Chapter 26: Lipids. Hydrophobic (non-polar, soluble in organic solvent), typically of low molecular compound or organic origin
• fatty acids and waxes
• essential oils
• many vitamins
• hormones (non-peptide)
• components of cell membranes (non-peptide)
Share a common biosynthesis that ultimately derives their carbon source from glucose (glycolysis)
Glucose
 pyruvate
 lactate
H
HO
H
H
CHO
OH
H
OH
OH
CH
2
OH
O O
H
3
C C C O
OH O
H
3
C C C
H
O
280

26.1: Acetyl Coenzyme A. AcSCoA is a thioester .
R= H, CoASH
R= acetyl, AcSCoA
R
S
H
N
O
H
N
O
OH O
O
P
O
O
O
P
O
O
O
N
O
O P O
O
OH
N
NH
2
N
N
Pyruvate dehydrogenase: Multi-enzyme complex that converts pyruvate to AcSCoA.
O
CO
2 pyruvate
+ CoASH +
H
2
N
N
N
N
N O O
O
P
O
O
O
P
O
O O N
HO OH HO OH
NAD thiamin diphosphate (vitamin B
1
)
Lipoic Acid
Flavin adenine diphosphate (VitaminB
2
)
O
S-CoA
AcSCoA
+
H
2
N
N
N
N
N
O
HO OH
O
O
P
O
O
O
P
O
O
HO
O N
OH
H
H
O
NH
2
NADH
O
NH
2
+ CO
2
+ H
+
281

Acetyl CoA is a thioester. Thioesters are more reactive toward nucleophilic acyl substitution than esters, but considerably less reactive than acid chlorides and anhydrides.
O O
+ CoASH
+ Nu-H
Nu S-CoA
O
S-CoA
+
HO
N(CH
3
)
3 choline acetyltransferase
O
N(CH
O acetylcholine
3
)
3
+ CoASH choline
Thioester enolize more readily than esters. The enol can react with electrophile to afford

-substitution products
O
S-CoA
OH
S-CoA
E
E
O
S-CoA
O
S-CoA
+ HCO
3 acetyl-CoA carboxylase biotin, ATP
O O
O S-CoA
Malonyl CoA
282

26.2: Fats, Oils, and Fatty Acids. Fatty acids : refers to long, straight-chain saturated and unsaturated acids, typically from
C
12
- C
20
(Table 26.1, p. 1069).
saturated fatty acids:
CH
3
(CH
2
) n
CO
2
H n=10, lauric acid (C
12
) n=12, myristic acid (C
14
) n=14, palmitic acid (C
16
) n=16, steric acid (C
18
) unsaturated fatty acid
CO
2
H
C
18
, oleic acid
3 polyunsaturated fatty acids (PUFA)
6
6
CO
2
H
CO
2
H
C
18
, linolenic acid (18:3)
C
18
, linoleic acid (18:4)
CO
2
H
C
20
, arachidonic acid (20:4)
283

Fats and Oils : Triglycerides (triaceylglycerols) are tri-esters of glycerol (1,2,3-trihydroxypropane) and fatty acids.
O
HO
OH glycerol
OH + fatty acids
- H
2
O
H
2
C
HC
O
O
H
2
C O
C
O
C
C R
1
O
R
2
R
3
The R groups can be saturated or unsaturated, the same or different
H
2
C
HC
O
O
H
2
C O
C
O
C
O
C R
1
O
R
2
R
3 when some of the R groups are unsaturated
H
2
, catalyst
H
2
C O
O
C
O
R
1
H
2
, catalyst
HC O C
O
R
2
H
2
C O C R
3
Partially hydrogenated: some cis double bond are isomerized to trans double bonds
H
2
C
HC
O
O
H
2
C O
C
O
C
O
C R
1
O
R
2
R
3
Hydrogenated- only saturated fatty acids
284

Soaps: sodium & potassium salts of fatty acid produced from the saponification (base hydrolysis) of animal fats (glycerides)
H
2
C
HC
O
O
H
2
C O
C
O
C
O
C R n
O
R n
R n
NaOH
3
R n
O
C O Na
H
2
C OH
+
HC OH
H
2
C OH
Soaps have a hydrophilic, polar “head group” (carboxylate salt) and a hydrophobic, nonpolar “tail.”
Fatty acid amides (FAA):
O
N
H
Anandamide an ethanolamine amide of arachidonic Acid (C
20
)
OH H
OH
H
O tetrahydrocannabinol
285

26.3: Fatty Acid Biosynthesis. Fatty acid biosynthesis is performed by a cluster of discrete enzymes in bacteria, and a very large multi-protein assembly in animals ( fatty acid synthase ,
FAS). The fatty acid is attached to an acyl carrier protein (ACP), while other proteins perform an iterative two-carbon chain extension reaction that will yield the fatty acid.
NH
2
N
N
O
S
H
N
H
N
OH
O
O
P
O
O
O
P
O
O
O
N
N
+
O O
O OH
AcS-CoA
O P O
O
R
H
N
O
HS
O
N
H
R
O
Cysteine of
Ketosynthase (KS)
CoA-SH
+
R
H
N
O
S
O
O R
N
H
O
AcS-KS
286

FAS chain extension reaction: Ketosynthase (KR)
O O
OH
O S-CoA
+
HS
H
N
H
N
Malonyl CoA
O O
Phosphopantetheine
O
O
P
O
O
O
O
N
H
NH
Serine of ACP
CoA-SH +
KS-S
O
+
O
O O
S-ACP
- CO
2
O
S-ACP
KS-SH +
O O
S-ACP
287

Ketoreductase: NADPH (nicotinamide adenine diphosphate phosphate) is a nucleophilic hydride (H – ) donor (reducing agent)
H
H
H
2
N O N
O O
N
N
N
O O P
O
O P
O
O O N NH
2
= H
–
2-
O
3
PO OH HO OH
NADPH
O O
S-ACP
+ NADPH
Ketoreductase
OH O
S-ACP
Dehydratase (DH):
OH O
S-ACP
Dehydratase
-H
2
O
Enoyl Reductase (ER)
O
S-ACP
+
NADPH
+ H
+
O
S-ACP
Enoyl Reductase
O

Iterative two-carbon chain extension
O
KS-SH
+
S-ACP
(Cysteine of
Ketosynthase)
O O
O S-CoA
Malonyl CoA
+
ACP-SH
O
S-KS
+
O
O O
S-ACP
KS
-CO
2
O
S-KS
+ ACP-SH
O
O O
S-ACP
+ CoA-SH
O O
S-ACP
KR
NADPH
OH O
S-ACP
DH
-H
2
O
O
S-ACP
ER
NADPH
KS
-CO
2
KR
NADPH
DH
-H
2
O
ER
NADPH
KS
O
S-ACP
KS
O
S-KS
O
S-KS
+
O
O O
S-ACP
289

Thioesterase
O
S-ACP
TE
H
2
O
O
OH C18 Fatty acid
(steric acid)
O
S-ACP
O
S-CoA
ROH
O
OR
CoA-SH
26.4 Phospholipids.
H
2
C OH H
2
C OH
O
H
2
C OPO
3
-2
HO H
H
2
C OPO
3
-2
L-glycerol-3phosphate
R
1
R
2
O
C SCoA
O
C SCoA
H
R
2
O
C O
2
C O
H
O
C R
1
H
2
O
- HPO
4
-3
H
2
C OPO
3
-2 phosphatidic acid
R
3
OH
H
2
C O
O
C R
1
O
R
2
C O H
O
H
2
C O P OR
3
O phosphoglycerodes
R
2
H
O
C O
2
C O
H
O
C R
1
H
2
C OH
Diacylglycerol
R
3
O
C SCoA
H
2
C O
R
2
O
C O H
O
C R
1
H
2
C O
O
C R
3
Triacylglycerol
290

Glycerophospholipids are important components of cell membranes. Nonpolar tails aggregate in the center of a bilayer ionic head is exposed to solvent Cell membranes are ~5 nm thick unsaturated
R
H
2
C O
O
C O C H
O
H
2
C O P
O
O
C R saturated
O CH
2
CH
2
N(CH
3
)
3
Phosphatidylcholine (lechtins)
26.6: Waxes.
esters of long chain fatty acids (C
16 chain alcohols (C
24
- C
36
)
- C
36
) with long
CH
3
(CH
2
) n
CO
2
–(CH
2
) n
CH
3
291

26.6: Prostaglandins. (eicosanoids) C
20 compounds derived from arachidonic acid and related fatty acids hormone : (Greek, horman , to set in motion) chemical messengers from one cell to another, that acts as a signal for a biochemical event.
CO
2
H phospholipid
HO
HO
OH
Prostaglandin F
2 
(PGF
2 
)
CO
2
H prostaglandin endoperoxide reductase
O
O prostaglandin endoperoxide D isomerase
Arachidonic acid prostaglandin H
(PGH) synthase , 2 O
2
CO
2
H prostacyclin (PGI) synthase
OH
Prostaglandin H
2
(PGH
2
) prostaglandin endoperoxide E isomerase
O
CO
2
H
HO
OH
Prostaglandin I
2
(Prostacyclin)
HO
O
CO
2
H
CO
2
H
O
OH
Prostaglandin D
2
(PGE
2
)
HO
OH
Prostaglandin E
2
(PGE
2
)
292

Prostaglandin biosynthesis
CO
2
H prostaglandin H synthase
O
O cyclooxygenase
(COX-1 or COX-2)
Arachidonic acid
COX-2
OOH
PGG
2
CO
2
H
O
O
OH
PGH
2
CO
2
H
Tyr-385 cell membrane
CO
2
H
O
+
O acetylsalicylic acid
OH
H
N
O
Ser-530
COX
N
H
Ser-385
O
H
N
O
N
H
O covalently modified

COX-1 is a constitutive enzyme that is expressed in virtually all mammalian cells
COX-2 is an inducible enzyme that is expressed as a results of a biochemical response; expressed in phagocytes
(macrophages) as part of an inflammation response.
NSAIDs: non-steroidal anti-inflammatory drugs
Aspirin, ibuprofren, and naproxen are non-selective inhibitors of COX
CO
2
H
CO
2
H CO
2
H
OAc
H
3
CO
F
3
C
Celebrex, vioxx, and brextra are selective inhibitors of COX-2 (coxibs)
O
S
O
NH
2
O
S
O
NH
2
O
S
O
NH
2
N
N
O O
N
294
O
CH
3

Thromboxanes: named for their role in thrombosis, the formation of a clot inside a blood vessel
OH
PGH
2 thromboxane synthase
O
O
CO
2
H H
2
O
HO
O
CO
2
H
OH
Thromboxane A
2
OH
Thromboxane B
2
Leukotrienes
Aracidonic acid
CO
2
H Lipoxygenase
Heme, O
2
O
C
5
H
11
Leukotriene A
4
CO
2
H
HO
C
5
H
11
S
Leukotriene D
4
NH
2
H
N
CO
2
H
CO
2
H
O
295

26.7: Terpenes: The Isoprene Rule.
Isoprenoids- C
10
C
15
( sesquiterpenes ) and C
20
( terpenes
( diterpenes ) plant; essential oils
),
Ruzicka isoprene rule: terpenoids are derived from “isoprene units” (C
5
) isoprene
(2-methyl-1,3-butadiene)
O
(+)-Carvone (caraway seeds)
(-)-Carvone (spearmint)
Citral
O
H
(lempon grass)
O
Camphour
(+)-limonene (oranges)
(-)-limonene (lemons)
H
3
C
H
3
C CH
3
CH
3 patchouli alcohol
(patchouli oil)
OH

-pinene

-pinene
Grandisol 296

The precursor to C
10 terpenoids ( monoterpenes ) is geraniol diphosphate (diphosphate), which consists of two C units” that are joined “head-to-tail”
5
“isoprene
O O head tail PP =
P O P O
O O head - tail head - tail
OPP
C
15 sesquiterpenoids are derived from farnesyl diphosphate, which consists of three C
“head-to-tail”
5
“isoprene units” that are joined
OPP
C
20 diterpenoids are derived from geranylgeranyl diphosphate, which consists of four C
“head-to-tail”
5
“isoprene units” that are joined
297
OPP

C
25 sesterpenoids are derived from geranylfarnesyl diphosphate, which consists of five C are joined “head-to-tail”
5
“isoprene units” that
OPP
C
30 triterpenoids and steroids are derived from squalene, which consists of two C
15 farnesyl units” that are joined “tail-to-tail”
C
40 tetraterpenoids are derived from phytocene, which consists of two C
20 geranylgeranyl units” that are joined “tail-to-tail”
298

H
3
C
H
CH
3
CH
3 cedrane
CH
3
H
3
C
H
CH
3
CH
3
CH
3
O
O
C
6
H
5
C
6
H
5
NH O
OH
O
Taxol
O O OH
HO
H
O
O
O
O
O O OH
O
C
6
H
5
C
6
H
5
NH O
OH
O
HO
H
O
O
O
HO
Lanosterol

-carotene
299

26.8: Isopentyl Diphosphate: The Biological Isoprene Unit.
Mevalonic acid is the biosynthetic precursor to the actual C
5
“isoprene units,” which are isopentyl diphosphate (IPP, tail) and dimethylallyl diphosphate (DMAPP, head)
26.10: The Pathway from Acetate to Isopentenyl Diphosphate.
Mevalonate Pathway
B:
H
2
C
H
O
C SCoA acetyl CoA acetoacetyl-CoA acetyltransferase O
H
2
C
C SCoA
Claisen condensation
O O
SCoA acetoacetyl CoA
H
3
C
O
C SCoA
Enzyme-Cys-SH
H
3
C
O
C S-Cys
-
Enzyme acetyl CoA
B:
H
2
C
H
O
C SCoA acetyl CoA
HMG-CoA synthase
B H
O
H
2
C
C SCoA aldol condensation
O O
HO
2
C
H
3
C OH O
SCoA
3-Hydroxy-3-methylglutaric acid
(HMG-CoA)
HMG-CoA reductase
2 NADPH
SCoA acetoacetyl CoA
HO
2
C
H
3
C OH
OH
Mevalonic acid
300

Conversion of mevalonic acid to IPP and DMAPP
HO
2
C
H
3
C OH
Mevalonic acid
OH
ATP
AMP
H
O
O H
3
C OH
O
O
P O
O -
O
P O
-
O
-
ATP ADP
H
O
O H
3
C
OPO
3
2-
O
O
P O
O
-
O
P O
-
O
-
- PO
4
3-
H
+
B:
H
O
O CH
3
O
O
P O
O
-
O
P O
-
O
B:
H H
O
O P O
O
-
O
P O
-
O
rearrangment
H
O
O P O
O
-
O
P O
-
O
isopentenyl-PP
(IPP) dimethylallyl-PP
(DMAPP)
26.9: Carbon-Carbon Bond Formation in Terpene Biosynthesis.
Conversion of IPP and DMAPP to geraniol-PP and farnesyl-PP electrophilic head group nucleophilic tail group
- OPP
Mg
2+
OPP
- OPP
Mg
2+
H H
OPP
DMAPP
OPP
B:
IPP
OPP geranyl pyrophosphate (C
10
) electrophilic head group
OPP
B:
H H
OPP nucleophilic tail group
OPP farnesyl pyrophosphate (C
15
) 301

OPP PPO squalene synthase
Conversion of genanyl-PP to monoterpenes
Limonene &

-Terpineol
OPP
OPP
OPP
H
2
O geranyl diphosphate neryl diphosphate
C=C bond acts as a nucleophile
- H
+
H
:B limonene
HO

-terpineol 302

26.11: Steroids.
2
3
12
17
1
11
10
9
A B
C
13
D
8
14
15
7
5
4 6
16
HO
H
H
H
H
H
Cholesterol biosynthesis (mechanism 26.3, p. 1089) part a: the cyclization
Squalene epoxidase
O
Cholesterol (C
27
H
46
O)
Heme , O
2
Squalene (C
30
H
50
) H A
Squalene Oxide (C
30
H
50
O)
Squalene cyclase +
HO
+
HO
HO HO
+ +
HO
+
HO
+
+
HO
Protosterol cation
303

Cholesterol biosynthesis, part b: the 1,2-shifts
HO
CH
3
CH
3
H
CH
3
H
H
3
C
H
CH
3
H
Protosterol cation (C
30
H
50
O)
+
1,2-hydride shift
HO
CH
3
H
3
C
H
CH
3
H
CH
3
CH
3
H
+
1,2-hydride shift
1,2-methyl shift
CH
3
CH
3
H
CH
3
HO
HO
H
3
C
H
CH
3
CH
3
CH
3
B:
H
H
3
C
H
H
+
H
3
C
+
3
C
H
H
H
H
H
1,2-methyl shift
- H +
H
3
C
H
CH
3
CH
3
H
HO
HO
H
3
C
+
H
CH
3
H
3
C
CH
3
CH
3
CH
3
H
CH
3
Lanosterol (C
30
H
50
O)
H
H
H
H
HO
H
Lanosterol (C
30
H
50
O)
HO
H
H
H
H
H
Cholesterol (C
27
H
46
O)
304

26.12: Vitamin D.
(please read)
H
HO
H
H H
7-Dehydrocholesterol sunlight
26.13: Bile Acids. (please read)
HO
26.14: Corticosteroids.
(please read)
O
O
O
H
H
H
Cortisone
OH
OH
H
H
H
Vitamin D
3
305

26.15: Sex hormones.
(please read) androgens (male)
OH O
H
3
C H
3
C
H
3
C H H
3
C H H
3
C
H H H H H
O
Testosterone
HO
H
Androsterone
O
H
3
C
H
H
O
Androstenedione
O estrogens (female)
H
H
3
C
O
H
H
HO HO
Estrone
H
H
3
C
OH
H
H
Estradiol
HO
H
H
3
C
H
H
Progesterone
O
HO
H
3
C
H
H
3
C
OH
CH
3
H
H dianabol
H
H
3
C
OH
H
C CH
H
Ethynylestradiol
26.16: Carotenoids.
(please read) derived from phytocene (C
40
)
Lycopene
306

-carotene