Download acetyl coenzyme A - Fakultas Farmasi Unand

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
Structure of Coenzyme A
O O
HO
P
O
P
O
O
HO P O
HO
HO
O
N
OH
OH
H
H
N
N
O
SR
H3C
CH3 O
O
N
NH2
N
N
R = H; Coenzyme A
O
R = CCH3; Acetyl coenzyme A
26- 2
Reactivity of Coenzyme A
Nucleophilic acyl substitution
O
CH3CSCoA
HY ••
O
CH3C
Y •• + HSCoA
Acetyl coenzyme A is a source of an acetyl group
toward biological nucleophiles; it is an acetyl transfer
agent.
26- 3
Reactivity of Coenzyme A
can react via enol
O
OH
H2C
CH3CSCoA
CSCoA
E+
Acetyl coenzyme A reacts
with biological electrophiles at
its  carbon atom.
O
E
CH2CSCoA
26- 4
Fats and Oils
O
O CH2OCR'
RCOCH
CH2OCR"
O
Fats and oils are naturally occurring mixture of
triacylglycerols (also called triglycerides).
Fats are solids; oils are liquids.
26- 5
Fats and Oils
O
O CH2OC(CH2)16CH3
CH3(CH2)16COCH
CH2OC(CH2)16CH3
O
Tristearin; mp 72°C
26- 6
Fats and Oils
O
O CH2OC(CH2)16CH3
CH3(CH2)6CH2
C
H
CH2(CH2)6COCH
C
CH2OC(CH2)16CH3
H
O
2-Oleyl-1,3-distearylglycerol; mp 43°C
26- 7
Fats and Oils
2-Oleyl-1,3-distearylglycerol
mp 43°C
H2, Pt
Tristearin
mp 72°C
26- 8
Fatty Acids
O
O
O CH2OCR
O
H2O
R'COCH
CH2OCR"
R'COH
CH2OH
HOCR
HOCH
CH2OH
HOCR"
O
O
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
Table 26.1
Systematic name Common name
O
CH3(CH2)10COH
Dodecanoic acid
Lauric acid
Tetradecanoic acid
Myristic acid
O
CH3(CH2)12COH
O
CH3(CH2)14COH
Hexadecanoic acid Palmitic acid
26- 10
Table 26.1
Systematic name Common name
O
CH3(CH2)16COH
Octadecanoic acid
Stearic acid
Icosanoic acid
Arachidic acid
O
CH3(CH2)18COH
26- 11
Table 26.1
O
CH3(CH2)7
(CH2)7COH
C
H
C
H
Systematic name: (Z)-9-Octadecenoic acid
Common name: Oleic acid
26- 12
Table 26.1
O
CH3(CH2)4
C
H
(CH2)7COH
CH2
C
C
H H
C
H
Systematic name: (9Z, 12Z)-9,12-Octadecadienoic acid
Common name: Linoleic acid
26- 13
Table 26.1
O
CH3CH2
C
H
C
C
H H
Systematic name:
(CH2)7COH
CH2
CH2
C
C
H H
C
H
(9Z, 12Z, 15Z)-9,12,15Octadecatrienoic acid
Common name: Linolenic acid
26- 14
Table 26.1
O
OH
H
H
H
H
H
H
H
Systematic name:
H
(5Z, 8Z, 11Z, 14Z)-5,8,11,14Icosatetraenoic acid
Common name: Arachidonic acid
Dr. Wolf's CHM 424
26- 15
trans-Fatty Acids
Are formed by isomerization that can occur when
esters of cis-fatty acids are hydrogenated.
H
O
H
OR
H2, cat
O
OR
Dr. Wolf's CHM 424
26- 16
H
O
OR
H
H
O
H
OR
H2, cat
O
OR
Dr. Wolf's CHM 424
26- 17
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
Fatty Acid Biosynthesis
An early step in fatty acid biosynthesis is the reaction
of acyl carrier protein with acetyl coenzyme A.
O
CH3CSCoA + HS—ACP
O
CH3CS—ACP
+ HSCoA
26- 19
Fatty Acid Biosynthesis
A second molecule of acetyl coenzyme A reacts at its 
carbon atom with carbon dioxide (as HCO3–) to give
malonyl coenzyme A.
O
–
+
HCO3
CH3CSCoA
Acetyl
coenzyme A
O
O
–
OCCH2CSCoA
Malonyl
coenzyme A
26- 20
Fatty Acid Biosynthesis
Malonyl coenzyme A then reacts with acyl carrier
protein.
O
O
O
–
OCCH2CS—ACP
ACP—SH
O
–
OCCH2CSCoA
Malonyl
coenzyme A
26- 21
Fatty Acid Biosynthesis
Malonyl—ACP and acetyl—ACP react by carboncarbon bond formation, accompanied by
decarboxylation.
O
CH3C
S—ACP
O
CH3C
– ••
•• O
••
O
C
O
CH2CS—ACP
O
CH2CS—ACP
S-Acetoacetyl—ACP
26- 22
Fatty Acid Biosynthesis
In the next step, the ketone carbonyl is reduced to a
secondary alcohol.
OH
CH3C
H
O
CH2CS—ACP
NADPH
O
CH3C
O
CH2CS—ACP
S-Acetoacetyl—ACP
26- 23
Fatty Acid Biosynthesis
The alcohol then dehydrates.
OH
CH3C
O
CH2CS—ACP
O
CH3CH
CHCS—ACP
H
26- 24
Fatty Acid Biosynthesis
Reduction of the double bond yields
ACP bearing an attached butanoyl group.
Repeating the process gives a 6-carbon acyl group,
then an 8-carbon one, then 10, etc.
O
CH3CH2CH2CS—ACP
O
CH3CH
CHCS—ACP
26- 25
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
CH2OH
HO
O
+
H
O
RCSCoA
+ R'CSCoA
CH2OPO3H2
The diacylated
species formed in
this step is called a
phosphatidic acid.
O
O
R'CO
CH2OCR
H
CH2OPO3H2Dr. Wolf's CHM 424
26- 27
O
O
R'CO
CH2OCR
H
CH2OH
The phosphatidic
acid then
undergoes
hydrolysis of its
phosphate ester
function.
H2O
O
O
R'CO
CH2OCR
H
CH2OPO3H2Dr. Wolf's CHM 424
26- 28
O
O
R'CO
CH2OCR
H
CH2OH
O
R"CSCoA
O
R'CO
Reaction with a
third acyl coenzyme
A molecule yields
the triacylglycerol.
O
CH2OCR
H
O
CH2OCR"
Dr. Wolf's CHM 424
26- 29
Phosphatidylcholine
Phosphatidic acids are intermediates in the formation of
phosphatidylcholine.
O
O
R'CO
CH2OCR
H
CH2OPO3H2
O
O
R'CO
CH2OCR
H
CH2OPO2–
+
(CH3)3NCH2CH2O
Dr. Wolf's CHM 424
26- 30
Phosphatidylcholine
O
O
R'CO
hydrophobic "tail"
CH2OCR hydrophobic "tail"
H
CH2OPO2–
+
(CH3)3NCH2CH2O
polar "head group"
26- 31
Phosphatidylcholine
hydrophobic
(lipophilic) "tails"
hydrophilic "head group"
26- 32
Cell Membranes
water
Cell membranes are
"lipid bilayers." Each
layer has an assembly of
phosphatidyl choline
molecules as its main
structural component.
water
26- 33
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
26- 34
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.
O
CH3(CH2)14COCH2(CH2)28CH3
Triacontyl hexadecanoate: occurs in beeswax
26- 35
Prostaglandins
Prostaglandins are involved in many biological
processes.
Are biosynthesized from linoleic acid (C18) via
arachidonic acid (C20). (See Table 26.1)
26- 36
Examples: PGE1 and PGF1
O
O
OH
HO
OH
O
HO
OH
HO
PGE1
OH
PGF1
26- 37
Prostaglandin Biosynthesis
PGE2 is biosynthesized from arachidonic acid
The oxygens come from O2
The enzyme involved (prostaglandin endoperoxide
synthase) has cyclooxygenase (COX) acitivity
26- 38
Prostaglandin Biosynthesis
CO2H
CH3
Arachidonic acid
O2
fatty acid cyclooxygenase
O
CO2H
O
HOO
CH3
PGG2
26- 39
Prostaglandin Biosynthesis
O
CO2H
O
HO
PGH2
CH3
reduction of
hydroperoxide
O
CO2H
O
HOO
CH3
PGG2
26- 40
Prostaglandin Biosynthesis
O
CO2H
O
HO
O
CH3
CO2H
CH3
HO
PGH2
HO
PGE2
Dr. Wolf's CHM 424
26- 41
Icosanoids
Icosanoids are compounds related to icosanoic acid
CH3(CH2)18CO2H.
Icosanoids include:
prostaglandins
thromboxanes
prostacyclins
leukotrienes
Dr. Wolf's CHM 424
26- 42
Thromboxane A2 (TXA2)
Thromboxane A2 is biosynthesized from PGH2
O
CO2H
O
HO
PGH2
CH3
TXA2 promotes platelet
aggregation and blood clotting
O
CO2H
O
HO
TXA2
CH3
Dr. Wolf's CHM 424
26- 43
Prostacyclin I2 (PGI2)
Like thromboxane A2, prostacyclin I2 is
biosynthesized from PGH2
HO2C
O
PGI2 inhibits platelet
aggregation and relaxes
coronary arteries
CH3
HO
OH
Dr. Wolf's CHM 424
PGI
26-244
Leukotriene 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.
26- 45
Leukotriene C4 (LTC4)
OH
CO2H
O
S
CH2CHCNHCH2CO2H
CH3
–
O2CCHCH2CH2
NH
C
O
+ NH3
26- 46
Terpenes
Terpenes are natural products that are
structurally related to isoprene.
CH3
H2C
C
CH
CH2
or
Isoprene
(2-methyl-1,3-butadiene)
26- 47
Terpenes
Myrcene (isolated from oil of bayberry) is a
typical terpene.
CH3
CH3C
CH2
CHCH2CH2CCH
CH2
or
26- 48
The Isoprene Unit
An isoprene unit is the carbon skeleton of isoprene
(ignoring the double bonds)
Myrcene contains two isoprene units.
26- 49
The Isoprene Unit
The isoprene units of myrcene are joined "head-to-tail."
head
tail
tail head
26- 50
Table 26.2
Classification of Terpenes
Class
Number of carbon atoms
Monoterpene
10
Sesquiterpene
15
Diterpene
20
Sesterpene
25
Triterpene
30
Tetraterpene
40
26- 51
Figure 26.6
Representative Monoterpenes
OH
O
H
-Phellandrene
Menthol
(eucalyptus)
(peppermint)
Citral
(lemon grass)
26- 52
Figure 26.6
Representative Monoterpenes
OH
O
H
-Phellandrene
Menthol
(eucalyptus)
(peppermint)
Citral
(lemon grass)
26- 53
Figure 26.6
Representative Monoterpenes
-Phellandrene
Menthol
(eucalyptus)
(peppermint)
Citral
(lemon grass)
26- 54
Figure 26.6
Representative Sesquiterpenes
H
-Selinene
(celery)
Dr. Wolf's CHM 424
26- 55
Figure 26.6
Representative Sesquiterpenes
H
-Selinene
(celery)
Dr. Wolf's CHM 424
26- 56
Figure 26.6
Representative Sesquiterpenes
-Selinene
(celery)
Dr. Wolf's CHM 424
26- 57
Figure 26.6
Representative Diterpenes
OH
Vitamin A
26- 58
Figure 26.6
Representative Diterpenes
OH
Vitamin A
26- 59
Figure 26.6
Representative Diterpenes
Vitamin A
26- 60
Figure 26.6
Representative Triterpene
tail-to-tail linkage of isoprene units
Squalene
(shark liver oil)
26- 61
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
The Biological Isoprene
Unit
O
O
3 CH3COH
CH3
HOCCH2CCH2CH2OH
OH
Mevalonic acid
CH3
H2C
O O
CCH2CH2OPOPOH
Isopentenyl pyrophosphate
Dr. Wolf's CHM 424
26- 63
Isopentenyl
Pyrophosphate
CH3
H2C
O O
CCH2CH2OPOPOH
or
OPP
Isopentenyl pyrophosphate
Dr. Wolf's CHM 424
26- 64
Isopentenyl and Dimethylallyl
Pyrophosphate
Isopentenyl pyrophosphate is interconvertible with
2-methylallyl pyrophosphate.
OPP
Isopentenyl pyrophosphate
OPP
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
Carbon-Carbon Bond
Formation
OPP
+
OPP
The key process involves the double bond of isopentenyl
pyrophosphate acting as a nucleophile toward the allylic
carbon of dimethylallyl pyrophosphate.
26- 66
Carbon-Carbon Bond
Formation
OPP
+
OPP
–
OPP
+
OPP
26- 67
After C—C Bond
Formation...
OPP
The carbocation
can lose a proton to
give a double bond.
–H
+
+
OPP
26- 68
After C—C Bond
Formation...
OPP
This compound is called geranyl pyrophosphate. It can
undergo hydrolysis of its pyrophosphate to give geraniol
(rose oil).
26- 69
After C—C Bond
Formation...
OPP
H2O
OH
Geraniol
26- 70
From 10 Carbons to 15
OPP
+
OPP
Geranyl pyrophosphate
+
OPP
26- 71
From 10 Carbons to 15
OPP
–H
+
+
OPP
26- 72
From 10 Carbons to 15
OPP
This compound is called farnesyl pyrophosphate.
Hydrolysis of the pyrophosphate ester gives the
alcohol farnesol (Figure 26.6).
26- 73
From 15 Carbons to 20
OPP
OPP
Farnesyl pyrophosphate is extended by another
isoprene unit by reaction with isopentenyl
pyrophosphate.
26- 74
Cyclization
Rings form by intramolecular carbon-carbon bond
formation.
+
OPP
OPP
E double
bond
Z double
bond
26- 75
Limonene
–H
+
+
OH
H2O
-Terpineol
Dr. Wolf's CHM 424
26- 76
Bicyclic Terpenes
+
+
+
+
-Pinene
-Pinene
Dr. Wolf's CHM 424
26- 77
Recall
O
O
3 CH3COH
CH3
HOCCH2CCH2CH2OH
OH
Mevalonic acid
CH3
H2C
O O
CCH2CH2OPOPOH
Isopentenyl pyrophosphate
26- 78
Biosynthesis of
Mevalonic Acid
In a sequence analogous to the early steps of fatty
acid biosynthesis, acetyl coenzyme A is converted to Sacetoacetyl coenzyme A.
O
O
CH3CCH2CSCoA
S-Acetoacetyl
coenzyme A
26- 79
Biosynthesis of
Mevalonic Acid
O
O
O
CH3CCH2CSCoA + CH3CSCoA
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
Biosynthesis of
Mevalonic Acid
O
O
O
CH3CCH2CSCoA + CH3CSCoA
HO
O
CH3CCH2CSCoA
CH2COH
O
26- 81
Biosynthesis of
Mevalonic Acid
Next, the acyl coenzyme A function is reduced.
The product of this reduction is mevalonic acid.
HO
O
CH3CCH2CSCoA
CH2COH
O
26- 82
HO
CH3CCH2CH2OH
Mevalonic
acid
CH2COH
O
HO
O
CH3CCH2CSCoA
CH2COH
O
26- 83
Isopentenyl
Pyrophosphate
2–
HO
OPO3
CH3CCH2CH2OH
CH3CCH2CH2OPP
CH2COH
CH2COH
O
O
The two hydroxyl groups of mevalonic acid undergo
phosphorylation.
Dr. Wolf's CHM 424
26- 84
Isopentenyl
Pyrophosphate
3–
2–
OPO3
OPO3
CH3CCH2CH2OPP
CH2
O
CH3CCH2CH2OPP
CH2
C
O
C
•• –
O ••
••
O
Phosphorylation is followed by a novel elimination
involving loss of CO2 and PO43–.
Dr. Wolf's CHM 424
26- 85
Isopentenyl
Pyrophosphate
CH3CCH2CH2OPP
CH2
The product of this elimination is isopentenyl
pyrophosphate.
Dr. Wolf's CHM 424
26- 86
based on experiments
with 14C-labeled acetate
O
O
CH3COH
CH3
HOCCH2CCH2CH2OH
OH
Mevalonic acid
CH3
H2C
O O
CCH2CH2OPOPOH
Isopentenyl pyrophosphate
26- 87
based on experiments
with 14C-labeled acetate
Citronellal biosynthesized using 14C-labeled acetate as
the carbon source had the labeled carbons in the
positions indicated.
CH3
O
CH3COH
H2C
•
•
•
•
•
O O
CCH2CH2OPOPOH
O
•
H
26- 88
Structure of Cholesterol
Fundamental framework of steroids is the tetracyclic
unit shown.
26- 89
Structure of Cholesterol
CH3
CH3
CH3
H
CH3
CH3
H
H
HO
Cholesterol has the fundamental steroid skeleton
modified as shown.
26- 90
Structure of Cholesterol
CH3
CH3
CH3
H
CH3
CH3
H
H
HO
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
Biosynthesis of
Cholesterol
Cholesterol is biosynthesized from the triterpene
squalene. In the first step, squalene is converted to its
2,3-epoxide.
O2, NADH, enzyme
O
26- 92
Biosynthesis of
Cholesterol
O
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
26- 93
Biosynthesis of
Cholesterol
HO
+
H
Cyclization is triggered by epoxide ring opening.
H+ O
26- 94
Biosynthesis of
Cholesterol
HO
+
H
The five-membered ring expands to a six-membered one.
H
HO
+
H
26- 95
Biosynthesis of
Cholesterol
H
+
HO
protosteryl cation
H
Cyclization to form a tetracyclic carbocation.
H
HO
+
H
26- 96
Biosynthesis of
Cholesterol
••
•• OH
2
H
HO
+
H
H
Deprotonation and multiple migrations.
H
HO
H
26- 97
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.
H
HO
H
26- 98
Cholesterol
Cholesterol is the biosynthetic precursor to a large
number of important steroids:

Bile acids
Vitamin D
Corticosteroids
Sex hormones
26- 99
Cholesterol
CH3
CH3
CH3
H
CH3
CH3
H
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.
26- 100
7-Dehydrocholesterol
CH3
CH3
CH3
CH3
H
CH3
H
HO
Sunlight converts 7-dehydrocholesterol on the skin's
surface to vitamin D3.
26- 101
Vitamin D3
CH3
CH3
CH3
CH3
H
HO
Insufficient sunlight can lead to a deficiency of vitamin
D3, interfering with Ca2+ transport and bone
development. Rickets can result.
26- 102
Cholesterol
CH3
CH3
CH3
H
CH3
CH3
H
H
HO
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
Cholic Acid
O
HO CH3
CH3
CH3
H
HO
OH
H
H
OH
H
Salts of cholic acid amides (bile salts), such as sodium
taurocholate (next slide), act as emulsifying agents to aid
digestion.
26- 104
Sodium Taurocholate
O
HO CH3
CH3
CH3
H
HO
NHCH2CH2SO3Na
H
H
OH
H
26- 105
Cholesterol
CH3
CH3
CH3
H
CH3
CH3
H
H
HO
Enzymatic degradation of the side chain and oxidation of
various positions on the steroid skeleton convert cholesterol
to corticosteroids.
26- 106
Cortisol
O
CH3
HO
CH3
H
OH
OH
H
H
O
Cortisol is the most abundant of the corticosteroids. Enzymecatalyzed oxidation of cortisol gives cortisone.
26- 107
Cortisone
O
CH3
OH
O
CH3
H
OH
H
H
O
Corticosteroids are involved in maintaining electrolyte
levels, in the metabolism of carbohydrates, and in
mediating the allergic response.
26- 108
Testosterone
H3C
H3C
OH
H
H
H
O
Testosterone is the main male sex hormone.
26- 109
Estradiol
H3C
OH
H
H
H
HO
Estradiol is a female sex hormone involved in regulating
the menstrual cycle and in reproduction.
26- 110
Progesterone
O
H3C
H3C
H
H
H
O
Supresses ovulation during pregnancy.
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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.
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Carotenoids
Lycopene (tomatoes)
-Carotene (carrots)
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