TERPENES

TERPENES
The Czech chemist Leopold Ruzicka ( born 1887) showed that
many compounds found in nature were formed from multiples
of five carbons arranged in the same pattern as an isoprene
molecule (obtained by pyrolysis of natural rubber).
natural
rubber

head

tail

C
C
isoprene

isoprene
unit

He called these compounds terpenes.

JOINING ISOPRENE UNITS

Head-to-Tail

individual
isoprene units
join head-to-tail

an extra
bond

Tail-to-Tail

larger terpenoid
units dimerize
tail-to-tail
.. explained later

The terms head-to-tail and

tail-to-tail are often used to
describe how the isoprene
units are joined.
3

TERPENES CAN BE SHOWN TO BE

FORMED FROM ISOPRENE UNITS

head to
tail

limonene
from lemon and
orange peels

diagram showing how two

isoprene units combine to
form the limonene skeleton
4

Beberapa contoh senyawa terpena

MEVALONIC ACID PATHWAY

TERPENES

ACETYL CoA UNITS ARE LINKED

BY A CLAISEN-LIKE CONDENSATION
Strong bases are not tolerated
by biological systems. Nature
does these condensations
using malonyl CoA.

H CH2

S CoA

O H
CH2

HOOC Biotin

:B

Differences between an
oxygen ester and a thioester:
Thioesters are more prone
to enolization.
Thioesters are more
reactive.

O
C

WHY THIOESTERS ?

Biotin

ATP ADP

S CoA
Biotin
Biotin-COOH

O
HOOC CH2

S CoA

malonyl CoA

THE ENZYMES THAT ASSEMBLE ACETYL-CoA UNITS

USE A DECARBOXYLATION OF MALONYL-CoA
A FREE ENOLATE ION IS NEVER FORMED

Enz-B:
CHAIN EXTENDER
malonyl CoA

Enz-B:
H

.. CH

CH3 C

x1

acetyl CoA
STARTER

.
.

x2

S CoA

S CoA

- CO2

CH2
O

S CoA

x3
O

x5 x4

CH2

CH2 C S CoA

CH3 C CH2 C CH2 C CH2 C CH2 C SCoA

a polyketide chain

CH3

S CoA

O
O

CH2

CH3

THERE ARE TWO CARBONYL GROUPS IN THE 2-UNIT POLYKETIDE CHAIN

EITHER ONE CAN REACT
O

O
H

.. CH

CH3 C

S CoA
CH3

- CO2

S CoA

CH2

LINEAR

BRANCHED

mevalonic acid

CH3
CH2
HO

CH2

OH
C

CH2
CH2 COOH

TERPENES

O
CH3

O
C

CH2

H3C

S CoA

CH2

O
CH2

SCoA

S CoA

CH2
O C

POLYKETIDE CHAINS
SCoA

STEROIDS

ACETOGENINS
9

MEVALONIC ACID PATHWAY

FORMATION OF MEVALONIC ACID FROM ACETYL UNITS
O

O
HO

CH2 C SCoA

3 acetylCoA

H3C

HO

NADPH

CH2 C SCoA

C
H3C

O
HO
C
H3C

CH2 CH2 OH

HO
C

H2O

H3C

H
CH2 C
O:
:..

HO

CH2 C SCoA
CH2 CH2 OH

SCoA

CH2 C OH

CH2 C SCoA

NADPH

H3C

CH2 C SCoA
CH2 C H
O

mevalonic acid

10

MEVALONIC ACID PATHWAY

The isopentenyl and 3,3-dimethylallyl pyrophosphate intermediates

O
HO
C
H3C

CH2 C OH

ADP
2 ATP AMP

O
C
H3C

CH2 CH2 OH

:B-Enz

O
CH2 C

CH2 CH2 O

H
P

mevalonic acid
These five-carbon
intermediates are
responsible for the
formation of all the
terpenes.

CH3
H

CH3

P P O CH2

DMAPP
3,3-dimethylallyl
pyrophosphate

CH3

Enz-B:
H

H+

CH2

P P O CH2

IPP

isopentenyl
pyrophosphate
11

HOW THE TERPENES ARE FORMED

12

CONCATENATION OF C5 (ISOPRENE) UNITS

CH3
H

IPP

CH3
H

CH2

OPP CH2
HEAD

CH3

OPP

CH2

DMAPP

OPP CH2

C5
H

CH3

C10

:B

C5

CH2 OPP

isopentenyl-PP
3,3-dimethylallyl-PP

CH2 OPP
H

TAIL

C10

geranyl-PP

OPP

C20
CH2 OPP

C15

C15

farnesyl-PP

C20

again

geranyl-geranyl-PP

CH2 OPP

EACH NEW UNIT IS JOINED HEAD-TO-TAIL

13

CLASSIFICATION OF TERPENES
TYPE OF
TERPENE

NUMBER OF
ISOPRENE
CARBON ATOMS
UNITS

hemiterpene

C5

one

terpene
sesquiterpene
diterpene
sesterterpene

C10
C15
C20
C25

three
four
five

triterpene

C30

six

tetraterpene

C40

eight

NOTE:

hemi = half
di
sesqui = one and a half
tri
tetra = four

two

= two
= three
14

SOME TERPENES (C10)

CH2OH

OH

geraniol

rose and other flowers

menthol
peppermint

camphor

-pinene

camphor tree

turpentine

15

Most cyclic monoterpenes have a distinctive odor

- basis of perfume & flavor industries
Stereoisomers have different characteristic smells
- demonstrates that smell receptors are 3D proteins,
i.e. chiral environments that can distinguish enantiomers

(+)-carvone = caraway seed

(+)-limonene = oranges

(-)-carvone = spearmint

(-)- limonene = lemons

16

SESQUITERPENES
CH3

CH3

CH CH3

guaiazulene

CH3

geranium oil

CH3
CH3

CH3

caryophyllene
oil of cloves

17

.. more sesquiterpenes
CH3
CH3

CH3

CH3
cedrene

cedar wood oil

CH3

CH3

H3C
longifolene

pine species

18

Biosynthesis of Sesquiterpenes (C15)

DMAP

IPP

Geranyl pyrophosphate
(C10)

Prenyl transferase +

Farnesyl
pyrophosphate (C15)

rearranged to form
sesquiterpenes (C15)

- if you introduce a
labeled carbon in the
precursor, you can see
where it ends up in the
final natural product
19

Biosynthesis of Sesquiterpenes (C15)

DMAP

IPP

Geranyl pyrophosphate
(C10)

Prenyl transferase +

Farnesyl
pyrophosphate (C15)

rearranged to form
sesquiterpenes (C15)

- if you introduce a
labeled carbon in the
precursor, you can see
where it ends up in the
final natural product
20

Labeling studies in Biosynthesis 1

Using isotopically enriched precursors, it is possible to trace
the incorporation of building blocks into complex metabolites
- follow the label and see which atoms in the natural
product end up labeled
Originally done with radioactive labels (14C, 3H)
- feed cells a precursor with one

14

- use chemical degradation to break natural product apart,

see which pieces contain the radioactivity
- drawback: sloppy, usually not possible to completely
determine biosynthetic route

21

Labeling studies in Biosynthesis 2

Now done by NMR using non-radioactive isotope
- common carbon isotope
- rare

13

12

13

C is invisible to NMR

C has nuclear spin I = n/2, so is detectable by NMR

- feed cells a precursor with one position 13C labeled;

then see which positions show exaggerated peaks in the
carbon NMR spectrum
since only 1% of carbons are naturally 13C, the positions
that incorporate the label will give much higher peaks

22

Kubanek et al. JOC 1997

C NMR spectrum of compound 2, after feeding sea slug with

[2-13C] mevalonate - increased size of peaks shows label incorporation
13

23

- allowed researchers to
infer biosynthetic pathway
for these related C-23 and
C-21 terpenes

24

TRITERPENES

CH3
CH3

CH3

OH
CH3
CH3

CH3

TAIL-TO-TAIL

CH3
ambrein
ambergis

25

STEROIDS ARE TRITERPENES (C30)

CH3
CH3
CH3
CH3
HO
CH3

CH3

All steroids are triterpenes

but their skeletons have been
rearranged so that they can
not be analyzed into isoprene
units.

rearrangements
in this area

26

TETRATERPENE
head-to-tail

tail-to-tail

head-to-tail

-carotene
carrots

27

CONCATENATION OF C5 (ISOPRENE) UNITS

CH3
H

IPP

CH3
H

CH2

OPP CH2
HEAD

CH3

OPP

CH2

DMAPP

OPP CH2

C5
H

CH3

C10

:B

C5

CH2 OPP

isopentenyl-PP
3,3-dimethylallyl-PP

CH2 OPP
H

TAIL

C10

geranyl-PP

OPP

C20
CH2 OPP

C15

C15

farnesyl-PP

C20

again

geranyl-geranyl-PP

CH2 OPP

EACH NEW UNIT IS JOINED HEAD-TO-TAIL

28

C30 AND C40 UNITS ARE FORMED DIFFERENTLY

Number
of Carbons

Class

HEMITERPENES C5 1

x2
x2

Isoprene
Units

Origin

IPP or DMAPP

MONOTERPENES

C102

geranyl-PP

SESQUITERPENES

C153

farnesyl-PP

DITERPENES

C204

geranyl-geranyl-PP

SESTERTERPENE
TRITERPENES

C255
C306
C357

TETRATERPENES

C408

uncommon
2 x (farnesyl-PP)
uncommon
2 x (geranyl-geranyl-PP)
29

DIMERIZATION OF C15 AND C20 UNITS

O

TAIL

O P O

O P O

rearrange

CH2

OPP CH2
CH3

CH3 R

TAIL

CH3

dimerize
O
O

Enz-B:

O P O
H

CH2

O
CH3 R

CH3 R

CH3

CH
CH2

CH
CH3

H:-

O P O

CH3

NADH NAD+
R

UNITS ARE JOINED TAIL-TO-TAIL

CH3

30

JOINED
SYMMETRICALLY
TAIL-TO-TAIL

COMMON TERPENOID SKELETONS

HEMITERPENES

C5

DITERPENES

C20

TERPENES

SESQUITERPENES

C10

C15

TRITERPENES

C30

31

TERPENOIDS

32

H H

OH

-myrcene
hops

geranial
geranium oil

neral
lemon oil

geraniol
geranium oil
OPP

OPP

OH

OPP

geranyl-PP (GPP)

citronellol
rose oil
H

linalyl-PP (LPP)

neryl-PP (NPP)

OH

O
OH
OH

citronellal
citronella oil

-terprneol

linalool
coriander oil

33

nerol
rose oil

OPP

OPP

ionize

methyl
-terpinyl cation

or

+
+

LPP

-pinene

- H+

- H+

1,2-alkyl
shift

H2O

H2O

+
borneol

NADP+

OH

NADP+
fenchone

- H+

OH

-pinene

1,2-alkyl
+
+ shift

fenchol

34

camphene

camphor

TAXOL
+

+
OPP

(+)

Phe
O
H3C
NH

GGPP

H+

3 100-yr-old trees = 1 g
Used clinically in treatment
of breast, ovarian, lung,
head, neck cancers.

acetylCoA
O

OH

HO

OH

taxadiene

O
H

O
OH

Phe

HO
O

O O

O acetylCoA

paclitaxel(taxol)
Pacific Yew (bark)
Phe

HO

CH3

many steps:
oxidations,
esterification

HO
O

O O
O
35

CH3