1. MEVALONATE PATHWAY
RAMANDEEP KAUR BRAR

2. 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)
O
O
C am phour
(+)-Carvone (caraw ay seeds)
(-)-Carvone (spearm int)
(+)-lim onene (oranges)
(-)-lim onene (lem ons)
-pinene -pinene
O H
G randisol
CH3H3C
H3C
CH3
patchouli alcohol
(patchouli oil)
H
O
Citral
(lem pon grass)
isoprene
(2-methyl-1,3-butadiene)

3. 3
The precursor to C10 terpenoids (monoterpenes) is geraniol diphosphate, which consists of
two C5 “isoprene units” that are joined “head-to-tail”
OPP
head - tail head - tail
head tail P
O
O
O P O
O
O
PP =
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

4. 4
C25 sesterpenoids are derived from geranylfarnesyl diphosphate, which consists of five
C5 “isoprene units” that are joined “head-to-tail”
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”
OPP

5. Despite great diversity in form and function, the terpenoids are
unified in their common biosynthetic origin. The biosynthesis of
all terpenoids from simple, primary metabolites can be divided
into four overall steps:
(a) Synthesis of the fundamental precursor IPP;
(b) Repetitive additions of IPP to form a series of prenyl
diphosphate homologs, which serve as the immediate
precursors of the different classes of terpenoids;
(c) Elaboration of these allylic prenyl diphosphates by specific
terpenoid synthases to yield terpenoid skeletons; and
(d) Secondary enzymatic modifications to the skeletons (largely
redox reactions) to give rise to the functional properties and
great chemical diversity of this family of natural products.

6. 6
O O H
O
O
H
O
O
O
O H
C6H5
NHC6H5
O
O
O
HO
O OH
O
O
H
O
O
O
OH
C6H5
NHC6H5
O
O
O
HO
CH3
CH3
CH3
H3C
H
cedrane
Taxol
CH3
CH3
CH3
H3C
H
HO
Lanosterol
-carotene

7. 7
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)
The Pathway from Acetate to Isopentenyl Diphosphate.
Mevalonate Pathway
H2C SCoA
C
O
SCoA
OO
SCoA
HO 2C
O HH3C O
3-Hydroxy-3-m ethylglutaric acid
(HM G-CoA)
HM G-CoA
reductase
2 NADPH O H
HO 2C
OHH3C
M evalonic acid
C
O
H2C SCoA
H
B:
acetyl CoA
B H
aldol
condensation
HM G-CoA
synthase
acetoacetyl CoA
C
O
H2C SCoA
H
B:
H2C SCoA
C
O
acetyl CoA
SCoA
OO
Claisen
condensation
acetoacetyl CoA
C
O
H3C S-Cys-Enzym e
acetyl CoA
acetoacetyl-CoA
acetyltransferase
C
O
H3C SCoA
Enzym e-Cys-SH

8. 8
Conversion of mevalonic acid to IPP and DMAPP
OH
HO2C
O HH3C
M evalonic acid
ATP AM P
O
OHH3C
P O
O -
O
P O -
O
O -
O
O
H
rearrangm ent
O P O
O -
O
P O -
O
O -
H
dim ethylallyl-PP
(DM APP)
isopentenyl-PP
(IPP)
B:
H+
ATP ADP
O
O PO 3
2-H3C
P O
O -
O
P O -
O
O -
O
O
H
O P O
O -
O
P O -
O
O -H H
B:
O
CH3
P O
O -
O
P O -
O
O -
O
O
H
- PO 4
3-
Carbon-Carbon Bond Formation in Terpene Biosynthesis.
Conversion of IPP and DMAPP to geraniol-PP and farnesyl-PP
electrophilic
head group
nucleophilic
tail group
electrophilic
head group
nucleophilic
tail group
O PP
OPP
H H
O PP
OPP B:
DM APP IPP
- OPP
M g2+
OPP
O PP
H H
B:
OPP
farnesyl pyrophosphate (C15)
geranyl pyrophosphate (C10)
- OPP
M g2+

9. 9
O PP PPO
squalene
synthase
Conversion of genanyl-PP to monoterpenes
Limonene & -Terpineol
O PP
OPP
geranyl
diphosphate
neryl
diphosphate
O PP
- H+
H
:B
HO
H2O
C=C bond acts
as a nucleophile
-terpineol
limonene

10. 10
Steroids
Cholesterol biosynthesis part a: the cyclization
O
H A
HO H O
S q u ale n e O xid e (C30H 50O )S q u ale n e (C30H 50)
+
Squa lene
ep o xid a se
+
Squa lene
cy cla se
HO
+
H O
+
HO +
H em e , O 2
Pro to ste ro l catio n
HO
+
H O
+
A B
C D1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
HO Ch o le stero l (C27H 46O )
H H
H
H
H

11. 11
P rotosterol ca tio n (C 30H 50O )
CH3
H3C
H O
CH 3
CH3
CH3
H
H
H
+
CH3
H3C
H O
CH 3
CH3
CH3
H
H
H
H
+ H
1,2-h y d rid e
sh ift
1,2-h y d rid e
sh ift
CH3
H3C
H O
CH 3
CH3
CH3
H
H
H+
H
1,2-m eth y l
sh ift
CH3
H3C
HO
CH3
CH3
H
H H3C
H
H
+
CH3
H3C
HO
CH3
H
H H3C
H
H
H3C
+
- H +
B:
1,2-m eth y l
sh ift
CH3
H3C
H O
CH 3
H
CH 3
CH3
H
Lan o ste ro l (C30H 50O )
Cholesterol biosynthesis, part b: the 1,2-shifts
HO HO
Ch o le ste ro l (C27H 46O )
Lan o ste ro l (C30H 50O )
H H
H
H
H
H
H
H

12. 12
Vitamin D
HO
7-D eh y d ro ch o le stero l
H H
H
H
HO
H
H
H
V itam in D 3
sunlight
Bile Acids
Corticosteroids
O
O
OH
H H
OH
H
O
C ortisone

13. 13
Sex hormones
androgens (male)
estrogens (female)
H3C
HO
H
O
H
H
Estrone
H3C
HO
H
OH
H
H
Estradiol
H3C
HO
HH
H
O
Progesterone
H3C
HO
H
O H
H
H
C CH
Ethynylestradiol
H3C
H3C
O
H
OH
H
H
Testosterone
H3C
H3C
HO
H
O
H
H
Androsterone
H3C
H3C
O
H
O
H
H
Androstenedione
H3C
H3C
O
H
OH
H
H
CH3
dianabol
H
Carotenoids derived from phytocene (C40)
Lycopene
-carotene