Chapter 24 Lipids Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. 4

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

24.1 Acetyl Coenzyme A: Not a lipid, it is a coenzyme used in fatty acid metabolism

Structure of Coenzyme A R = H; Coenzyme A R = CCH3; Acetyl coenzyme A O

Reactivity of Coenzyme A Nucleophilic acyl substitution CH3CSCoA O CH3C O HY • • 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 CSCoA OH H2C E+ Acetyl coenzyme A reacts with biological electrophiles at its  carbon atom. CH2CSCoA O E

24.2 Fats, Oils, and Fatty Acids

Fats and Oils RCOCH CH2OCR' O CH2OCR" Fats and oils are naturally occurring mixture of triacylglycerols (also called triglycerides). Fats are solids; oils are liquids.

Fats and Oils CH3(CH2)16COCH CH2OC(CH2)16CH3 O Tristearin; mp 72°C

Fats and Oils CH2OC(CH2)16CH3 O CH2(CH2)6COCH C H CH3(CH2)6CH2 2-Oleyl-1,3-distearylglycerol; mp 43°C

2-Oleyl-1,3-distearylglycerol mp 43°C Fats and Oils 2-Oleyl-1,3-distearylglycerol mp 43°C H2, Pt Tristearin mp 72°C

Fatty Acids O R'COCH CH2OCR CH2OCR" O HOCR O R'COH HOCH CH2OH H2O O HOCR" 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.

Table 24.1 Systematic name Common name O CH3(CH2)10COH Dodecanoic acid Lauric acid O CH3(CH2)12COH Tetradecanoic acid Myristic acid O CH3(CH2)14COH Hexadecanoic acid Palmitic acid

Table 24.1 Systematic name Common name O CH3(CH2)16COH Octadecanoic acid Stearic acid O CH3(CH2)18COH Eicosanoic acid Arachidic acid

Table 24.1 O C H CH3(CH2)7 (CH2)7COH Systematic name: (Z)-9-Octadecenoic acid Common name: Oleic acid

Table 24.1 C H CH3(CH2)4 O (CH2)7COH CH2 Systematic name: (9Z, 12Z)-9,12-Octadecadienoic acid Common name: Linoleic acid

Table 24.1 C H O (CH2)7COH CH2 CH3CH2 Systematic name: (9Z, 12Z, 15Z)-9,12,15- Octadecatrienoic acid Common name: Linolenic acid

Table 24.1 H OH O Systematic name: (5Z, 8Z, 11Z, 14Z)-5,8,11,14- Icosatetraenoic acid Common name: Arachidonic acid

trans-Fatty Acids Are formed by isomerization that can occur when esters of cis-fatty acids are hydrogenated. O OR H H2, cat

H O OR H O OR O OR H2, cat

24.4 Phospholipids A major component of cell 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.

Phosphatidic Acid Synthesis CH2OPO3H2 CH2OH H HO RCSCoA O R'CSCoA O + + The diacylated species formed in this step is called a phosphatidic acid. CH2OPO3H2 CH2OCR H R'CO O

CH2OPO3H2 CH2OCR H R'CO O TAG Synthesis The phosphatidic acid then undergoes hydrolysis of its phosphate ester function. H2O CH2OH CH2OCR H R'CO O

CH2OH CH2OCR H R'CO O TAG Synthesis Reaction with a third acyl coenzyme A molecule yields a triacylglycerol (TAG). R"CSCoA O CH2OCR" CH2OCR H R'CO O This shows triglyceride (TAG) formation. TAG is not a phospholipid.

Phosphatidylcholine Phosphatidic acids are intermediates in the formation of the phospholipid phosphatidylcholine. CH2OPO2 CH2OCR H R'CO O – (CH3)3NCH2CH2O + CH2OPO3H2 CH2OCR H R'CO O Phosphatidylcholine

Phosphatidylcholine CH2OPO2 CH2OCR H R'CO O – (CH3)3NCH2CH2O + hydrophobic "tail" polar "head group"

hydrophobic (lipophilic) "tails" Phosphatidylcholine hydrophobic (lipophilic) "tails" hydrophilic "head group"

Cell Membranes water Cell membranes are "lipid bilayers." Each layer has an assembly of phospholipid molecules as the main structural component. water

Cell Membranes water The interior of the cell membrane is hydrocarbon-like. Polar materials cannot pass from one side to the other of the membrane. water

Sphingomyelins Ceramide Phosphate with a head group attached (usually choline) are sphingomyelins. Ceramide phosphate HO O CHCH=CH(CH2)12CH3 R'CNH H A sphingomyelin HO CH2OPO3H2 O CHCH=CH(CH2)12CH3 R'CNH H – CH2OPO2 + (CH3)3NCH2CH2O

24.5 Waxes 4

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

24.6 Prostaglandins 4

Eicosanoids are compounds related to eicosanoic acid CH3(CH2)18CO2H. Eicosanoids include: prostaglandins thromboxanes prostacyclins leukotrienes

Prostaglandins 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)

Examples: PGE1 and PGF1 O HO OH PGE1 HO OH O PGF1

Prostaglandin Biosynthesis PGE2 is biosynthesized from arachidonic acid. The oxygens come from O2. The enzyme involved (prostaglandin endoperoxide synthase) has cyclooxygenase (COX) acitivity.

Prostaglandin Biosynthesis CO2H CH3 Arachidonic acid O2 fatty acid cyclooxygenase PGG2 O HOO CO2H CH3

Prostaglandin Biosynthesis PGG2 O HOO CO2H CH3 reduction of hydroperoxide PGH2 O HO CO2H CH3

Prostaglandin Biosynthesis PGH2 O HO CO2H CH3 O HO CO2H CH3 PGE2 Cleavage of cyclic peroxide

TXA2 promotes platelet aggregation and blood clotting Thromboxane A2 (TXA2) Thromboxane A2 is biosynthesized from PGH2 PGH2 O HO CO2H CH3 TXA2 O HO CO2H CH3 TXA2 promotes platelet aggregation and blood clotting

PGI2 inhibits platelet aggregation and relaxes coronary arteries. Prostacyclin I2 (PGI2) Like thromboxane A2, prostacyclin I2 is biosynthesized from PGH2. OH HO2C CH3 HO O PGI2 inhibits platelet aggregation and relaxes coronary arteries. PGI2

Leucotriene C4 (LTC4) Leukotrienes arise from arachidonic acid via a different biosynthetic pathway. They are the substances most responsible for constricting bronchial passages during asthma attacks.

Leucotriene C4 (LTC4) CO2H OH CH3 S CH2CHCNHCH2CO2H O NH C O2CCHCH2CH2 NH3 + –

24.7 Terpenes: The Isoprene Rule

Isoprene (2-methyl-1,3-butadiene) 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 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 Classification of Terpenes Class Number of carbon atoms Monoterpene 10 Sesquiterpene 15 Diterpene 20 Sesterpene 25 Triterpene 30 Tetraterpene 40

-Phellandrene (eucalyptus) Figure 24.7 Representative Monoterpenes OH O H -Phellandrene (eucalyptus) Menthol (peppermint) Citral (lemon grass)

-Phellandrene (eucalyptus) Figure 24.7 Locating the isoprene units. OH O H -Phellandrene (eucalyptus) Menthol (peppermint) Citral (lemon grass)

-Phellandrene (eucalyptus) Figure 24.7 Locating the isoprene units. -Phellandrene (eucalyptus) Menthol (peppermint) Citral (lemon grass)

Representative Sesquiterpenes Figure 24.7 Representative Sesquiterpenes H -Selinene (celery)

Locating the isoprene units. Figure 24.7 Locating the isoprene units. H -Selinene (celery)

Locating the isoprene units. Figure 24.7 Locating the isoprene units. -Selinene (celery)

Representative Diterpene Figure 24.7 Representative Diterpene OH Vitamin A

Locating the isoprene units. Figure 24.7 Locating the isoprene units. OH Vitamin A

Locating the isoprene units. Figure 24.7 Locating the isoprene units. Vitamin A

Squalene (shark liver oil) Figure 24.7 Representative Triterpene Squalene (shark liver oil) tail-to-tail linkage of isoprene units Locating the isoprene units.

24.8 Isopentenyl Pyrophosphate: The 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 HOCCH2CCH2CH2OH CH3 OH O 3 Mevalonic acid H2C CCH2CH2OPOPOH CH3 O Isopentenyl pyrophosphate

Isopentenyl Diphosphate H2C CCH2CH2OPOPOH CH3 O OPP or Isopentenyl pyrophosphate

Isopentenyl and Dimethylallyl Diphosphate Isopentenyl diphosphate is interconvertible with 2-methylallyl diphosphate. OPP OPP Isopentenyl pyrophosphate Dimethylallyl pyrophosphate Dimethylallyl pyrophosphate has a leaving group (pyrophosphate) at an allylic carbon; it is reactive toward nucleophilic substitution at this position.

24.9 Carbon-Carbon Bond Formation in Terpene Biosynthesis

Carbon-Carbon Bond Formation + OPP The key process involves the double bond of isopentenyl pyrophosphate acting as a nucleophile toward the allylic carbon of dimethylallyl pyrophosphate.

Carbon-Carbon Bond Formation + OPP + OPP –

After C—C Bond Formation... OPP H – + The carbocation can lose a proton to give a double bond. + OPP

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 H2O OH Geraniol

From 10 Carbons to 15 + OPP Geranyl pyrophosphate + OPP

From 10 Carbons to 15 OPP 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 OPP Farnesyl pyrophosphate is extended by another isoprene unit by reaction with isopentenyl pyrophosphate.

Rings form by intramolecular carbon-carbon bond formation. Cyclization Rings form by intramolecular carbon-carbon bond formation. + OPP OPP E double bond Z double bond

Limonene H – + + OH H2O -Terpineol

Bicyclic Terpenes + + + -Pinene + -Pinene

24.10 The Pathway from Acetate to Isopentenyl Diphosphate

Recall CH3COH O HOCCH2CCH2CH2OH CH3 OH O 3 Mevalonic acid H2C CCH2CH2OPOPOH CH3 O Isopentenyl pyrophosphate

Biosynthesis of Mevalonic Acid In a sequence analogous to the early steps of fatty acid biosynthesis, acetyl coenzyme A is converted to S-acetoacetyl coenzyme A. CH3CCH2CSCoA O S-Acetoacetyl coenzyme A

Biosynthesis of Mevalonic Acid CH3CCH2CSCoA O CH3CSCoA O + 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 CH3CCH2CSCoA O CH3CSCoA O + CH3CCH2CSCoA CH2COH HO O 3-hydroxy-3-methyl glutarylCoA

Biosynthesis of Mevalonic Acid Next, the acyl coenzyme A function is reduced. The product of this reduction is mevalonic acid. CH3CCH2CSCoA CH2COH HO O CH3CCH2CH2OH CH2COH HO O Mevalonic acid

Conversion of Mevalonic Acid to Isopentenyl Pyrophosphate CH3CCH2CH2OPP CH2COH O OPO3 2– CH3CCH2CH2OH CH2COH HO O The two hydroxyl groups of mevalonic acid undergo phosphorylation.

Conversion of Mevalonic Acid to Isopentenyl Pyrophosphate OPO3 3– CH3CCH2CH2OPP CH2 O OPO3 2– C •• • • – CH3CCH2CH2OPP CH2 O C Phosphorylation is followed by a novel elimination involving loss of CO2 and PO43– giving isopentenyl pyrophosphate.

Biosynthetic Pathway is Based on Experiments with 14C-labeled Acetate Citronellal biosynthesized using 14C-labeled acetate as the carbon source has the labeled carbons in the positions indicated. CH3COH O H2C CCH2CH2OPOPOH CH3 O O H •

24.11 Steroids: 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.

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.

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

Biosynthesis of Cholesterol + HO H Cyclization is triggered by epoxide ring opening. H+ O

Biosynthesis of Cholesterol + HO H The five-membered ring expands to a six-membered one. H HO

Biosynthesis of Cholesterol protosteryl cation Cyclization to form a tetracyclic carbocation. H HO

Biosynthesis of Cholesterol OH2 •• • • H Deprotonation and multiple migrations. HO 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

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)

24.12 Vitamin D 4

Cholesterol CH3 H HO 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 CH3 CH3 CH3 CH3 CH3 H H HO Sunlight converts 7-dehydrocholesterol on the skin's surface to vitamin D3.

Vitamin D3 HO H CH3 CH3 Insufficient sunlight can lead to a deficiency of vitamin D3, interfering with Ca2+ transport and bone development. Rickets can result.

24.13 Bile Acids 4

Cholesterol HO CH3 H 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 HO CH3 H OH O Salts of cholic acid amides (bile salts), such as sodium taurocholate (next slide), act as emulsifying agents to aid digestion.

Sodium Taurocholate HO CH3 H OH O NHCH2CH2SO3Na

24.14 Cortiosteroids and Progesterone

Cholesterol HO CH3 H Enzymatic degradation of the side chain and oxidation of various positions on the steroid skeleton convert cholesterol to corticosteroids.

Cortisol O OH CH3 HO OH CH3 H H H O Cortisol is the most abundant of the corticosteroids. Enzyme-catalyzed oxidation of cortisol gives cortisone.

Cortisone O OH CH3 O OH CH3 H H H O Corticosteroids are involved in maintaining electrolyte levels, in the metabolism of carbohydrates, and in mediating the allergic response.

Supresses ovulation during pregnancy. Progesterone O H H3C Supresses ovulation during pregnancy.

24.15 Sex Hormones 4

Testosterone is the main male sex hormone. H3C OH Testosterone is the main male sex hormone.

Estradiol OH H3C H H H HO Estradiol is a female sex hormone involved in regulating the menstrual cycle and in reproduction.

24.16 Carotenoids 4

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 24 Lipids 4