1. Lipids Lipids are naturally occurring substances grouped together on the basis of a common property—they are more soluble in nonpolar solvents than in water. 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 the source of acetate. 26- 1

2. Structure of Coenzyme A 26- 2 R = H; Coenzyme A R = CCH 3 ; Acetyl coenzyme A O

3. Reactivity of Coenzyme A Acetyl coenzyme A is a source of an acetyl group toward biological nucleophiles; it is an acetyl transfer agent. 26- 3 Nucleophilic acyl substitution CH 3 CSCoA O HYHYHYHY CH 3 C O Y + HSCoA

4. Reactivity of Coenzyme A Acetyl coenzyme A reacts with biological electrophiles at its  carbon atom. 26- 4 can react via enol CH 3 CSCoA O CSCoA OH H2CH2CH2CH2C E+E+E+E+ CH 2 CSCoA OE

5. Fats and Oils Fats and oils are naturally occurring mixture of triacylglycerols (also called triglycerides). Fats are solids; oils are liquids. 26- 5 RCOCH CH 2 OCR' O CH 2 OCR" OO

6. Fats and Oils Tristearin; mp 72°C 26- 6 CH 3 (CH 2 ) 16 COCH CH 2 OC(CH 2 ) 16 CH 3 O OO

7. Fats and Oils 2-Oleyl-1,3-distearylglycerol; mp 43°C 26- 7 CH 2 OC(CH 2 ) 16 CH 3 OO CH 2 (CH 2 ) 6 COCH O C H C H CH 3 (CH 2 ) 6 CH 2

8. Fats and Oils 2-Oleyl-1,3-distearylglycerol mp 43°C 26- 8 H 2, Pt Tristearin mp 72°C

9. 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. 26- 9 O R'COCH CH 2 OCR O CH 2 OCR" O H2OH2OH2OH2O HOCH CH 2 OH OHOCR OR'COH OHOCR"

10. Table 26.1 26- 10O CH 3 (CH 2 ) 10 COH Dodecanoic acid Lauric acid Systematic name Common name O CH 3 (CH 2 ) 12 COH Tetradecanoic acid Myristic acid O CH 3 (CH 2 ) 14 COH Hexadecanoic acid Palmitic acid

11. Table 26.1 26- 11O CH 3 (CH 2 ) 16 COH Octadecanoic acid Stearic acid O CH 3 (CH 2 ) 18 COH Icosanoic acid Arachidic acid Systematic name Common name

12. Table 26.1 26- 12OC H C H CH 3 (CH 2 ) 7 (CH 2 ) 7 COH Systematic name: (Z)-9-Octadecenoic acid Common name: Oleic acid

13. Table 26.1 26- 13 Systematic name: (9Z, 12Z)-9,12-Octadecadienoic acid Common name: Linoleic acid C H C H CH 3 (CH 2 ) 4 O (CH 2 ) 7 COH CH 2 C H C H

14. Table 26.1 26- 14 Systematic name: (9Z, 12Z, 15Z)-9,12,15- Octadecatrienoic acid Common name: Linolenic acid C H C HO (CH 2 ) 7 COH CH 2 C H C H CH 3 CH 2 C H C H CH 2

15. Table 26.1 Dr. Wolf's CHM 424 26- 15 Systematic name: (5Z, 8Z, 11Z, 14Z)-5,8,11,14- Icosatetraenoic acid Common name: Arachidonic acid H HH H HH H H OHO

16. trans-Fatty Acids Are formed by isomerization that can occur when esters of cis-fatty acids are hydrogenated. Dr. Wolf's CHM 424 26- 16 O ORHOOR H H 2, cat

17. Dr. Wolf's CHM 424 26- 17OOR HOOR H H O ORH H 2, cat

18. Fatty Acid Biosynthesis Fatty acids are biosynthesized via acetyl coenzyme A. The group of enzymes involved in the overall process is called fatty acid synthetase. One of the key components of fatty acid synthetase is acyl carrier protein (ACP—SH). 26- 18

19. Fatty Acid Biosynthesis An early step in fatty acid biosynthesis is the reaction of acyl carrier protein with acetyl coenzyme A. 26- 19 CH 3 CSCoA O+ HS—ACP CH 3 CS—ACP O+ HSCoA

20. Fatty Acid Biosynthesis A second molecule of acetyl coenzyme A reacts at its  carbon atom with carbon dioxide (as HCO 3 – ) to give malonyl coenzyme A. 26- 20 CH 3 CSCoA O+ HCO 3 – Acetyl coenzyme A OCCH 2 CSCoA O –O Malonyl coenzyme A

21. Fatty Acid Biosynthesis Malonyl coenzyme A then reacts with acyl carrier protein. 26- 21 OCCH 2 CSCoA O –O Malonyl coenzyme A ACP—SH OCCH 2 CS—ACP O –O

22. Fatty Acid Biosynthesis Malonyl—ACP and acetyl—ACP react by carbon- carbon bond formation, accompanied by decarboxylation. 26- 22 CH 2 CS—ACP O –OCO CH 3 C S—ACPO CH 2 CS—ACP O CH 3 C O S-Acetoacetyl—ACP

23. Fatty Acid Biosynthesis In the next step, the ketone carbonyl is reduced to a secondary alcohol. 26- 23 CH 2 CS—ACP O CH 3 C O S-Acetoacetyl—ACP NADPH CH 2 CS—ACP O CH 3 C OH H

24. Fatty Acid Biosynthesis The alcohol then dehydrates. 26- 24 CH 2 CS—ACP O CH 3 C OH H CHCS—ACP O CH 3 CH

25. Fatty Acid Biosynthesis Repeating the process gives a 6-carbon acyl group, then an 8-carbon one, then 10, etc. 26- 25 CH 3 CH 2 CH 2 CS—ACP O CHCS—ACP O CH 3 CH Reduction of the double bond yields ACP bearing an attached butanoyl group.

26. Phospholipids Phospholipids are intermediates in the biosynthesis of triacylglycerols. The starting materials are L-glycerol 3-phosphate and the appropriate acyl coenzyme A molecules. 26- 26

27. The diacylated species formed in this step is called a phosphatidic acid. Dr. Wolf's CHM 424 26- 27 CH 2 OPO 3 H 2 CH 2 OH H HO + R'CSCoA O RCSCoA O+ CH 2 OPO 3 H 2 CH 2 OCR H R'CO O O

28. The phosphatidic acid then undergoes hydrolysis of its phosphate ester function. Dr. Wolf's CHM 424 26- 28 CH 2 OPO 3 H 2 CH 2 OCR H R'CO OO CH 2 OH CH 2 OCR H R'CO OO H2OH2OH2OH2O

29. Reaction with a third acyl coenzyme A molecule yields the triacylglycerol. Dr. Wolf's CHM 424 26- 29 CH 2 OH CH 2 OCR H R'CO OO R"CSCoAO CH 2 OCR" CH 2 OCR H R'CO O O O

30. Phosphatidylcholine Phosphatidic acids are intermediates in the formation of phosphatidylcholine. Dr. Wolf's CHM 424 26- 30 CH 2 OPO 3 H 2 CH 2 OCR H R'CO OO CH 2 OPO 2 CH 2 OCR H R'CO OO– (CH 3 ) 3 NCH 2 CH 2 O +

31. Phosphatidylcholine 26- 31 CH 2 OPO 2 CH 2 OCR H R'CO OO– (CH 3 ) 3 NCH 2 CH 2 O + polar "head group" hydrophobic "tail"

32. Phosphatidylcholine 26- 32 hydrophilic "head group" hydrophobic (lipophilic) "tails"

33. Cell Membranes Cell membranes are "lipid bilayers." Each layer has an assembly of phosphatidyl choline molecules as its main structural component. 26- 33 water water

34. Cell Membranes The interior of the cell membrane is hydrocarbon-like. Polar materials cannot pass from one side to the other of the membrane. 26- 34 water water

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. 26- 35 CH 3 (CH 2 ) 14 COCH 2 (CH 2 ) 28 CH 3 O Triacontyl hexadecanoate: occurs in beeswax

36. Prostaglandins Prostaglandins are involved in many biological processes. Are biosynthesized from linoleic acid (C 18 ) via arachidonic acid (C 20 ). (See Table 26.1) 26- 36

37. Examples: PGE 1 and PGF 1  26- 37 O HOOOH OH HO HO OHOOH PGE 1 PGF 1 

38. Prostaglandin Biosynthesis PGE 2 is biosynthesized from arachidonic acid The oxygens come from O 2 The enzyme involved (prostaglandin endoperoxide synthase) has cyclooxygenase (COX) acitivity 26- 38

39. Prostaglandin Biosynthesis 26- 39 Arachidonic acid O 2 fatty acid cyclooxygenase CO 2 H CH 3 PGG 2 O HOO CO 2 H CH 3 O

40. Prostaglandin Biosynthesis 26- 40 reduction of hydroperoxide PGG 2 O HOO CO 2 H CH 3 O PGH 2 O HO CO 2 H CH 3 O

41. Prostaglandin Biosynthesis Dr. Wolf's CHM 424 26- 41 O HO HO CO 2 H CH 3 PGE 2 PGH 2 O HO CO 2 H CH 3 O

42. Icosanoids Icosanoids include: prostaglandins thromboxanes prostacyclins leukotrienes Dr. Wolf's CHM 424 26- 42 Icosanoids are compounds related to icosanoic acid CH 3 (CH 2 ) 18 CO 2 H.

43. Thromboxane A 2 (TXA 2 ) Dr. Wolf's CHM 424 26- 43 PGH 2 O HO CO 2 H CH 3 O TXA 2 O O HO CO 2 H CH 3 Thromboxane A 2 is biosynthesized from PGH 2 TXA 2 promotes platelet aggregation and blood clotting

44. Prostacyclin I 2 (PGI 2 ) Dr. Wolf's CHM 424 26- 44 PGI 2 Like thromboxane A 2, prostacyclin I 2 is biosynthesized from PGH 2 PGI 2 inhibits platelet aggregation and relaxes coronary arteries OH HO 2 C CH 3 HO O

45. Leukotriene C 4 (LTC 4 ) 26- 45 Leukotrienes arise from arachidonic acid via a different biosynthetic pathway. They are the substances most responsible for constricting bronchial passages during asthma attacks.

46. Leukotriene C 4 (LTC 4 ) 26- 46 CO 2 H OH CH 3 S CH 2 CHCNHCH 2 CO 2 H O NH CO O 2 CCHCH 2 CH 2 NH 3 + –

47. Terpenes Terpenes are natural products that are structurally related to isoprene. 26- 47 H2CH2CH2CH2C C CH 3 CH CH 2 or Isoprene (2-methyl-1,3-butadiene)

48. Terpenes Myrcene (isolated from oil of bayberry) is a typical terpene. 26- 48 CH 2 CH 3 CH 3 C CHCH 2 CH 2 CCH CH 2 or

49. The Isoprene Unit An isoprene unit is the carbon skeleton of isoprene (ignoring the double bonds) 26- 49 Myrcene contains two isoprene units.

50. The Isoprene Unit The isoprene units of myrcene are joined "head-to-tail." 26- 50 headtail tail head

51. Table 26.2 ClassNumber of carbon atoms Monoterpene10 Sesquiterpene15 Diterpene20 Sesterpene25 Triterpene30 Tetraterpene40 26- 51 Classification of Terpenes

52. Figure 26.6 26- 52 Representative Monoterpenes  -Phellandrene (eucalyptus) Menthol (peppermint) Citral (lemon grass) OH OH

53. Figure 26.6 26- 53 Representative Monoterpenes  -Phellandrene (eucalyptus) Menthol (peppermint) Citral (lemon grass) OH OH

54. Figure 26.6 26- 54 Representative Monoterpenes  -Phellandrene (eucalyptus) Menthol (peppermint) Citral (lemon grass)

55. Figure 26.6 Dr. Wolf's CHM 424 26- 55 Representative Sesquiterpenes  -Selinene (celery) H

56. Figure 26.6 Dr. Wolf's CHM 424 26- 56 Representative Sesquiterpenes  -Selinene (celery) H

57. Figure 26.6 Dr. Wolf's CHM 424 26- 57 Representative Sesquiterpenes  -Selinene (celery)

58. Figure 26.6 26- 58 Representative Diterpenes Vitamin A OH

59. Figure 26.6 26- 59 Representative Diterpenes Vitamin A OH

60. Figure 26.6 26- 60 Representative Diterpenes Vitamin A

61. Figure 26.6 26- 61 Representative Triterpene Squalene (shark liver oil) tail-to-tail linkage of isoprene units

62. 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). 26- 62

63. The Biological Isoprene Unit Dr. Wolf's CHM 424 26- 63 CH 3 COH O3 HOCCH 2 CCH 2 CH 2 OH CH 3 OH O Mevalonic acid H2CH2CH2CH2C CCH 2 CH 2 OPOPOH CH 3 OO Isopentenyl pyrophosphate

64. Isopentenyl Pyrophosphate Dr. Wolf's CHM 424 26- 64 H2CH2CH2CH2C CCH 2 CH 2 OPOPOH CH 3 OO Isopentenyl pyrophosphate or OPP

65. Isopentenyl and Dimethylallyl Pyrophosphate Dimethylallyl pyrophosphate has a leaving group (pyrophosphate) at an allylic carbon; it is reactive toward nucleophilic substitution at this position. Dr. Wolf's CHM 424 26- 65 Isopentenyl pyrophosphate is interconvertible with 2-methylallyl pyrophosphate. OPP OPP Isopentenyl pyrophosphate Dimethylallyl pyrophosphate

66. 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. 26- 66 + OPPOPP

67. Carbon-Carbon Bond Formation 26- 67 + OPP OPP – + OPPOPP

68. After C—C Bond Formation... The carbocation can lose a proton to give a double bond. 26- 68 + OPP OPP H – +

69. After C—C Bond Formation... This compound is called geranyl pyrophosphate. It can undergo hydrolysis of its pyrophosphate to give geraniol (rose oil). 26- 69 OPP

70. After C—C Bond Formation... 26- 70 OPP OH Geraniol H2OH2OH2OH2O

71. From 10 Carbons to 15 26- 71 + OPPOPP Geranyl pyrophosphate + OPP

72. From 10 Carbons to 15 26- 72 + OPP H –+ OPP

73. From 10 Carbons to 15 This compound is called farnesyl pyrophosphate. Hydrolysis of the pyrophosphate ester gives the alcohol farnesol (Figure 26.6). 26- 73 OPP

74. From 15 Carbons to 20 Farnesyl pyrophosphate is extended by another isoprene unit by reaction with isopentenyl pyrophosphate. 26- 74 OPP OPP

75. Cyclization Rings form by intramolecular carbon-carbon bond formation. 26- 75 OPP OPP + E double bond Z double bond

76. Dr. Wolf's CHM 424 26- 76+OH H –+ H2OH2OH2OH2O Limonene  -Terpineol

77. Bicyclic Terpenes Dr. Wolf's CHM 424 26- 77++ +  -Pinene +  -Pinene

78. Recall 26- 78 CH 3 COH O3 HOCCH 2 CCH 2 CH 2 OH CH 3 OH O Mevalonic acid H2CH2CH2CH2C CCH 2 CH 2 OPOPOH CH 3 OO Isopentenyl pyrophosphate

79. 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. 26- 79 CH 3 CCH 2 CSCoA OO S-Acetoacetyl coenzyme A

80. Biosynthesis of Mevalonic Acid 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. 26- 80 CH 3 CSCoA O+ CH 3 CCH 2 CSCoA OO

81. Biosynthesis of Mevalonic Acid 26- 81 CH 3 CSCoA O CH 3 CCH 2 CSCoA CH 2 COH HOO O + CH 3 CCH 2 CSCoA OO

82. Biosynthesis of Mevalonic Acid Next, the acyl coenzyme A function is reduced. The product of this reduction is mevalonic acid. 26- 82 CH 3 CCH 2 CSCoA CH 2 COH HOO O

83. 26- 83 CH 3 CCH 2 CSCoA CH 2 COH HOO O CH 3 CCH 2 CH 2 OH CH 2 COH HOO Mevalonic acid

84. Conversion of Mevalonic Acid to Isopentenyl Pyrophosphate The two hydroxyl groups of mevalonic acid undergo phosphorylation. Dr. Wolf's CHM 424 26- 84 CH 3 CCH 2 CH 2 OH CH 2 COH HOHOHOHOO CH 3 CCH 2 CH 2 OPP CH 2 COH O OPO 3 2–

85. Conversion of Mevalonic Acid to Isopentenyl Pyrophosphate Phosphorylation is followed by a novel elimination involving loss of CO 2 and PO 4 3–. Dr. Wolf's CHM 424 26- 85 CH 3 CCH 2 CH 2 OPP CH 2 O OPO 3 2–C O – CH 3 CCH 2 CH 2 OPP CH 2 OPO 3 3–OCO

86. Conversion of Mevalonic Acid to Isopentenyl Pyrophosphate The product of this elimination is isopentenyl pyrophosphate. Dr. Wolf's CHM 424 26- 86 CH 3 CCH 2 CH 2 OPP CH 2

87. Biosynthetic pathway is based on experiments with 14 C-labeled acetate 26- 87 CH 3 COH O HOCCH 2 CCH 2 CH 2 OH CH3CH3CH3CH3OH O Mevalonic acid H2CH2CH2CH2C CCH 2 CH 2 OPOPOH CH3CH3CH3CH3OO Isopentenyl pyrophosphate

88. Biosynthetic pathway is based on experiments with 14 C-labeled acetate Citronellal biosynthesized using 14 C-labeled acetate as the carbon source had the labeled carbons in the positions indicated. 26- 88 CH 3 COH O H2CH2CH2CH2C CCH 2 CH 2 OPOPOH CH3CH3CH3CH3OO O H

89. Structure of Cholesterol Fundamental framework of steroids is the tetracyclic unit shown. 26- 89

90. Structure of Cholesterol Cholesterol has the fundamental steroid skeleton modified as shown. 26- 90 HO CH 3 H H H

91. Structure of Cholesterol Some parts of the cholesterol molecule are isoprenoid. But other parts don't obey the isoprene rule. Also, cholesterol has 27 carbons, which is not a multiple of 5. 26- 91 HO CH 3 H H H

92. Biosynthesis of Cholesterol Cholesterol is biosynthesized from the triterpene squalene. In the first step, squalene is converted to its 2,3-epoxide. 26- 92 O O 2, NADH, enzyme

93. 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. 26- 93 O O

94. Biosynthesis of Cholesterol Cyclization is triggered by epoxide ring opening. 26- 94 O H+H+H+H+ + HO H

95. Biosynthesis of Cholesterol The five-membered ring expands to a six-membered one. 26- 95 + HO H H HOH

96. Biosynthesis of Cholesterol Cyclization to form a tetracyclic carbocation. 26- 96 H HOH HHHO protosteryl cation

97. Biosynthesis of Cholesterol Deprotonation and multiple migrations. 26- 97 HO OH 2 H H HO H H

98. 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. 26- 98 HO H H

99. Cholesterol Cholesterol is the biosynthetic precursor to a large number of important steroids: Bile acids Vitamin D Corticosteroids Sex hormones 26- 99

100. Cholesterol 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. 26- 100 HO CH 3 H H H

101. 7-Dehydrocholesterol Sunlight converts 7-dehydrocholesterol on the skin's surface to vitamin D 3. 26- 101 HO CH 3 H H

102. Vitamin D 3 Insufficient sunlight can lead to a deficiency of vitamin D 3, interfering with Ca 2+ transport and bone development. Rickets can result. 26- 102 CH 3 HO H

103. Cholesterol 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. 26- 103 HO CH 3 H H H

104. Cholic Acid Salts of cholic acid amides (bile salts), such as sodium taurocholate (next slide), act as emulsifying agents to aid digestion. 26- 104 HOHOHOHO CH 3 H H H H OHOHOHOH HOHOHOHOOOH

105. Sodium Taurocholate 26- 105 HOHOHOHO CH 3 H H H H OHOHOHOH HOHOHOHOO NHCH 2 CH 2 SO 3 Na

106. Cholesterol Enzymatic degradation of the side chain and oxidation of various positions on the steroid skeleton convert cholesterol to corticosteroids. 26- 106 HO CH 3 H H H

107. Cortisol Cortisol is the most abundant of the corticosteroids. Enzyme- catalyzed oxidation of cortisol gives cortisone. 26- 107 O CH 3 H H H OHOHOHOH HOHOHOHO O OHOHOHOH

108. Cortisone Corticosteroids are involved in maintaining electrolyte levels, in the metabolism of carbohydrates, and in mediating the allergic response. 26- 108 O CH 3 H H H OHOHOHOH O O OHOHOHOH

109. Testosterone Testosterone is the main male sex hormone. 26- 109 O H H H H3CH3CH3CH3C H3CH3CH3CH3COH

110. Estradiol Estradiol is a female sex hormone involved in regulating the menstrual cycle and in reproduction. 26- 110 HO H H H H3CH3CH3CH3C OH

111. Progesterone Supresses ovulation during pregnancy. 26- 111 O H H H H3CH3CH3CH3C H3CH3CH3CH3CO

112. Carotenoids Carotenoids are naturally occurring pigments. Structurally, carotenoids are tetraterpenes. They have 40 carbons. Two C 20 units are linked in a tail-to-tail fashion. Examples are lycopene and  -carotene. 26- 112

113. Carotenoids 26- 113 Lycopene (tomatoes)  -Carotene (carrots)