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

CHO
H OH O O OH O
HO H H3C C C O H3C C C O
H OH H
H OH
CH2OH

1
26.1: Acetyl Coenzyme A. AcSCoA is a thioester. NH2
N
R= H, CoASH R
H
N
H
N
OH O O O O
P P O N
N

N
R= acetyl, AcSCoA
S O O O
O O
O OH
O P O
O

Pyruvate dehydrogenase: Multi-enzyme complex that converts

pyruvate to AcSCoA.
H2N N O
O O O
+ CoASH + N N O O P O P O O N NH2
CO2
N O O

pyruvate HO OH HO OH

NAD
thiamin diphosphate (vitamin B1)
Lipoic Acid
Flavin adenine diphosphate (VitaminB2)

H
H
H2N N O
O O
O
+ N N O O P O P O O N NH2
+ CO2 + H+
S-CoA N O O

AcSCoA HO OH HO OH

NADH
2
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 + CoASH
S-CoA Nu

choline
acetyltransferase O
O
N(CH3)3 N(CH3)3 + CoASH
+ HO O
S-CoA
choline acetylcholine

Thioester enolize more readily than esters. The enol can react
with electrophile to afford -substitution products
O OH E O
E
S-CoA S-CoA S-CoA

acetyl-CoA
O carboxylase O O
+ HCO3
S-CoA biotin, ATP O S-CoA
Malonyl CoA
3
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 acidCO H

2

C18, oleic acid

3 polyunsaturated fatty acids (PUFA)

CO2H

6
CO2H C18, linolenic acid (18:3)
6
CO2H C18, linoleic acid (18:4)
4
C20, arachidonic acid (20:4)
Fats and Oils: Triglycerides (triaceylglycerols) are tri-esters of
glycerol (1,2,3-trihydroxypropane) and fatty acids.
O
H2C O C R1
OH The R groups can be
fatty O
HO OH +
acids HC O C R2
saturated or unsaturated,
- H2O
O the same or different
glycerol
H2C O C R3

O O O
when some of H2C O C R1 H2C O
H2C O C R1 C R1
the R groups are
O O H2, catalyst O
unsaturated
HC O C R2 HC O C R2 HC O C R2
H2, catalyst
O O O
H2C O C R3 H2C O C R3 H2C O C R3
Partially hydrogenated: Hydrogenated- only saturated
some cis double bond are fatty acids
isomerized to trans double bonds

5
Soaps: sodium & potassium salts of fatty acid produced from the
saponification (base hydrolysis) of animal fats (glycerides)
O
H2C O C Rn H2C OH
O NaOH O
HC O C Rn 3 + HC OH
Rn C O Na
O
H2C O C Rn H2C OH

Soaps have a hydrophilic, polar “head group” (carboxylate salt)

and a hydrophobic, non-polar “tail.”

Fatty acid amides (FAA):

O
OH
OH H
N
H
H
O
Anandamide tetrahydrocannabinol
an ethanolamine amide of
arachidonic Acid (C20)

6
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 N R O R
OH O O O O H
H H N
N N P P O N
S O O N N
O + H
O O O O
O OH HS

AcS-CoA O P O
Cysteine of
O
Ketosynthase (KS)

R O R
H
+ N
CoA-SH N
H
O O
S

AcS-KS
7
O
FAS chain extension reaction: Ketosynthase (KR)
O O
OH O O O
H H
O S-CoA + N N P
HS O O N
Malonyl CoA H
O O O NH
Serine
Phosphopantetheine of ACP

O O
CoA-SH +
O S-ACP

- CO2

O O
+
KS-S S-ACP

O O
KS-SH +
S-ACP

8
Ketoreductase: NADPH (nicotinamide adenine diphosphate
phosphate) is a nucleophilic hydride (H–) donor (reducing agent)
H
H
H2N N O
O O
N
N
N O O P
O
O P
O
O O N NH2
= H–
2- O PO OH HO OH
3

NADPH

O O OH O
+ Ketoreductase
NADPH
S-ACP S-ACP

Dehydratase (DH):
OH O O
Dehydratase
S-ACP S-ACP
-H2O

Enoyl Reductase (ER)

O Enoyl Reductase O
+ NADPH + H+
S-ACP S-ACP
9
Iterative two-carbon chain extension
O
KS-SH O
+
S-ACP + ACP-SH
S-KS
(Cysteine of
Ketosynthase)

O O
O O
O S-CoA + ACP-SH + CoA-SH
O S-ACP
Malonyl CoA

KS O O KR OH O
O O O
+
S-KS O S-ACP -CO2 S-ACP NADPH S-ACP

DH O ER O
O KS +
O O

-H2O S-ACP NADPH S-ACP S-KS O S-ACP

KS KR ER O
DH KS
-CO2 NADPH -H2O NADPH S-KS

10
Thioesterase O
O
TE
S-ACP
OH C18 Fatty acid
H2O
(steric acid)

O O O

S-CoA ROH OR
S-ACP

CoA-SH

26.4 Phospholipids.
O O
H2C OH H2C OH O
H2C O C R1 H2C O C R1
R1 C SCoA O O
H H2O
O HO R2 C O H R2 C O H
O
- HPO4-3
H2C OPO3 -2 H2C OPO3-2 R2 C SCoA
H2C OPO3-2 H2C OH

L-glycerol-3- phosphatidic acid Diacylglycerol

phosphate
O
R3OH
R3 C SCoA
O
O
H2C O C R1
H2C O C R1
O
O
R2 C O H
O R2 C O H
O
H2C O P OR3
H2C O C R3
O
phosphoglycerodes Triacylglycerol

11
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

12
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 prostaglandin
prostacyclin (PGI) O
CO2H endoperoxide O
CO2H synthase
reductase
O
HO OH OH
prostaglandin HO OH
Prostaglandin F2 Prostaglandin H2 prostaglandin
endoperoxide D endoperoxide E
(PGF2 ) (PGH2) Prostaglandin I2
isomerase isomerase
(Prostacyclin)

HO
O
CO2H
CO2H

O OH
HO OH
Prostaglandin D2 Prostaglandin E2
(PGE2 ) (PGE2) 13
Prostaglandin biosynthesis
prostaglandin H
CO2H O O
synthase CO2H CO2H

O O
cyclooxygenase
(COX-1 or COX-2) OOH OH
Arachidonic acid
PGG2 PGH2

COX-2

cell membrane
CO2H OH
H
+ N
O N
Tyr-385 O
H
O

acetylsalicylic acid Ser-530

COX
Ser-385

O
covalently modified
H
enzyme
N
N
14
H
O
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 O O O O
S S S
NH2 NH2 NH2
N
N
F3C O O
N
O 15
CH3
Thromboxanes: named for their role in thrombosis, the formation
of a clot inside a blood vessel OH
thromboxane CO2H H2O CO2H
synthase O
PGH2
O HO O
OH OH
Thromboxane A2 Thromboxane B2

Leukotrienes
O
CO2H Lipoxygenase CO2H

Heme, O2 C5H11

Aracidonic acid Leukotriene A4

HO
CO2H

NH2
C5H11 H
S N CO2H

O
Leukotriene D4 16
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)

(+)-Carvone (caraway seeds) (+)-limonene (oranges)

(-)-Carvone (spearmint) (-)-limonene (lemons)

O H3C CH3
CH3
H3C
H
O
Citral patchouli alcohol
(lempon grass) Camphour (patchouli oil)

OH

-pinene -pinene
Grandisol 17
The precursor to C10 terpenoids (monoterpenes) is geraniol
diphosphate (diphosphate), which consists of two C5 “isoprene
units” that are joined “head-to-tail” O O
head tail PP = P O P O
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 18
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”

19
 O
H3C
CH3 O O OH
O
CH3
H C6H5 NH O
CH3
H O
C6H5 O HO
HO O
cedrane OH
O
Taxol Lanosterol

O
O O OH
H3C O
CH3

C6H5 NH O
CH3
H O
H
CH3 C6H5 O
HO O
OH
O

-carotene

20
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
O acetoacetyl-CoA
acetyltransferase O
H2C C SCoA
C
H H2C SCoA
B:
acetyl CoA Claisen
condensation O O

SCoA

acetoacetyl CoA
O O
Enzyme-Cys-SH
H3C C SCoA H3C C S-Cys-Enzyme

acetyl CoA

HMG-CoA aldol HMG-CoA

O
synthase O condensation H3C OH O reductase H3C OH
H2C C SCoA HO2C HO2C
C SCoA 2 NADPH OH
H H2C SCoA
B: 3-Hydroxy-3-methylglutaric acid Mevalonic acid
acetyl CoA
B H (HMG-CoA)
O O

SCoA
21
acetoacetyl CoA
Conversion of mevalonic acid to IPP and DMAPP
ATP AMP ATP ADP
H3C OH O H3C OH O H3C OPO 2-
O O
3 O O - PO43-
HO2C H H -
OH O O P O P O- O O P O P O
O- O- O- O-
Mevalonic acid

H+
O CH3 O O O O
O O rearrangment
H O P O P O- O P O P O-
O O P O P O- H H O- O- H O- O-
B: O- O- B:

isopentenyl-PP dimethylallyl-PP
(IPP) (DMAPP)

26.9: Carbon-Carbon Bond Formation in Terpene Biosynthesis.

Conversion of IPP and DMAPP to geraniol-PP and farnesyl-PP
electrophilic nucleophilic
tail group
head group
- OPP - OPP
OPP
Mg2+ H H Mg2+
OPP OPP
OPP B:
DMAPP IPP geranyl pyrophosphate (C10)

OPP
H H OPP

B: nucleophilic
electrophilic OPP farnesyl pyrophosphate (C15) 22
tail group
head group
 OPP PPO

squalene
synthase

Conversion of genanyl-PP to monoterpenes

Limonene & -Terpineol
OPP
OPP
- H+
OPP
H
H2 O :B
geranyl neryl
diphosphate diphosphate
C=C bond acts limonene
as a nucleophile

HO

-terpineol 23
 H
12 17

26.11: Steroids. 2
1
11
10
9
C
13
D
14
16
H
H

A 8 15
B
3 7 H H
5
4 6 HO Cholesterol (C27H46O)

Cholesterol biosynthesis (mechanism 26.3, p. 1089)

part a: the cyclization
Squalene
epoxidase

Heme , O2 O

Squalene (C30H50) H A
Squalene Oxide (C30H50O)

Squalene
cyclase +
HO HO
+

HO HO
+ +

HO
+ HO
+

HO +

24
Protosterol cation
Cholesterol biosynthesis, part b: the 1,2-shifts
CH3 H
CH3 H CH3 CH3
CH3 CH3 1,2-hydride
H shift HO +
HO
+ H3C H
H 3C H CH3
H CH3 H
H
Protosterol cation (C30H50O)

H
CH3 H CH3 H H3C
1,2-hydride H
CH3 CH3 1,2-methyl CH3
shift
shift
HO HO H
+ H
H3C H3C +
H CH3 H CH3
B:
CH3
H CH3
1,2-methyl CH3 H H3C CH3
shift CH3 - H+
HO
HO H H
H3C CH3
H3C + H
H H 3C
Lanosterol (C30H50O)

H H

H H
H

H H
HO HO
H

Lanosterol (C30H50O) Cholesterol (C27H46O)

25
26.12: Vitamin D. (please read)
H
H

H
H
sunlight

H
H H
HO HO
Vitamin D3
7-Dehydrocholesterol

26.13: Bile Acids. (please read)

26.14: Corticosteroids. (please read)

O
OH
O OH
H

H H
O
Cortisone

26
26.15: Sex hormones. (please read)
androgens (male)
H3C OH O O OH
H3C H3C H3C
CH3
H3C H H3C H H3C H H3C H

H H H H H H H H
O HO O O
H
Testosterone Androsterone Androstenedione dianabol

estrogens (female)
O
H3C O
H3C OH H3C H3C OH
C CH
H H H H

H H H H H H H H
HO HO HO HO

Estrone Estradiol Progesterone Ethynylestradiol

26.16: Carotenoids. (please read) derived from phytocene (C40)

Lycopene

-carotene 27