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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
CH2OH
O O
H3C C C O
OH O
H3C C C O
H
280
26.1: Acetyl Coenzyme A. AcSCoA is a thioester.
NH2
N
R= H, CoASH
R= acetyl, AcSCoA
R
H
N
S
H
N
O
O O O O
P
P
O
O
O
OH
N
O
O
O
N
N
OH
O P O
O
Pyruvate dehydrogenase: Multi-enzyme complex that converts
pyruvate to AcSCoA.
H2N
O
CO2
+ CoASH +
O
N
O
N
N
O
O
N
P
O
O
HO
O
O
N
NH2
O
O
pyruvate
P
HO
OH
OH
NAD
thiamin diphosphate (vitamin B1)
Lipoic Acid
Flavin adenine diphosphate (VitaminB2)
H
H2N
O
+
S-CoA
AcSCoA
N
O
N
N
O
O
N
P
O
O
HO
O
P
O
O
N
O
OH
HO
NADH
H
O
NH2
+ CO2
+ H+
OH
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
+
+ Nu-H
S-CoA
choline
acetyltransferase
O
+
S-CoA
HO
CoASH
Nu
O
N(CH3)3
N(CH3)3
O
+
CoASH
acetylcholine
choline
Thioester enolize more readily than esters. The enol can react
with electrophile to afford -substitution products
O
OH
S-CoA
O
E
E
S-CoA
acetyl-CoA
carboxylase
O
S-CoA
+ HCO3
biotin, ATP
O
O
S-CoA
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
C12 - C20 (Table 26.1, p. 1069).
saturated fatty acids:
CH3(CH2)nCO2H
n=10, lauric acid (C12)
n=12, myristic acid (C14)
n=14, palmitic acid (C16)
n=16, steric acid (C18)
unsaturated fatty acid
C18, oleic acid
CO2H
polyunsaturated fatty acids (PUFA)
3
CO2H
6
6
C18, linolenic acid (18:3)
C18, linoleic acid (18:4)
CO2H
CO2H
C20, arachidonic acid (20:4)
283
Fats and Oils: Triglycerides (triaceylglycerols) are tri-esters of
glycerol (1,2,3-trihydroxypropane) and fatty acids.
O
H2C O
OH
HO
OH
+
fatty
acids
HC O C R2
O
- H2O
glycerol
C R1
O
HC O C R2
O
H2C O C R3
The R groups can be
saturated or unsaturated,
the same or different
H2C O C R3
O
O
H2C O
C R1
O
when some of
the R groups are
unsaturated
H2, catalyst
H2C O
C R1
O
O
H2C O
H2, catalyst
C R1
O
HC O C R2
O
HC O C R2
O
H2C O C R3
H2C O C R3
Partially hydrogenated:
some cis double bond are
isomerized to trans double bonds
Hydrogenated- only saturated
fatty acids
284
Soaps: sodium & potassium salts of fatty acid produced from the
saponification (base hydrolysis) of animal fats (glycerides)
O
H2C O
C Rn
O
H2C OH
NaOH
3
HC O C Rn
O
O
Rn
+
Na
C O
H2C O C Rn
HC OH
H2C OH
Soaps have a hydrophilic, polar “head group” (carboxylate salt)
and a hydrophobic, non-polar “tail.”
Fatty acid amides (FAA):
O
N
H
OH
H
OH
H
O
Anandamide
an ethanolamine amide of
arachidonic Acid (C20)
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.
NH2
N
O
S
H
N
OH
H
N
O
O O O O
P
P
O
O
O
N
O
N
N
R
N
H
+
O
O
O
OH
Cysteine of
Ketosynthase (KS)
O
R
CoA-SH
O
HS
O P O
AcS-CoA
R
O
H
N
H
N
+
O
R
O
N
H
O
S
O
AcS-KS
286
FAS chain extension reaction: Ketosynthase (KR)
O
O
O
S-CoA
+
H
N
HS
Malonyl CoA
OH
H
N
O
O
O
Phosphopantetheine
P
O
O
NH
N
H
Serine
of ACP
O
O
CoA-SH
O
O O
+
S-ACP
O
- CO2
O
O
+
KS-S
S-ACP
O
KS-SH
+
O
S-ACP
287
Ketoreductase: NADPH (nicotinamide adenine diphosphate
phosphate) is a nucleophilic hydride (H–) donor (reducing agent)
H
H2N
N
O
N
N
O
O
N
P
O
O
O
2- O PO
3
H
P
O
N
O
O
OH
HO
O
NH2
= H–
OH
NADPH
O
O
+
NADPH
Ketoreductase
OH
S-ACP
O
S-ACP
Dehydratase (DH):
OH
O
Dehydratase
S-ACP
O
S-ACP
-H2O
Enoyl Reductase (ER)
O
Enoyl Reductase
+
S-ACP
NADPH
+
H+
O
S-ACP
288
Iterative two-carbon chain extension
O
S-ACP
O
KS-SH
+
+
ACP-SH
S-KS
(Cysteine of
Ketosynthase)
O
O
O
O
+
ACP-SH
+
S-CoA
O
CoA-SH
S-ACP
O
Malonyl CoA
O
O
+
S-KS
DH
O
S-ACP
KS
KR
-CO2
NADPH
S-ACP
O
DH
-H2O
O
NADPH
ER
NADPH
KR
O
S-ACP
-CO2
ER
O
-H2O
KS
O
O
NADPH
S-ACP
O
KS
O
+
S-KS
S-ACP
KS
OH
O
S-ACP
O
O
S-KS
289
Thioesterase
O
O
TE
S-ACP
C18 Fatty acid
(steric acid)
OH
H2O
O
O
O
S-CoA
S-ACP
ROH
OR
CoA-SH
26.4 Phospholipids.
H2C OH
O
H2C OPO3 -2
H2C OH
HO
H
R1
C SCoA
O
H2C OPO3-2
R2
O
H2C O C R1
O
H2C O C R1
O
R2
C SCoA
O
C O
H
H2O
- HPO4-3
R2
H2C OPO3-2
L-glycerol-3phosphate
O
C O
H
H2C OH
Diacylglycerol
phosphatidic acid
O
R3OH
R3
O
H2C O C R1
R2
O
C O
H
O
H2C O P OR3
O
phosphoglycerodes
C SCoA
O
H2C O C R1
R2
O
C O
H
O
H2C O C R3
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
O
H2C O
C Rsaturated
O
unsaturatedR
C O C H
O
H2C O P O CH2CH2N(CH3)3
O
Phosphatidylcholine (lechtins)
26.6: Waxes. esters of long chain fatty acids (C16 - C36) with long
chain alcohols (C24 - C36)
CH3(CH2)nCO2–(CH2)nCH3
291
26.6: Prostaglandins. (eicosanoids) C20 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.
CO2H
phospholipid
Arachidonic acid
CO2H
prostaglandin H
(PGH) synthase, 2 O2
HO
CO2H
prostaglandin
endoperoxide
reductase
O
CO2H
prostacyclin (PGI)
synthase
O
O
HO
OH
OH
Prostaglandin F2
(PGF2 )
prostaglandin
endoperoxide D
isomerase
Prostaglandin H2
(PGH2)
prostaglandin
endoperoxide E
isomerase
HO
OH
Prostaglandin I2
(Prostacyclin)
HO
O
CO2H
O
OH
Prostaglandin D2
(PGE2 )
CO2H
HO
OH
Prostaglandin E2
(PGE2)
292
Prostaglandin biosynthesis
CO2H
prostaglandin H
synthase
cyclooxygenase
(COX-1 or COX-2)
O
O
CO2H
CO2H
O
O
OH
OOH
Arachidonic acid
PGH2
PGG2
COX-2
cell membrane
OH
CO2H
H
N
+
O
Tyr-385
O
N
H
O
Ser-530
COX
acetylsalicylic acid
Ser-385
O
O
H
N
O
N
H
covalently modified
enzyme
293
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
CO2H
CO2H
CO2H
OAc
H3CO
Celebrex, vioxx, and brextra are selective inhibitors
of COX-2 (coxibs)
O O
S
NH2
N
F3C
O O
S
NH2
O O
S
NH2
N
O
O
N
CH3
O
294
Thromboxanes: named for their role in thrombosis, the formation
of a clot inside a blood vessel
OH
PGH2
thromboxane
synthase
CO2H
O
H2O
CO2H
HO
O
O
OH
OH
Thromboxane A2
Thromboxane B2
Leukotrienes
O
CO2H
CO2H
Lipoxygenase
C5H11
Heme, O2
Leukotriene A4
Aracidonic acid
HO
CO2H
C5H11
NH2
S
Leukotriene D4
O
H
N
CO2H
295
26.7: Terpenes: The Isoprene Rule. Isoprenoids- C10 (terpenes),
C15 (sesquiterpenes) and C20 (diterpenes) plant; essential oils
Ruzicka isoprene rule: terpenoids are derived from “isoprene
units” (C5)
isoprene
(2-methyl-1,3-butadiene)
O
(+)-Carvone (caraway seeds)
(-)-Carvone (spearmint)
(+)-limonene (oranges)
(-)-limonene (lemons)
H 3C
O
H3C
H
CH3
CH3
O
Citral
(lempon grass)
Camphour
patchouli alcohol
(patchouli oil)
OH
-pinene
-pinene
Grandisol
296
The precursor to C10 terpenoids (monoterpenes) is geraniol
diphosphate (diphosphate), which consists of two C5 “isoprene
units” that are joined “head-to-tail”
O
head
tail
PP =
P
O
O
O
P
O
O
OPP
head - tail head - tail
C15 sesquiterpenoids are derived from farnesyl diphosphate,
which consists of three C5 “isoprene units” that are joined
“head-to-tail”
OPP
C20 diterpenoids are derived from geranylgeranyl diphosphate,
which consists of four C5 “isoprene units” that are joined
“head-to-tail”
OPP
297
C25 sesterpenoids are derived from geranylfarnesyl
diphosphate, which consists of five C5 “isoprene units” that
are joined “head-to-tail”
OPP
C30 triterpenoids and steroids are derived from squalene, which
consists of two C15 farnesyl units” that are joined “tail-to-tail”
C40 tetraterpenoids are derived from phytocene, which consists
of two C20 geranylgeranyl units” that are joined “tail-to-tail”
298
O
H3C
O OH
O
CH3
O
CH3
H
CH3
cedrane
NH
C6H5
O
O
C6H5
HO
OH
O
H
O
HO
O
Taxol
Lanosterol
O
O OH
O
H3C
O
CH3
CH3
H
CH3
C6H5
NH
O
O
C6H5
OH
H
HO O
O
O
-carotene
299
26.8: Isopentyl Diphosphate: The Biological Isoprene Unit.
Mevalonic acid is the biosynthetic precursor to the actual C5
“isoprene units,” which are isopentyl diphosphate (IPP, tail)
and dimethylallyl diphosphate (DMAPP, head)
26.10: The Pathway from Acetate to Isopentenyl Diphosphate.
Mevalonate Pathway
acetoacetyl-CoA
O
acetyltransferase
H2C C SCoA
H
B:
acetyl CoA
H2C
O
C
SCoA
Claisen
condensation
O
O
SCoA
acetoacetyl CoA
O
O
Enzyme-Cys-SH
H3C C S-Cys-Enzyme
H3C C SCoA
acetyl CoA
O
H2C C SCoA
H
B:
acetyl CoA
HMG-CoA
synthase
H2C
B H
O
O
C
aldol
condensation
SCoA
H3C OH O
HO2C
HMG-CoA
reductase
SCoA
3-Hydroxy-3-methylglutaric acid
(HMG-CoA)
O
SCoA
acetoacetyl CoA
2 NADPH
H3C OH
HO2C
OH
Mevalonic acid
300
Conversion of mevalonic acid to IPP and DMAPP
ATP
H3C OH
HO2C
AMP
O H3C OH
H
OH
O
Mevalonic acid
ATP
ADP
O
O
O P O P OOO-
O H3C OPO 23
H
O
O
O
- PO43O P O P O
OO-
H+
O
H
CH3
O
B:
O
O
O P O P OOO-
H H
B:
O
O
O P O P OOO-
isopentenyl-PP
(IPP)
rearrangment
H
O
O
O P O P OOO-
dimethylallyl-PP
(DMAPP)
26.9: Carbon-Carbon Bond Formation in Terpene Biosynthesis.
Conversion of IPP and DMAPP to geraniol-PP and farnesyl-PP
nucleophilic
tail group
electrophilic
head group
- OPP
Mg2+
H H
OPP
B:
OPP
DMAPP
- OPP
Mg2+
OPP
IPP
OPP
geranyl pyrophosphate (C10)
OPP
OPP
H H
electrophilic
head group
OPP
B:
nucleophilic
tail group
farnesyl pyrophosphate (C15)
301
OPP
PPO
squalene
synthase
Conversion of genanyl-PP to monoterpenes
Limonene & -Terpineol
OPP
OPP
- H+
OPP
H
geranyl
diphosphate
neryl
diphosphate
:B
H2O
limonene
C=C bond acts
as a nucleophile
HO
-terpineol
302
H
12
26.11: Steroids.
11
1
2
3
10
A
4
13
C
9
B
5
17
8
D
14
H
16
H
15
H
7
6
H
Cholesterol (C27H46O)
HO
Cholesterol biosynthesis (mechanism 26.3, p. 1089)
part a: the cyclization
Squalene
epoxidase
Heme , O2
O
H A
Squalene (C30H50)
Squalene Oxide (C30H50O)
Squalene
cyclase
+
HO
HO
+
HO
HO
+
HO
+
+
HO
+
+
HO
Protosterol cation
303
Cholesterol biosynthesis, part b: the 1,2-shifts
CH3
CH3
H
CH3
CH3
1,2-hydride
shift
H
HO
H3C
CH3
+
HO
+
H
H
CH3
H3C
H
H
CH3
CH3
H
H
Protosterol cation (C30H50O)
CH3
1,2-hydride
shift
H
CH3
H
CH3
HO
+
H3C
H
1,2-methyl
shift
CH3
H
H3C
CH3
H
H3C
+
H
CH3
H
CH3
CH3
CH3
- H+
HO
HO
H
H3C
+
H
H3C
CH3
H
H3C
H
Lanosterol (C30H50O)
H
H
H
H
H
H
HO
H
HO
H
B:
1,2-methyl
shift
H3C
CH3
CH3
CH3
H
H
Lanosterol (C30H50O)
H
HO
Cholesterol (C27H46O)
304
26.12: Vitamin D. (please read)
H
H
H
H
H
HO
sunlight
H
H
HO
7-Dehydrocholesterol
Vitamin D3
26.13: Bile Acids. (please read)
26.14: Corticosteroids. (please read)
O
O
OH
OH
H
H
H
O
Cortisone
305
26.15: Sex hormones. (please read)
androgens (male)
H3C
H3C
OH
H
H
O
H3C
H3C
H
HO
Testosterone
H3C
H
H
O
H3C
H3C
H
CH3
H
O
dianabol
Androstenedione
Androsterone
OH
H
H
O
H
H3C
H
H
H
O
estrogens (female)
H3C
O
H3C
H
H
HO
OH
H
H
O
H3C OH
H
H
H
H
H
HO
HO
Progesterone
Estradiol
C CH
H
H
H
HO
Estrone
H3C
Ethynylestradiol
26.16: Carotenoids. (please read) derived from phytocene (C40)
Lycopene
-carotene
306