7. Triterpenes and Sterols
RA Macahig
FM. Dayrit
H
H
3C
H
H
3C
C
H
3
H
C
H
3
H
C
H
3
C
H
3
H
H
O
H
lanosterol
H
O
cholesterol
Introduction
Triterpenes and sterols comprise a large group of distinctive
polycyclic terpenes.
• Triterpenes are C30 compounds which have four or five
fused cyclohexyl rings.
• Sterols are C21 to C29 compounds with a characteristic
fused ring system of three cyclohexyl rings and one
cyclopentyl ring.
• Triterpenes and sterols can be isolated in free form,
glycosylated, or bound to fatty acids.
• Sterols are well known to have important hormonal activity
in insects and mammals (including humans).
7.0 Triterpenes & steroids (Dayrit)
2
Squalene
Triterpenes arise from the reductive dimerization of two
farnesyl diphosphate chains (2 x C15) which condense in a
head-to-head manner to form squalene.
• Squalene is the key intermediate in the biosynthetic
pathway to the two key triterpene intermediates:
cycloartenol (in plants) and lanosterol (in animals).
Important features of squalene:
• It does not have a -OPP leaving group.
• It is a symmetric molecule.
7.0 Triterpenes & steroids (Dayrit)
3
Biosynthetic mechanism for the head-to-head dimerization of two
farnesyl diphosphate chains to produce squalene.
H
OPP
R
R
H
R
PPO
PPO
R
X
X
_
+
-H _
-X
H
D
H
R
R
_
D
H
NADP(D) R
-OPP
+
H
R
R
PPO
R
D
squalene
7.0 Triterpenes & steroids (Dayrit)
4
Squalene
Squalene itself is found in large quantities in shark liver oil,
thus its name (squalus = shark). It is also obtained from
vegetable oils, such as rice bran, wheat germ, and olives. It is
marketed as a cosmetic and health supplement for protection
against oxidative processes which lead to aging, atherosclerosis
and other immune diseases.
Squalene is found only in the all-trans double-bond
configuration. All variations of structures among triterpenes
arise from the conformation of folding; there are no geometric
isomers of double bonds.
7.0 Triterpenes & steroids (Dayrit)
5
OPP
Overview of squalene formation
and the biogenetic relationships of
triterpenes and sterols.
DMAPP
IPP
2x
OPP
OPP + PPO
(farnesyl pyrophosphate, C15) x 2
squalene, C30
epoxidation
2
O
3
(3S)-2,3-oxidosqualene
cyclization
21
7.0 Triterpenes & steroids (Dayrit)
18
11
22
20
17
6
26
27
epoxidation
2
3
O
(3S)-2,3-oxidosqualene
cyclization
21
22
26
20
18
17
19 11
27
13
1
10
3
28
HO
29
21
18
19 11
1
22
20
21
17
18
13
19
10
3
Cycloartenol
30
11
1
28
HO
20
22
26
17
27
13
10
29
30
3
Lanosterol
(29 Triterpene skeletal types)
7.0 Triterpenes & steroids (Dayrit)
HO
5
6
Cholesterol
7
Early studies on the enzymes involved in cholesterol biosynthesis proposed that
all the enzymes involved in the conversion of acetyl-CoA to farnesyl diphosphate
(FPP), with the exception of 3-hydroxy-3-methylglutaryl-coenzyme A reductase
(HMG-CoA reductase), are cytosolic or are located on the endoplasmic reticulum.
This study shows that FPP is found in peroxisomes.
Peroxisomes are ubiquitous organelles in eukaryotic cells
that participate in the metabolism of fatty acids and other
metabolites. Peroxisomes have a single lipid bilayer
membrane that separates their contents from the cytosol
TEM of peroxisome
(the internal fluid of the cell) and contain membrane
showing crystalline and
proteins critical for various functions.
non-crystalline inclusions
7.0 Triterpenes & steroids (Dayrit)
8
2,3-Oxidosqualene cyclase is an integral membrane enzyme that catalyzes the
cyclization of squalene epoxide to lanosterol. The solubilized enzyme was
purified to homogeneity by fast protein liquid chromatography. The purified
enzyme consists of a single subunit that has an apparent molecular weight of
65,000 as determined by sodium dodecyl sulfate-polyacrylamide gel
electrophoresis (SDS-PAGE). The enzyme obeys saturation kinetics
and the apparent Km of (2,3)-oxidosqualene is 15 mM and the apparent kcat/Km
is 200 M-1 min-1.
7.0 Triterpenes & steroids (Dayrit)
9
Terpene biosynthetic pathways differ in prokaryotes and eukaryotes. The two pathways shown
here diverge after presqualene diphosphate.
(A) Staphyloxanthin biosynthesis in S. aureus. The NADPH reduction step is absent, resulting in formation of
dehydrosqualene, not squalene.
(B) Steroid biosynthesis in humans and yeasts passes through squalene.
(Liu et al., Science 319, 1391 -1394 (2008))
S. aureus: CrtM
Humans and yeast:
squalene synthase (SQS)
7.0 Triterpenes & steroids (Dayrit)
10
Overview of cyclization reactions in triterpenes
•
The triterpene structures are formed from the enzymecatalyzed cyclization of squalene. The first step involves the
activation of the asymmetric squalene by epoxidation of a
terminal olefin group producing the chiral intermediate
(3S)-2,3-oxidosqualene.
•
Various modes of cyclization produce 29 major triterpene
skeletal types plus about 5 irregular ones. The main sources
of variation among the triterpenes are due to:
1. Conformation of folding (regiochemistry)
2. Conformation of folding (stereochemistry)
3. Skeletal rearrangements
4. Further chemical transformations, such as oxidation,
methylation, and glycosylation.
7.0 Triterpenes & steroids (Dayrit)
11
Overview of cyclization reactions in triterpenes
1. The conformation of folding: regiochemistry. (3S)-2,3oxidosqualene is folded into specific geometries under
enzyme control during the cyclization process. These
conformations are either chair or boat (c = chair; b = boat).
There are four conformational folding patterns:
a. To form tetracyclic products, two folding conformations
are observed: (c - c - c - b) and (c - b - c - b);
b. To form pentacyclic products, the folding conformations
are: (c - c - c - c - c) and (c - b - c - c - b); and
c. Irregular cyclization leads to other types of triterpenes.
7.0 Triterpenes & steroids (Dayrit)
12
Model for the oxidosqualene cyclase enzyme which controls the
transition state conformation of triterpene formation.
hydrophobic pocket
+
chair
AH
chair
O
boat
boat
Oxidosqualene cyclase enzyme
Each folding conformation and product is presumed to require
a unique enzyme. A number of cyclases have been isolated
and sequences from a number of plants and microorganisms,
as well as from pig liver, has been determined.
7.0 Triterpenes & steroids (Dayrit)
13
2. The conformation of folding: stereochemistry.
2
3
O
(3S)-2,3-oxidosqualene
"left-handed" coil
"right-handed" coil
3
H
+
+
O
3
2
O
H
2
cyclization
cyclization
HO
3
1
1
3
HO
(+) Tetrahymanol
(-) Tetrahymanol
7.0 Triterpenes & steroids (Dayrit)
14
A.c - c - c - b
CH3 R
Triterpenes:
an overview
H
CH3
CH3
CH3
CH3
CH3
CH3
HO
HO
H 3C
CH3
e u p h a n e
HO
t a r a x a s t e r o l s k e le t o n
CH3
CH3
CH3
CH3
CH3
HO
H
CH3
H 3C
CH3
H
CH3
H
H 3C
CH3
H
CH3
s k e el t o n
H 3C
lu p e o l s k e le t o n
a m
CH3
y r in
s k e le t o n
B.c - b - c - b
R
CH3
H
8
1 0
1 7
1 3
1 4
H
1 3
CH3
CH3
3
HO
R
CH3
1 0
H
3
HO
c y c lo a r t e n o l s k e le t o n
1 7
1 8
CH
H
1 4
8
1 9C H
3
CH3
1 3
R
3
1 7
H
1 0
3
H
la n o s t e r o l s k e le t Ho On
s t e r o id
g r o u p
C.c - c - c - c - c
H
H
H
H
C H3
C H3
C H3
H
C H3
C H3
C H3
C H3
H
HO
C H3
C H3
C H3
HO
H
h o p a n e
s k e le t o n
H
t e t r a h y m
a n e
s k e le t o n
D.c - b - c - c - b
CH3
1 8
1 7
1 1
C H3
H
1 3
1 4
H
2 1
H
CH3
C H3
C H3
15
C H3
HO
H 3C
H
C H3
a r b o r a n e
s k e le t o n
squalene
[O]
Chair - chair - chair boat conformation of
squalene folding to
form tetracyclic
triterpenes: the
Dammaranes.
O
H+
+
H
+
CH3
C H3
CH3
HO
HO
H 3C
C H3
dammarane skeleton
_
OH
OH
H
C H3
10
CH 3
C H3
H3 C
13
17
14
C H3
H
HO
H 3C
CH 3
CH 3
10 9
dammarenediol
H
13
C H3
17
14
1
HO
C H3
CH3
+
-H (9)
C H3
CH3
H
9
1
HO
H
+
C H3
H3 C
to Figure 8.6
CH 3
CH3
CH3
HO
H 3C
CH3
euphol (euphane skeleton)
16
squalene
Chair - chair chair - boat
conformation: the
Dammaranes.
[O]
O
H+
+
H
+
CH3
C H3
CH3
HO
HO
H 3C
C H3
dammarane skeleton
_
OH
OH
H
CH 3
C H3
10
C H3
H3 C
13
17
14
C H3
H
C H3
CH3
HO
+
-H (9)
H 3C
CH 3
CH 3
CH3
H
9
1
HO
H
+
dammarenediol
H
13
C H3
17
17
HO
H 3C
C H3
dammarane skeleton
_
OH
OH
H
C H3
10
CH 3
C H3
H3 C
13
17
14
C H3
H
HO
H 3C
CH 3
C H3
C H3
dammarenediol
H
13
17
14
1
HO
C H3
CH3
+
-H (9)
CH 3
10 9
CH3
H
9
1
HO
H
+
C H3
H3 C
to Figure 8.6
CH 3
CH3
CH3
HO
H 3C
CH3
euphol (euphane skeleton)
18
+
+
Further
modifications on
the dammarane
skeleton.
H
C H3
C H 3
HO
C H3
H O
H 3C
C H3
d a m m a r a n e s k e le t o n ( f r o m F ig u r e 8 .6 )
b o n d m ig r a t io n
H
b
a
+
C H3
a
b
+
CH3
C H3
HO
C H3
HO
H 3C
C H3
a
b
+
+
+
C H3
H
+
H
C H3
C H3
C H3
-H
+
1 , 2 - m e t h y l m ig r a t io n ;
-H +
C H3
H
H
CH3
C H 3
C H 3
H
C H 3
H O
H O
C H 3
C H 3
H
H 3C
H 3C
H
C H 3
C H 3
C H 3
ta ra x a s te ro l
lu p e o l
1 , 2 - m e t h y l m ig r a t io n
C H3
C H 3
C H3
CH3
C H3
H
H
H
C H3
C H 3
C H 3
O
H O
H 3C
C H 3
 - a m y r in
CH3
C H 3
f r ie d e lin
19
+
+
H
C H3
CH3
HO
C H3
HO
Further
modifications on
the dammarane
skeleton.
H 3C
C H3
d a m m a ra n e s k e le to n ( f r o m F ig u r e 8 .6 )
b o n d m ig ra tio n
H
b
a
+
C H3
a
b
+
CH3
C H3
HO
CH3
HO
H 3C
a
CH3
b
+
+
+
H
C H3
+
H
C H3
C H3
C H3
+
20
b o n d m ig ra tio n
H
b
a
+
C H3
a
b
+
CH3
C H3
HO
CH3
HO
H 3C
CH3
a
b
+
+
+
C H3
H
+
H
C H3
C H3
C H3
-H
+
1 ,2 - m e th y l m ig r a tio n ;
-H +
C H3
H
H
CH3
CH3
CH3
H
CH3
HO
HO
CH3
ta r a x a s te r o l
CH3
H
H 3C
H 3C
H
CH3
CH3
CH3
lu p e o l
21
a
b
+
+
+
C H3
H
+
H
C H3
C H3
C H3
-H
+
1 ,2 - m e th y l m ig r a tio n ;
-H +
C H3
H
H
CH3
CH3
CH3
H
CH3
HO
HO
CH3
CH3
H
H 3C
H 3C
H
CH3
CH3
CH3
ta r a x a s te r o l
lu p e o l
1 ,2 -m e th y l m ig ra tio n
C H3
CH3
C H3
CH3
CH3
H
H
H
C H3
CH3
CH3
O
HO
H 3C
CH3
 - a m y r in
CH3
CH3
f r ie d e lin
22
H
Chair-boatchair-boat
conformation:
Cycloartenol
and Lanosterol.
+
O
21
H
19
C H3
26
17
H
C H3
C H3
13
3
H
C H3
+
20
17
14
8
H3 C
19
H
10
HO
22
+
20
1
10
H
27
8
3
C H3
H
28
18
HO
H
29
30
protostane skeleton
-H
19
C H3
H
10
9
C H3
C H3
HO
H
C H3
+
20
17
14
8
H3 C
H
H
13
3
+
H
C H3
H
HO
H
H: 9  to 8
protosterol
H: 1 7 to 2 0
H: 1 3 to 17 
Me: 14 to 1 3
Me: 8 to 14 
+
-H (9 )
19
C H2 -H
C H3
+
9
10
HO
H
C H3
3
14
C H3
in plants
-H+(8 )
17
H
8
H
C H3
20
13
H
H3 C
in anim als
HO
H3 C
10
9
13
3
H3 C
14
C H3
H3 C
H3 C
10
H
C H3
9
3
13
H
H3 C
14
C H3
H
C H3
17
13
9
10
C H3
8
3
HO
H
lanosterol
H
H3 C
20
H
H 14
10
9
8
H3 C
C H3
18 C H
3
3
HO
H
20
H
14
20
17
H
8
17
13
20
17
H
8
H
C H3
19
H
C H3
-H+ (1 9)
C H3
HO
19
C H3
H3 C
19 CH
H
13
17
H
20
H
3
cycloartenol
10
H
3
HO
cholesterol
23
Chair-boat-chair-boat:
Cycloartenol and
Lanosterol.
H
+
O
21
H
19
C H3
C H3
13
3
H
CH3
+
20
17
14
8
19
H
10
H3 C
26
17
H
C H3
HO
22
+
20
1
10
H
27
8
3
C H3
H
28
18
HO
H
29
30
protostane skeleton
-H
19
C H3
H
10
9
CH3
C H3
HO
H
C H3
+
20
17
14
8
H3 C
H
H
13
3
+
H
C H3
H
HO
H
H: 9  to 8
protosterol
H: 1 7 to 20
H: 1 3 to 17 
Me: 14 to 13
Me: 8 to 14 
+
-H (9 )
19
C H2 -H
CH3
10
HO
+
9
H
8
H
H
C H3
3
H3 C
19
CH3
H3 C
14
C H3
13
20
17
H
CH3
-H+(8)
in anim als
HO
10
H3 C
9
13
3
H3 C
8
H
H
C H3
14
C H3
20
17
H
24
CH3
H
3
HO
H
cycloartenol and lanosterol.
29
30
protostane skeleton
-H
19
C H3
H
10
9
CH3
C H3
HO
H
C H3
+
20
17
14
8
H
H
13
3
H3 C
+
H
C H3
H
HO
H
H: 9  to 8
protosterol
H: 1 7 to 20
H: 1 3 to 17 
Me: 14 to 13
Me: 8 to 14 
+
-H (9 )
19
C H2 -H
CH3
+
9
10
HO
14
C H3
in plants
9
13
3
H3 C
14
C H3
H
13
H
14
CH3
10
CH3
17
H
20
H
20
H
9
8
C H3
3
HO
H3 C
17
H
14
20
17
H
8
13
13
20
17
H
8
H3 C
C H3
9
H
C H3
C H3
3
H
10
H
H3 C
CH3
H3 C
in anim als
HO
H3 C
-H+ (19)
19
HO
-H+(8)
17
H
8
H
CH3
20
13
H
H3 C
H
C H3
3
10
19
CH3
H3 C
H
lanosterol
25
3
H
C H3
C H3
H
HO
H
H: 9  to 8
protosterol
H: 1 7 to 20
H: 1 3 to 17 
Me: 14 to 13
Me: 8 to 14 
+
-H (9 )
19
C H2 -H
CH3
+
9
10
HO
H
C H3
3
14
C H3
in plants
-H+(8)
17
H
8
H
CH3
20
13
H
H3 C
in anim als
HO
H3 C
10
9
13
3
H3 C
14
C H3
H3 C
C H3
CH3
10
H
C H3
9
3
13
H
H3 C
14
CH3
H
CH3
17
13
9
10
C H3
8
H
lanosterol
H
20
H
H 14
10
9
8
H3 C
C H3
18 C H
3
3
HO
20
H
3
HO
H3 C
H
14
20
17
H
8
17
13
20
17
H
8
H
H3 C
H
C H3
-H+ (19)
19
HO
19
CH3
H3 C
19 CH
H
13
17
H
20
H
3
cycloartenol
10
H
3
HO
cholesterol
26
H+
A.
O
Unusual
triterpenes.
Ambrein and
malabaricol
are examples
of
interrupted
cyclization.
H+
O
OH
1. cyclization
2. reduction at
C3
3. epoxidation at
terminal olefin
OH
H
1. cyclization
2. reduction of terminal alcohol
OH
OH
H
Ambrein
OH+
B.
H+
O
OH
OH-
H
O
OH
H
H
(+) Malabaricol
7.0 Triterpenes & steroids (Dayrit)
27
Some important triterpenes
Corosolic acid (2-hydroxyursolic acid) has been identified as one
of the active constituents in the leaves of Banaba (Lagerstroemia
speciosa). It has been shown to lower blood sugar in animals. The
leaves are very popular as a remedy for diabetes. Maslinic acid
(2-hydroxyoleanolic acid), a structurally-related triterpene, has
also been identified in the leaves.
20
19
20
12
12
17
HO
2
14
17
CO2H
HO
14
2
CO2H
3
3
HO
HO
Corosolic acid
(2-hydroxyursolic acid)
Maslinic acid
(2-hydroxyoleanolic acid)
7.0 Triterpenes & steroids (Dayrit)
28
Triterpene glycosides
• In plants, triterpenes have been isolated in either of two forms:
in its free form as an aglycone (that is, without any sugar
attached) or as the glycoside (aglycone + sugar).
• It is likely that in many cases, the aglycone may have been an
artifact of the isolation process; for example, enzymes present
in the leaves may hydrolyze the triterpene glycosides, or the
extraction process itself may cause hydrolysis.
• At any rate, it is reasonable to assume that triterpene
glycosides are common constituents of plants and that many
triterpenes may exist in the glycoside form in the intact plant.
7.0 Triterpenes & steroids (Dayrit)
29
Ginseng is a very complex mixture of at least 31 ginsenoside
triterpenes. Ginseng is used in both traditional and modern
forms, especially for maintenance of health in old-age. It is
widely used in both Europe and East Asia. In 1994 retail sales in
Europe reached about $50M.
glucose
O
H H
O
O
H
H
O
O
O
O
arabinose
O
H
O
H
O
O
H
glucose
H
O
O
H
O
H
O
O
A
cO
H
O
H
O
O
O
O
H
ginsenoside Rs2
glucose-6-acetyl
7.0 Triterpenes & steroids (Dayrit)
30
Triterpenes: summary of cyclization modes: c-c-c-b
H+
O
+
H
+
CH3
CH3
CH3
HO
HO
H3C
CH3
dammarane skeleton
CH3
10
CH3
CH3
H3C
+
17
H
9
14
CH3
1
HO
H
13
H
+
-H (9)
CH3
CH3
CH3
1
HO
CH3
H3C
CH3
10 9
H
13
17
14
CH3
CH3
euphol (euphane skeleton)
HO
H3C
CH3
31
Introduction to sterols
The sterols make up a large group of compounds which are
derived from triterpenes and have the characteristic tetracyclic
ring ranging from C27 to C29. The various sterols are differentiated
by the following main structural features:
18
1. Side chain on C17 position
R
11
2. Modifications on the A-ring
17
19
13
D
C
3. Other modifications
14
8
10
4. Alcohol in the C3 position with the
A
B
3
5
exception of some human hormones.
steroid skelet
Notes on the structure:
• The C3-hydroxy is always .
• The A/B ring fusion can be cis or trans (5-H is  or ,
respectively).
7.0 Triterpenes & steroids (Dayrit)
32
Introduction to sterols
• Sterols are found in all kingdoms. In many organisms, these
are synthesized de novo from mevalonic acid  squalene; in
some, they are obtained from the diet; in others, they are both
synthesized and ingested.
• The sterols in the various kingdoms have characteristic
structural features, and so are classified according to their
respective kingdoms: e.g., mycosterols (fungi), phytosterols
(plants), marine sterols (sponges and other invertebrate marine
organisms), and zoosterols (animals).
• However, it is important to note that the occurrence of specific
sterol compounds is not always unique to an organism. For
example, although cholesterol is the prototypical zoosterol, it is
also produced by some algae and plants. On the other hand,
stigmasterol, a typical plant sterol, is not produced by animals.
7.0 Triterpenes & steroids (Dayrit)
33
Introduction to sterols
• Sterols perform diverse functions in various organisms. For
example, sterols are essential constituents of biological
membranes of different organisms. They function as hormones
and pheromones in a wide range of organisms ranging from
mammals to insects. Synthetic steroids have also been
developed to control or mediate in various aspects of human
physiology, disease and reproduction.
• Sterols are derived from the group of tetracyclic triterpenes
using the c-b-c-b folding conformation via a series of
transformations starting with lanosterol (in mammals) and
cycloartenol (in plants). The primary mammalian sterol is
cholesterol (C27) while the primary plant sterol is stigmasterol
(C29).
7.0 Triterpenes & steroids (Dayrit)
34
Introduction to sterols
In the literature, the sterols are also classified the following
groups, partly based on structure, and partly based on activity:
• sterols: steroidal skeleton with a C3 alcohol group
• cardiotonic sterols and steroidal saponins: physiologic activity
• ecdysones: insect hormones
• bile acids: modified steroids in humans
• steroidal hormones: steroids which affect physiology
7.0 Triterpenes & steroids (Dayrit)
35
From triterpenes to sterols: A. lanosterol to cholesterol in
mammals; B. cycloartenol to stigmasterol in plants and fungi.
2,3-Oxidosqualene
in plants and
fungi
in mammals
B. Plant sterols
A. Zoosterols
H3C
H
H3C
CH3
CH3
CH3
CH3
CH3
CH3
H
CH3
19
H
9
10
8
CH3
3
HO
H3C
CH3
3
HO
H
CH3
8
lanosterol
H3C
H
CH3
cycloartenol
29
H3C
H
18
CH3
19
CH3
13
21
20
17
H3C
HO
28
22
18
CH3
CH3
19
CH3
CH3
13
20
17
CH3
CH3
10
10
3
H
3
5
cholesterol (C27)
HO
5
stigmasterol (C29)
36
other mammalian steroids
other plant and fungal steroids
A. Mammalian steroids
24
18
Major
mammalian
sterol skeletal
structures.
(Estrogens and
some androgens
do not have the
C3 alcohol
group.)
CO2H
18
20
19
20
17
13
19
10
17
10
3
3
HO
sterols (C27)
HO
bile acids
18
18
20
19
17
13
19
10
3
HO
13
13
10
corticosteroids
and gestogens
3
(O)
androgens
18
13
estrogens
7.0 Triterpenes & steroids (Dayrit)
37
Major sterol
skeletal
structures in
plants and
fungi.
B. Plant and fungal steroids
R
18
20
20
13 17
19
O
18
13 17
19
10
O
10
3
3
H
O
spirostane (C2
steroidal sapon
O
phytosterols (C28, R
C29)
18
18
20
20
13 17
19
19
N
13 17
N
10
10
3
3
R
O
R
O
steroid alkaloids (C27)
7.0 Triterpenes & steroids (Dayrit)
38
Survey of some important sterols
Cholesterol is the principal zoosterol. It is
found in all body tissues of animals,
especially in cell membranes. Animal
tissues contain between 0.05% to 5% of
cholesterol; the brain contains 17%
cholesterol by weight. It is also found in
some higher plants.
-Sitosterol and -stigmasterol are the most
common phytosterols. These compounds
are often isolated as 3-O-glycosides. The
ethyl substituent at C24 has the Sconfiguration. -Sitosterol has a saturated
side-chain while -stigmasterol is 22,23.
18
20
19
H
10
3
17
13
14
H
H
5
HO
cholesterol
H
21
18
22
20
19
13
H
10
3
17
14
H
H
24S
5
HO
-sitosterol
-stigmasterol if 22,23
H
21
Ergosterol is a typical mycosterol (fungi).
It differs from the phytosterols in two
aspects: there is a methyl group at C24 with
the R configuration. Ergosterol has been
shown to arise from lanosterol in fungi.
18
22
20
19
13
24R
17
14
10
3
HO
7.0 Triterpenes & steroids (Dayrit)
5
H
H
7
ergosterol
39
Insect moulting hormones are steroidal
compounds called ecdysones. Insects
generally ingest steroids (e.g., cholesterol)
in their diet and metabolize these into
insect hormones.
22
20
25
OH
17
14
HO
2
3
5
HO
6
H
OH
7
ecdysone
O
H3C
Tomatidine is a steroidal alkaloid found in
the roots of the tomato plant. Tomatine, the
3-O-glycosylated derivative is found in the
leaves of the tomato plant.
N
20
CH3
25S
CH3
22
17
O
CH3
3
27
14
16
H
5
HO
Tomatidine
H
Soft corals (Coelenterata) produce marine
sterols which are derived from the 24methylene-cholesterane and pregnane
skeletons. Many of these compounds
feature extra hydroxyl and glycosidic
groups.
24
H
3
O
HO
HO
HO
O
H
H
7
OH
OH
3-Mannosyl-7 -hydroxy-24-methylenecholesterol
7.0 Triterpenes & steroids (Dayrit)
40
Phytosterols
• The path from squalene to sterols In plants and fungi:
squalene  cycloartenol  phytosterols and fungal sterols
1. Artificially introduced cycloartenol in plants is incorporated
into phytosterols.
2. In plants, cycloartenol is found in large amounts while
lanosterol is rare.
3. The conversion of cycloartenol to the phytosterols has also been
shown to follow a metabolic grid. Cycloartenol can be funneled
into two main pathways: methylation of the intermediate to C28
and C29 phytosterols, or formation of C27 sterols (which
includes cholesterol). The most common phytosterol is
stigmasterol which is a C29 compound.
7.0 Triterpenes & steroids (Dayrit)
41
Proposed pathway for the conversion of cycloartenol in plants to sitosterol.
24
24
1. [O] (C28,C29,C30)
2. -3CO2 (C28,C29,C30)
CH3
28
HO
H3C
HO
H
CH3
H
cycloartenol
29 30
29
28
22
*
*
28
*
24
24
H
3
H
3
HO
HO
5
5
7
ergosterol
sitosterol
(*) :
from methyl methionine
7.0 Triterpenes & steroids (Dayrit)
42
Proposed mechanism for the conversion of cycloartenol to phytosterols.
H
B2
19
9
10
H
B2
Enzyme
pocket
CH3
10
8
B3 HO
3
B3 HO
B1
Enzyme
H
9
8
B1
Cycloeucalenol
HB2
19
CH3
10
B3 HO
9
_
8
B1
Obtusifoliol
7.0 Triterpenes & steroids (Dayrit)
43
Phytosterols: mixed metabolites
B
.F
a
tty
a
c
y
lg
lu
c
o
s
y
ls
te
r
o
lf
r
o
m
a
m
p
a
la
y
a(M
o
m
o
r
d
ic
a
c
h
a
r
a
n
tia
)
.(
G
u
e
v
a
r
a
,S
y
lia
n
c
o
,D
a
y
r
it,
a
n
d
F
in
c
h
,P
h
y
to
c
h
e
m
.,2
8
,1
7
2
1
1
7
2
4
(
1
9
8
9
)
.
25
27
O
O6'
H
O
H
O
3
O
5
O
O
H
3 -O-[6 ' -O

-g
-Pa
l ulc
m
ois
to
yy
l ]-s
l - ti g m as ta -5,2 5 (2
7.0 Triterpenes & steroids (Dayrit)
44
Cardiotonic sterols
A. Cardiotonic glycosides
R
20
20
17
3
HO
5
zoos tero l o r
phytosterol
O
20
17
17
3
5
3
pre gneno lone
HO
O
5
progesterone
O
in toads
in plants
O
O
O
O
17
17
14
14
OH
3
HO
OH
5
3
digitoxigenin
H
7.0 Triterpenes & steroids (Dayrit)
16
HO
5
bufotalin
H
45
OAc
O
O
OH
HO
H
7.0 Triterpenes & steroids (Dayrit)
46
H+
A. Steroidal saponins
[O]
Steroidal
saponins
O
[O]
26
22
26
22
20
OH
20
17
16
17
16
OH
[O]
3
3
5
5
HO
HO
H
chole stero l
2[H]
H+
OH
26
OH
20
22
26
20
17
16
22 O
O
25R
17
16
O
3
5
HO
3
RO
5
H
diosgenin, R=H
dioscin, R= rhamnose(1->4)glucose(1->2)
rhamnose
26
20
17
16
22 O
O
HO
3
5
RO
H
OH
digitogenin, R=H
digitonin, R= xyl(1->3)glu(1->4)gal-(1->2)
glu(1->3)gal
47
Zoosterols
The conversion of lanosterol to cholesterol in mammals has been
extensively studied using rat liver tissues and in vitro enzyme
preparations. It has been found that there is no unique, sequential
biosynthetic pathway. That is, the enzymes which catalyze the
various transformations are not absolutely specific for a
particular substrate. It has also been observed that different
enzymes are able to catalyze the same reaction on different
substrates. The biosynthesis of cholesterol is best described as a
metabolic grid. Lanosterol is converted into cholesterol, the entry
compound for all of the steroids in mammals, and are called
zoosterols. In the animal liver, lanosterol is converted into
cholesterol, while cycloartenol is not metabolized. This sequence
of transformations in mammals is as follows:
squalene  lanosterol  cholesterol  steroid hormones
7.0 Triterpenes & steroids (Dayrit)
48
H
H3C
25
CH3
CH3
CH3
CH3
8
CH3
HO
H
CH3
H
CH3
[O]
8
H3C
CH3
CH3
CH3
HO
H3C
24
H
CH3
H3C
24,25-dihydrolanosterol
CHO
-CH 2 O
H3C
H
CH3
CH3
H3C
CH3
CH3
CH3
14
1. [O]
2. +2[H] (-14,15)
8
H
CH3
CH3
CH3
HO
H3C
8
HO
H
CO 2H
H
CH3
H3C
-CO 2
H3C
H
CH3
CH3
[O]
8
HO
H
H3C
CH3
CH3
8
HO
CH3
CH3
CH3
CH3
H
H3C
H
HO 2C
H
H
The pathway for
the conversion of
lanosterol to
cholesterol in
mammals is
believed to occur
through a
metabolic grid
where there is no
single pathway
and
transformations
occur in random
order.
1. -CO 2
2. +2[H] (-8,9)
3. -2[H] (+5,6)
H3C
H
18
CH3
19
CH3
13
20
17
3
HO
CH3
49
10
other mammalian steroids
CH3
5
cholesterol (C27)
Lanosterol to cholesterol.
H
H3C
25
CH3
CH3
CH3
CH3
8
CH3
HO
H
CH3
H
CH3
[O]
8
H3C
CH3
CH3
CH3
HO
H3C
24
H3C
24,25-dihydrolanosterol
CHO
H
CH3
-CH 2 O
H3C
H
CH3
CH3
H3C
14
8
HO
H
CO 2H
CH3
CH3
CH3
1. [O]
2. +2[H] (-14,15)
8
H
CH3
CH3
CH3
HO
H3C
H3C
H
CH3
-CO 2
H3C
CH3
H
H3C
CH3
CH3
H
50
CH3
Lanosterol to cholesterol. H3C
H
CH3
CH3
H3C
14
8
HO
H
CO 2H
CH3
CH3
CH3
1. [O]
2. +2[H] (-14,15)
8
H
CH3
CH3
CH3
HO
H3C
H
CH3
H3C
-CO 2
H3C
CH3
H
CH3
[O]
H
H3C
H
CH3
CH3
8
8
HO
CH3
CH3
CH3
CH3
H
H3C
HO
H
HO 2C
H
1. -CO 2
2. +2[H] (-8,9)
3. -2[H] (+5,6)
H3C
H
18
CH3
19
CH3
13
20
17
CH3
CH51
3
Lanosterol to cholesterol.
-CO 2
H3C
H
CH3
CH3
8
8
H3C
CH3
CH3
[O]
HO
H
CH3
CH3
CH3
CH3
HO
H
H3C
H
H
HO 2C
H
1. -CO 2
2. +2[H] (-8,9)
3. -2[H] (+5,6)
H3C
H
18
CH3
19
CH3
13
20
17
CH3
CH3
10
other mammalian steroids
3
5
HO
7.0 Triterpenes & steroids (Dayrit)
cholesterol (C27)
52
Cholesterol is the most decorated
small molecule. The discovery of
LDL by Goldstein and Brown is the
most recent Nobel Prize (1985) in
the field of cholesterol metabolism.
Lipoprotein metabolism. Abbreviations:
apoB48, apolipoprotein B48; apo A1,
apolipoprotein A1; apoB100, apolipoprotein B100;
TG, Triglyceride; LRP, LDL receptor-like protein;
ABCA1, ATP-binding cassette A1; SRA1, SRB1,
CD36, 3 members of the scavenger receptor family;
CETP, cholesteryl ester transfer protein; VLDL,
very low density lipoprotein; IDL, intermediate
density lipoprotein; LDL, low density lipoprotein;
and HDL, high density lipoprotein.
• Cholesterol is an important component of cell
membranes, reducing its fluidity.
• Cholesterol is the precursor molecule for the
synthesis of steroid hormones, vitamin D and bile
salts.
• Cholesterol is derived from the diet or
synthesized within the body. The typical human
diet contains 200–500 mg of cholesterol. 30–
60% of intestinal cholesterol is absorbed.
• The principal sites of cholesterol biosynthesis are
the liver and the CNS, using fatty acids.
• Cholesterol can be lost from the body as bile
salts and intestinal cholesterol which are not
absorbed, and in sebum. The daily faecal loss of
cholesterol from bile and desquamated cells is
550 mg and as unabsorbed bile salts 250 mg.
Daily losses in sebum are 100 mg.
• A total of some 900 mg must therefore be
derived from the diet or synthesized each day.
54
• Cholesterol circulates as a component of
lipoproteins. Its concentration in humans is
typically in the range 100–300 mg dl−1. In
many Asian countries, adult levels are often less
than 200 mg dl−1 (5 mmol l−1), whereas in
Europe and the USA they are generally greater
than 200 mg dl−1.
• The principal plasma lipoproteins are the
chylomicrons, VLDL, LDL and HDL.
Chylomicron remnants, VLDL and LDL, cause
atherosclerosis and HDL opposes this.
• Chylomicrons are secreted by enterocytes into
the intestine and enter blood circulation from
lymph via the thoracic duct. They are rich in
triglycerides.
55
• Triglycerides, the principal fat in the diet, are
absorbed from mixed micelles formed in the
intestinal lumen as fatty acids and
monoglycerides after its hydrolysis by intestinal
and pancreatic lipases.
• In the enterocyte, triglyceride is resynthesized
and complexed with Apo B48, a process
involving microsomal triglyceride transfer
protein (MTP), to form chylomicrons.
• Short chain fatty acids (C8–10) escape this
process and enter the portal blood directly.
• Free cholesterol is absorbed from mixed
micelles by the enterocytes from the gut lumen,
and is re-esterified and is packaged with
triglyceride to form the core of chylomicrons.
56
Carotenoids, C40
• The carotenoids make up an important and ubiquitous group of
C40 terpenes. Many of the yellow, orange, red and purple
colors of organisms are due to carotenoids. Approximately 600
naturally-occurring carotenoids have been isolated.
• The carotenes arise from the head-to-head condensation of
geranylgeranyl diphosphate (2 x C20) to form lycopersene, the
biosynthetic equivalent of squalene. This process takes place in
the chloroplasts of plants or the chromatophores of bacteria and
fungi. It is believed to be a secondary metabolite of ancient
origin.
7.0 Triterpenes & steroids (Dayrit)
57
The carotenoids are C40 all-trans polyolefinic constituents of
green plants, as well as in a number of algae, bacteria and fungi.
Many of them are accessory pigments in photosynthesis. Carotene is the most important member of this group.
2 x geranylgeranyl 20
pyrophosphate
)
(C
lycopersene
lycopene

carotene
7.0 Triterpenes & steroids (Dayrit)
58
Carotenoids
-Carotene is widely distributed in the plant kingdom. It is
almost always found with chlorophyll. -Carotene is the most
important pro-vitamin A compound in humans. It is believed to
be one of the natural anti-oxidants.
Isomers of -carotene are known which are double-bond isomers
(e.g., -carotene) or open-ring analogues (- and -carotene).
The xanthines are oxidized derivatives which are also widely
found in nature.
Industrially, it is obtained by chemical synthesis or fermentation.
7.0 Triterpenes & steroids (Dayrit)
59
Some carotenoids.
Carotene
Carotene
OH
Xanthophyll
HO
OH
O
O
HO
Violoxanthin
7.0 Triterpenes & steroids (Dayrit)
60
Some well-known commercial carotenoids: retinol (Vitamin A)
and all-trans retinoic acid (tretinoin), a topic cream for skin care
and acne.
H3C
CH3
CH3
CH3
H3C
CH3
CH3
CH3
CO2H
CH2OH
CH3
CH3
All-trans retinoic acid (Tretinoin)
Vitamin A (Retinol)
7.0 Triterpenes & steroids (Dayrit)
61
Bixin is a commerically-important food colorant which is obtained from the
seeds of Bixa orellana (annato, achuete). Bixin imparts the yellow-orange color
of Cheez Whiz. It was recently discovered that bixin is derived from lycopene.
Molecular biologists are now trying to engineer tomatoes with dioxygenase
genes to convert lycopene to bixin aldehyde, then an aldehyde dehydrogenase
and methyoltransferase to yield bixin. (Camara et al., Science, 300, 2089 (2003).)
lycopene
Dioxygenase
C
H
O
O
H
C
bixin aldehyde
1. Aldehyde dehydrogenase
2. Methyl transferase
C
O
C
H
2
3
H
O
C
2
bixin
(Camara
Science,
et300
al.,
, 2089 (20
7.0 Triterpenes & steroids (Dayrit)
62
Bixin biosynthesis
(from: http://www.plantcyc.org)
Bixin, also known as 'annatto', is a pigment synthesized naturally by a single
terrestrial plant, Bixa orellana, native from the tropical Americas. The pigments
are found on the surface of the seeds where they accumulate in a resinous, oily
substance.
Norbixin is a strong colorant: one liter of a 1% norbixin solution is sufficient for
the coloring of 16 tons of cheese. It is also used in the cosmetic industry and as a
dye for leather.
7.0 Triterpenes & steroids (Dayrit)
63
Annato
• Annatto is used in traditional medicine to cure diabetes,
as an antimicrobial, against snake bites or sunburns.
Today, annatto is used as a food colorant and dye for
traditional silk. It is also still used in the cosmetic
industry for body care products.
• A recent paper in Food Chemistry claimed that annatto can be used to
replace nitrites in cured meats without affecting the microbial or
sensory profiles of the finished product. Nitrite salts (sodium nitrite)
have traditionally been added to meat to retard rancidity, stabilize
flavor, and establish the characteristic pink color of cured meat. Many
studies warned against the use of nitrites for curing meats. The results
showed that the sample formulated with 60% annatto was the best for
its color. In addition, this sausage formulation also did not differ
significantly from the control (100% nitrite) sausage in terms of flavor
and aroma, and microbial contamination.
7.0 Triterpenes & steroids (Dayrit)
64
Summary
• Head-to-head reductive dimerization of two farnesyl
diphosphate units yields squalene. Squalene, a symmetric
C30 all-trans hexaene, is the starting point of the triterpenes.
• The various triterpenes are formed from conformational
folding of squalene, in particular chair and boat. There are
four main folding conformations: (c - c - c - b) and
(c - b - c - b) form tetracyclic triterpenes, and
(c - c - c - c - c) and (c - b - c - c - b) form pentacyclic
triterpenes.
• The chair - boat - chair - boat conformation yields the
important intermediates cycloartenol (in plants) and
lanosterol (in animals). The various sterols arise from these
compounds.
7.0 Triterpenes & steroids (Dayrit)
65
Summary
• Sterols are modified by various organisms to yield
compounds which are characteristic of the organism. These
include the steroidal hormones, sterol glycosides,
phytoecdysones, and bile acids.
• Head-to-head reductive dimerization of two geranylgeranyl
diphosphate units yields lycopersene, the squalene
equivalent of the C40 terpenes. Lycopersene is starting point
of the carotenoids.
7.0 Triterpenes & steroids (Dayrit)
66