

Locating the isoprene units.

Figure 24.7

Representative Sesquiterpenes

-Selinene(celery)

H

Figure 24.7

-Selinene(celery)

H

Locating the isoprene units.

Figure 24.7

-Selinene(celery)

Locating the isoprene units.

Figure 24.7

Representative Diterpene

Vitamin A

OH

Figure 24.7

Vitamin A

OH

Locating the isoprene units.

Figure 24.7

Vitamin A

Locating the isoprene units.

Figure 24.7

Representative Triterpene

Squalene (shark liver oil)

tail-to-tail linkage of isoprene units

Locating the isoprene units.

24.824.8Isopentenyl Pyrophosphate: Isopentenyl Pyrophosphate:

The Biological Isoprene UnitThe Biological Isoprene Unit

The Biological Isoprene Unit

The isoprene units in terpenes do not come from isoprene.

They come from isopentenyl pyrophosphate.

Isopentenyl pyrophosphate (5 carbons) comes from acetate (2 carbons) via mevalonate (6 carbons).

The Biological Isoprene Unit

CH3COH

O

3 HOCCH2CCH2CH2OH

CH3

OH

O

Mevalonic acid

H2C CCH2CH2OPOPOH

CH3 O O

Isopentenyl pyrophosphate

Isopentenyl Diphosphate

H2C CCH2CH2OPOPOH

CH3 O O

Isopentenyl pyrophosphate

or

OPP

Isopentenyl and Dimethylallyl Diphosphate

Isopentenyl diphosphate is interconvertible with2-methylallyl diphosphate.

OPP

OPP

Dimethylallyl pyrophosphate has a leaving group (pyrophosphate) at an allylic carbon; it is reactive toward nucleophilic substitution at this position.

Isopentenyl pyrophosphate Dimethylallyl pyrophosphate

24.924.9Carbon-Carbon Bond FormationCarbon-Carbon Bond Formation

in Terpene Biosynthesisin Terpene Biosynthesis

Carbon-Carbon Bond Formation

The key process involves the double bond of isopentenyl pyrophosphate acting as a nucleophile toward the allylic carbon of dimethylallyl pyrophosphate.

+OPP

OPP

Carbon-Carbon Bond Formation

+OPP

OPP–

+OPP

OPP

After C—C Bond Formation...

+

OPP

The carbocation can lose a proton to give a double bond.

OPP

H–+

After C—C Bond Formation... OPP

This compound is called geranyl pyrophosphate. It can undergo hydrolysis of its pyrophosphate to give geraniol (rose oil).

After C—C Bond Formation... OPP OH

Geraniol

H2O

From 10 Carbons to 15 +

OPP

OPP

Geranyl pyrophosphate +

OPPOPP

+

OPP

From 10 Carbons to 15

H–+

OPP

From 10 Carbons to 15 OPP

This compound is called farnesyl pyrophosphate.

Hydrolysis of the pyrophosphate ester gives the alcohol farnesol (Figure 24.7).

From 15 Carbons to 20 OPP

Farnesyl pyrophosphate is extended by another isoprene unit by reaction with isopentenyl pyrophosphate.

OPP

Cyclization

Rings form by intramolecular carbon-carbon bond formation.

OPP

OPP

+

E double bond

Z double bond

+

OH

H–+

H2O

Limonene

-Terpineol

Bicyclic Terpenes +

+

+

-Pinene

+

-Pinene

24.1024.10The Pathway from AcetateThe Pathway from Acetate

to Isopentenyl Diphosphateto Isopentenyl Diphosphate

Recall

CH3COH

O

3 HOCCH2CCH2CH2OH

CH3

OH

O

Mevalonic acid

H2C CCH2CH2OPOPOH

CH3 O O

Isopentenyl pyrophosphate

Biosynthesis of Mevalonic Acid

CH3CCH2CSCoA

OO

S-Acetoacetylcoenzyme A

In a sequence analogous to the early steps of fatty acid biosynthesis, acetyl coenzyme A is converted to S-acetoacetyl coenzyme A.

Biosynthesis of Mevalonic Acid

CH3CSCoA

O

+CH3CCH2CSCoA

OO

In the next step, S-acetoacetyl coenzyme A reacts with acetyl coenzyme A.

Nucleophilic addition of acetyl coenzyme A (probably via its enol) to the ketone carbonyl of S-acetoacetyl coenzyme A occurs.

Biosynthesis of Mevalonic Acid

CH3CSCoA

O

CH3CCH2CSCoA

CH2COH

HO O

O

+CH3CCH2CSCoA

OO

3-hydroxy-3-methylglutarylCoA

Biosynthesis of Mevalonic Acid

Next, the acyl coenzyme A function is reduced.

The product of this reduction is mevalonic acid.

CH3CCH2CSCoA

CH2COH

HO O

O

CH3CCH2CH2OH

CH2COH

HO

OMevalonic acid

Conversion of Mevalonic Acid to Isopentenyl Pyrophosphate

CH3CCH2CH2OH

CH2COH

HO

O

The two hydroxyl groups of mevalonic acid undergo phosphorylation.

CH3CCH2CH2OPP

CH2COH

O

OPO3

2–

Conversion of Mevalonic Acid to Isopentenyl Pyrophosphate

Phosphorylation is followed by a novel elimination involving loss of CO2 and PO4

3– giving isopentenyl pyrophosphate.

CH3CCH2CH2OPP

CH2

O

OPO3

2–

C O••

••••–

CH3CCH2CH2OPP

CH2

OPO3

3–

O C O

Biosynthetic Pathway is Based on Experiments with 14C-labeled Acetate

CH3COH

O

Citronellal biosynthesized using 14C-labeled acetate as the carbon source has the labeled carbons in the positions indicated.

H2C CCH2CH2OPOPOH

CH3 O O O

H

•

• • •

•

•

24.1124.11Steroids: CholesterolSteroids: Cholesterol

Structure of Cholesterol Fundamental framework of steroids is the tetracyclic unit shown.

Structure of Cholesterol

Cholesterol has the fundamental steroid skeleton modified as shown.

Cholesterol has 27 carbons.

HO

CH3

H

H

H

CH3

CH3 CH3

CH3

Structure of Cholesterol

Some parts of the cholesterol molecule are isoprenoid. Other parts don't obey the isoprene rule, it does not have a multiple of 5 carbons.

HO

CH3

H

H

H

CH3

CH3 CH3

CH3

Biosynthesis of Cholesterol

Cholesterol is biosynthesized from the triterpene squalene. In the first step, squalene is converted to its 2,3-epoxide. O

O2, NADH, enzyme

Biosynthesis of Cholesterol

To understand the second step, we need to look at squalene oxide in a different conformation, one that is in a geometry suitable for cyclization.

O

O

H+

Biosynthesis of Cholesterol

Cyclization is triggered by epoxide ring opening. O

+

HO

H

Biosynthesis of Cholesterol

The five-membered ring expands to a six-membered one.

+

HO

H

H

+

HO

H

Biosynthesis of Cholesterol

Cyclization to form a tetracyclic carbocation.

H

+

HO

H

+

H

H

HO

protosteryl cation

Biosynthesis of Cholesterol

Deprotonation and multiple migrations.

H

+HO

OH2

••••

H

H HO

H

H

Biosynthesis of Cholesterol

The product of this rearrangement is a triterpene called lanosterol. A number of enzyme-catalyzed steps follow that convert lanosterol to cholesterol.

HO

H

H

Molecules Made from Cholesterol

Cholesterol (C27) is the biosynthetic precursor to a large number of important steroids:

Vitamin D (27 carbons)

Bile acids (24 carbons)

Adrenocortico hormones + progesterone (21 carbons)

Sex hormones: Male (19 carbons)

Female (18 carbons)

24.1224.12Vitamin DVitamin D

Cholesterol HO

CH3

H

H

H

CH3

CH3 CH3

CH3

Cholesterol is the precursor to vitamin D.

Enzymes dehydrogenate cholesterol to introduce a second double bond in conjugation with the existing one. The product of this reaction is called 7-dehydrocholesterol.

7-Dehydrocholesterol

HO

CH3

H H

CH3

CH3 CH3

CH3

Sunlight converts 7-dehydrocholesterol on the skin's surface to vitamin D3.

Vitamin D3

CH3

HO

H

CH3 CH3

CH3

Insufficient sunlight can lead to a deficiency of vitamin D3, interfering with Ca2+ transport and bone development. Rickets can result.

24.1324.13Bile AcidsBile Acids

Cholesterol HO

CH3

H

H

H

CH3

CH3 CH3

CH3

Oxidation in the liver degrades the cholesterol side chain and introduces OH groups at various positions on the steroid skeleton. Cholic acid (next slide) is the most abundant of the bile acids.

Cholic Acid

Salts of cholic acid amides (bile salts), such as sodium taurocholate (next slide), act as emulsifying agents to aid digestion.

HO

CH3

H

H

H

CH3

CH3

HOH

HO

O

OH

Sodium Taurocholate HO

CH3

H

H

H

CH3

CH3

HOH

HO

O

NHCH2CH2SO3Na

24.1424.14Cortiosteroids and Cortiosteroids and

ProgesteroneProgesterone

Cholesterol HO

CH3

H

H

H

CH3

CH3 CH3

CH3

Enzymatic degradation of the side chain and oxidation of various positions on the steroid skeleton convert cholesterol to corticosteroids.

Cortisol

Cortisol is the most abundant of the corticosteroids. Enzyme-catalyzed oxidation of cortisol gives cortisone.

O

CH3

H

H

H

CH3OH

HO

O

OH

Cortisone

Corticosteroids are involved in maintaining electrolyte levels, in the metabolism of carbohydrates, and in mediating the allergic response.

O

CH3

H

H

H

CH3OH

O

O

OH

Progesterone

Supresses ovulation during pregnancy.

O

H

H

H

H3C

H3CO

24.1524.15Sex HormonesSex Hormones

Testosterone

Testosterone is the main male sex hormone.

O

H

H

H

H3C

H3COH

Estradiol

Estradiol is a female sex hormone involved in regulating the menstrual cycle and in reproduction.

HO

H

H

H

H3COH

24.1624.16CarotenoidsCarotenoids

Carotenoids

Carotenoids are naturally occurring pigments.

Structurally, carotenoids are tetraterpenes. They have 40 carbons. Two C20 units are linked in a tail-to-tail fashion.

Examples are lycopene and -carotene.

Carotenoids

Lycopene (tomatoes) -Carotene (carrots)

End of Chapter 24End of Chapter 24LipidsLipids