21
22
24
26
19
Cholesterol
Fig.16.1. Cholesterol (5-cholesten-3~-ol)
derable problems with nomenclature, and trivial
names are often used instead of the systematic
names derived, according to certain rules, from
the structural elements [25, 133].
16.1 Biosynthesis of Cholesterol
The complicated reaction series of cholesterol
biosynthesis is more easily understood when it is
considered in separate parts [25]. The biosynAcetacetyl- GoA
Acetyl-GoA ~ ®
["COA
16.1 Biosynthesis of Cholesterol
625
thetic pathway begins with the production of
mevalonate from acetyl-CoA and its conversion
to the "active isoprenoids" isopentenyl and dimethylallyl pyrophosphate (Fig. 16.2). Condensation of these Cs components leads to the CIS compound farnesyl pyrophosphate, from which arise
various higher polyprenols such as dolichol, terpenes, the ubiquinone side-chain, the juvenile
hormones of the insects and, finally, squalene and
cholesterol. Two molecules of farnesyl pyrophosphate produce the C30 polyprenol squalene
by head-to-head condensation. The formation of
cholesterol by the cyclization of squalene requires
oxygen. Thus, the sterols can have arisen on the
earth only after the appearance of oxygen in the
atmosphere. In the prokaryotes and several
primitive eukaryotes, squalene is cyclicized, without the participation of oxygen, to the so-called
hopanoids, which here assume the role of the sterols as membrane components [92]. The ciliate
Tetrahymena also produces a hopanoid-like triterpene, tetrahymanol (Fig. 16.3). The nature of the
Acetyl-GoA
. /
2NADPH
2NADP+
Acetyl-GoA
HO" /CH3
~
HOOC-CH2-C-CH2-C.-v SCoA
+ 2H+
HO" /CH 3
--~~-L~---HOOC-CH2-C-CH2-CH20H
Fig.16.2. The biosynthesis
of active isoprenoids and
squalenes. 1, AcetoacetylCoA thiolase; 2, 3-hydroxy-3methylglutaryl-CoA synthetase (HMG-CoA synthetase);
3, HMG-CoA reductase;
4, mevalonate-5-phosphotransferase; 5, phosphomevalonate kinase; 6, pyrophosphomevalonate decarboxylase; 7, isopentenylpyrophosphate isomerase
HMG-CoA
Dimethylallyl-pyrophosphate
C5
I
~o-®-®
HSGoA
@
.......
Isopentenyl- pyrophosphate
C'
I
5~0_®_®
C5+CS+C5 -
C15 Farnesyl-pyrophosphate
2C15 -
C30 Squalene
22
24
26
19
Cholesterol
Fig.16.1. Cholesterol (5-cholesten-3~-ol)
derable problems with nomenclature, and trivial
names are often used instead of the systematic
names derived, according to certain rules, from
the structural elements [25, 133].
16.1 Biosynthesis of Cholesterol
The complicated reaction series of cholesterol
biosynthesis is more easily understood when it is
considered in separate parts [25]. The biosynAcetacetyl- GoA
Acetyl-GoA ~ ®
["COA
16.1 Biosynthesis of Cholesterol
625
thetic pathway begins with the production of
mevalonate from acetyl-CoA and its conversion
to the "active isoprenoids" isopentenyl and dimethylallyl pyrophosphate (Fig. 16.2). Condensation of these Cs components leads to the CIS compound farnesyl pyrophosphate, from which arise
various higher polyprenols such as dolichol, terpenes, the ubiquinone side-chain, the juvenile
hormones of the insects and, finally, squalene and
cholesterol. Two molecules of farnesyl pyrophosphate produce the C30 polyprenol squalene
by head-to-head condensation. The formation of
cholesterol by the cyclization of squalene requires
oxygen. Thus, the sterols can have arisen on the
earth only after the appearance of oxygen in the
atmosphere. In the prokaryotes and several
primitive eukaryotes, squalene is cyclicized, without the participation of oxygen, to the so-called
hopanoids, which here assume the role of the sterols as membrane components [92]. The ciliate
Tetrahymena also produces a hopanoid-like triterpene, tetrahymanol (Fig. 16.3). The nature of the
Acetyl-GoA
. /
2NADPH
2NADP+
Acetyl-GoA
HO" /CH3
~
HOOC-CH2-C-CH2-C.-v SCoA
+ 2H+
HO" /CH 3
--~~-L~---HOOC-CH2-C-CH2-CH20H
Fig.16.2. The biosynthesis
of active isoprenoids and
squalenes. 1, AcetoacetylCoA thiolase; 2, 3-hydroxy-3methylglutaryl-CoA synthetase (HMG-CoA synthetase);
3, HMG-CoA reductase;
4, mevalonate-5-phosphotransferase; 5, phosphomevalonate kinase; 6, pyrophosphomevalonate decarboxylase; 7, isopentenylpyrophosphate isomerase
HMG-CoA
Dimethylallyl-pyrophosphate
C5
I
~o-®-®
HSGoA
@
.......
Isopentenyl- pyrophosphate
C'
I
5~0_®_®
C5+CS+C5 -
C15 Farnesyl-pyrophosphate
2C15 -
C30 Squalene