1. Chapter 24 Lipids
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2. 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.

3. 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

4. 24.1 Acetyl Coenzyme A: Not a lipid, it is a coenzyme used in fatty acid metabolism

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

6. 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.

7. 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

8. 24.2 Fats, Oils, and Fatty Acids

9. 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.

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

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

12. 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

13. 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.

14. 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

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

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

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

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

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

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

21. H O OR H O OR O OR
H2, cat

22. 24.4 Phospholipids A major component of cell membranes.

23. 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).

24. 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.

25. 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

26. 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

27. 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.

28. 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

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

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

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

32. 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

33. 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

34. 24.5 Waxes 4

35. 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

36. 24.6 Prostaglandins 4

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

38. 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)

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

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

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

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

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

44. 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

45. 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

46. 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.

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

48. 24.7 Terpenes: The Isoprene Rule

49. 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)

50. Terpenes
Myrcene (isolated from oil of bayberry) is a typical terpene.
CH2
CH3
CH3C
CHCH2CH2CCH or

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

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

53. Table 24.2
Classification of Terpenes
Class Number of carbon atoms
Monoterpene 10
Sesquiterpene 15
Diterpene 20
Sesterpene 25
Triterpene 30
Tetraterpene 40

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

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

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

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

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

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

60. Representative Diterpene
Figure 24.7
Representative Diterpene OH
Vitamin A

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

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

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

64. 24.8 Isopentenyl Pyrophosphate: The Biological Isoprene Unit

65. 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).

66. The Biological Isoprene Unit
CH3COH O
HOCCH2CCH2CH2OH
CH3 OH O 3
Mevalonic acid
H2C
CCH2CH2OPOPOH
CH3 O
Isopentenyl pyrophosphate

67. Isopentenyl Diphosphate
H2C
CCH2CH2OPOPOH
CH3 O
OPP or
Isopentenyl pyrophosphate

68. 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.

69. 24.9 Carbon-Carbon Bond Formation in Terpene Biosynthesis

70. 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.

71. Carbon-Carbon Bond Formation+
OPP +
OPP –

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

73. After C—C Bond Formation...
OPP
This compound is called geranyl pyrophosphate. It can undergo hydrolysis of its pyrophosphate to give geraniol (rose oil).

74. After C—C Bond Formation...
OPP
H2O OH
Geraniol

75. From 10 Carbons to 15 +
OPP
Geranyl pyrophosphate +
OPP

76. From 10 Carbons to 15
OPP H – + +
OPP

77. From 10 Carbons to 15
OPP
This compound is called farnesyl pyrophosphate.
Hydrolysis of the pyrophosphate ester gives the alcohol farnesol (Figure 24.7).

78. From 15 Carbons to 20
OPP
OPP
Farnesyl pyrophosphate is extended by another isoprene unit by reaction with isopentenyl pyrophosphate.

79. 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

80. Limonene H – + + OH
H2O
-Terpineol

81. Bicyclic Terpenes + + +
-Pinene +
-Pinene

82. 24.10 The Pathway from Acetate to Isopentenyl Diphosphate

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

84. 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

85. 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.

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

87. 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

88. 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.

89. 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.

90. 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 •

91. 24.11 Steroids: Cholesterol

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

93. Structure of Cholesterol
Cholesterol has the fundamental steroid skeleton modified as shown.
Cholesterol has 27 carbons.

94. 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.

95. 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

96. 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

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

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

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

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

101. 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

102. 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)

103. 24.12 Vitamin D 4

104. 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.

105. 7-Dehydrocholesterol
CH3
CH3
CH3
CH3
CH3 H H HO
Sunlight converts 7-dehydrocholesterol on the skin's surface to vitamin D3.

106. 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.

107. 24.13 Bile Acids 4

108. 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.

109. 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.

110. Sodium Taurocholate HO
CH3 H OH O
NHCH2CH2SO3Na

111. 24.14 Cortiosteroids and Progesterone

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

113. 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.

114. 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.

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

116. 24.15 Sex Hormones 4

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

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

119. 24.16 Carotenoids 4

120. 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.

121. Carotenoids
Lycopene (tomatoes)
-Carotene (carrots)

122. End of Chapter 24 Lipids 4