ACETATE MEVALONATE

PATHWAY

Mandar B. Mulik
Dept. of Pharmacognosy, Prin. K. M. Kundnani College of Pharmacy, Cuffe Parade, Mumbai 400 005.
 Terpenes: The Isoprene Rule
Isoprenoids- C10 (terpenes), C15 (sesquiterpenes) and C20 (diterpenes) plant; essential oils
Ruzicka isoprene rule: terpenoids are derived from “isoprene units” (C 5)

(+ )-C arvone (caraw ay seeds) (-)-C (+)-lim onene (oranges) (-)-

arvone (spearm in t) lim onene (lem ons)

O H 3C CH3
CH3
H H 3C

O
C itral patchouli alcohol
(lem pon grass) C am (patchouli oil)
phour
OH

-pinene G randisol
-p in e n e
 The precursor to C10 terpenoids (monoterpenes) is geraniol
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

O PP

head - tail head - tail

C15 sesquiterpenoids are derived from farnesyl diphosphate, which

consists of three C5 “isoprene units” that are joined “head-to-tail”

O PP

C20 diterpenoids are derived from geranylgeranyl diphosphate, which

consists of four C5 “isoprene units” that are joined “head-to-tail”

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

O PP

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”

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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 a series of
formdiphosphate homologs, which prenyl as the
serve
precursors of the different classes of terpenoids;
immediate
(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.
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
O acetoacetyl-C o A
acetyltransferase O C
H 2C C S C H 2C S
CoA
oA H
B
acetyl C o C la ise n
: O O
A conde nsation

SCoA

a ce toacetyl C o A
O O
E nzym e-C ys-S
H 3C C S C o A H H 3 C C S -C ys - E n zym e

a cetyl C o
A

HM G-Co A aldol HM G-Co A

O
O c o n d e n s a tio n reductase
H 3C O H O H 3C O H
synthase
H 2 C C SC o A H O 2C H O 2C
SCo 2 NAD OH
H 2C SC o PH
C A A
B: 3 -H ydroxy-3 -m ethylglutaric acid (H M evalonic acid
Hacetyl C o
BH M G -C o A )
A O O

SC o A

acetoacetyl C o A
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Conversion of mevalonic acid to IPP and DMAPP
AT AM A TP AD
P P P O H 3C O P O2 -
H 3C OH OH 3 COH O O O - P O 43 -
H O 2C H H 3 -
OH O O
O O- OPOPO O-
M evalonic acid OPOP O O-
-

H+

O CH O O. O
3 O- re arr ang m ent
O
H O O- O P. O P O-
O O- HH
O H O- O-
B B OPOP O-
: OPOP O- :

isopentenyl-P P dim ethylallyl-PP

O-
O- (IP P) (D M A P P )

Carbon-Carbon Bond Formation in Terpene Biosynthesis.

Conversion of IPP and DMAPP to geraniol-PP and farnesyl-PP
nucleophilic
electrophilic
tail group
head group
-OP -OPP
OP
P 2+ Mg2+
Mg HH P
OP OP
P B P
DMAP OP IP
P : g eranyl p yro ph o sp h at e (C 10 )
P P

OP
HH P OP
P
B nucleophilic
electrophilic OP fa rn e s yl p y ro p h o sp h ate (C 1 5 )
head group : tail group 8
P
 OP PP
P O
squalene
synthase

Conversion of genanyl-PP to monoterpenes

Limonene & α-Terpineol
O PP
O PP
-H+
OP
P
H
:B
H 2O
geranyl neryl
diphosphate diphosphate
C=C bond acts limonene
as a nucleophile

H
O

-terpineol
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 Representative Monoterpenes

OH O

a-Phellandrene Menthol Citral

(eucalyptus) (peppermint) (lemon grass)
GAE= Geranyl acetate estarase
GDPase= Geranyla di-phosphatase
GDH= Geraniol de-hydrogenase
E3= cinnamoyl reductase
 H
12 17
Steroids 11
13
1 C D 16 H
10
2 9 14 H
8 15
A B
3 5 7 H H Cholesterol
4 HO
Cholesterol biosynthesis part A: 6the cyclization
Squa l ene ep o xid a s e

O
H em e , O 2

HA
S q u ale n e (C 30 H 50 ) S q u ale n e O xid e (C 30 H 50 O )
Sq ua l ene
cy cla s e +
HO HO
+

H HO
O
+ +

HO
+ HO
+

HO +

P rotosterol cation
10
vz
 Cholesterol biosynthesis, part b: the 1,2-shifts
CH3 H
CH3 H CH3 CH3
CH3 CH3 1 ,2 -h y d r id e
H HO +
HO s h ift
+ H 3C H
H 3C H CH3
H C H3 H
H

P r o to s t e r o l ca t io n (C 30 H 50 O )
H
C H3 H C H3 H H 3C
1 ,2 -h y d r id e H
CH3 CH3 CH3
1 ,2 -m e th y l
s h ift HO
+
sh ift HO H
H
H 3C H 3C +
H CH3 H CH3

B:
CH3
H CH3
1 ,2 -h y d r id e C H3 H H 3C CH3
s h ift
C H3 -H+
HO
HO H H
H 3C CH3
H 3C + H
H H 3C

Lanosterol

H H

H H
H

H H

HO HO
H

C h o l e s te ro l
Lanosterol
(C 27 H 46 O ) 11
 O
H 3C
C H3 O O O
O H
CH 3

H C 6H 5 NH
CH O
3
H O
C 6H 5 O HO
H O
cedrane O O
H O
Taxol Lanosterol

O
O O O
H 3C O H
CH 3

C 6H 5 NH
CH 3 O
H O
H C 6H 5 O
CH3 H O
O O
H O

-carotene

6
 Vitamin D H
H

H
H
s u n lig h t

H
H H

HO HO

7 -D e h y d ro ch o l e s te ro l V i tam in D 3

Corticosteroids

O
OH
O OH
H

H H

C ortiso ne

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 Sex hormones-androgens (male)
OH O O OH
H 3C H 3C H 3C H 3C
CH 3

H 3C H H 3C H H 3C H H 3C H

H H H H H H H H
O HO O O
H
Testosterone A ndrosterone A ndrostenedione dia na bol

estrogens (female)
O OH
O OH H 3C
H 3C H 3C H 3C
C CH
H H H H

H H H H H H H H

HO HO HO HO

Estrone E s trad iol P rogesterone E thynylestradiol

Carotenoids derived from phytocene (C40)

Lyc op e ne

-ca roten e
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