Biosynthesis of Terpenes

Biosynthesis of
Terpenes
Biosynthesis of Terpenes
The biogenetic route for

terpenes synthesis started
from acetyl-CoA through
mevalonic acid pathway,
ended with the production
of all types of terpenoids
and steroids
What is Acetyl CoA?
Acetyl Coenzyme A is a thioester derivative of acetic acid
What is Acetyl
COA
SCoA Component of Acetyl Coenzyme A

Biosynthetic route for terpenes
Ruzicka proposed the isoprene rule for terpenoids biosynthesis according to which 2-methyl-1,
3-butadiene (a five carbon isoprene unit) combine together in head to tail manner to produce
various types of terpenes
Following three steps are involved in terpenes biosynthesis.
1. Formation of isoprene unit from acetate.
2. Condensation of isoprene unit to produce acyclic terpenoids
3. Conversion of acyclic terpenes to cyclic one and introduction of functional
group.
Formation of isoprene- Preparation of Mevalonic acid
The biosynthesis of terpenes started by the production of an isopentane unit, for this production first step is the
conversion of acetyl CoA (first biogenetic precursor) to mevalonic acid.
Three molecules of acetyl CoA (derived mainly from carbohydrate or fat metabolism) combined to each other to
form mevalonic acid.
The initial step is the conversion of two molecules of acetyl-CoA to acetoacetyl-CoA (2) through Clasien
condensation
First Step
Preparation of Mevalonic acid
In the next step aldol condensation occurs between acetoacetyl-CoA and third molecule of acetyl-CoA affording β-
hydroxy-β-methylglutaryl-CoA (HMG-CoA) (3).
After the removal of thioester group from 3 by enzymatic reduction by the action of nicotinamide-adenine
dinucleotidephosphate (NADPH) to yield another intermediate mevaldic acid (4), which is responsible for the
production of mevalonic acid (MVA), mevalonic acid (5) is produced, which is the main building block of nearly
all the isoprenoids
Conversion of Malonic acid to Isoprenoid
Since mevalonic acid contains six carbon
atoms, one carbon must be lost to form the
isopentane unit. Starting with labelled MVA
(2-14C), it has been demonstrated that it is the
carboxyl group in mevalonic acid which is
lost.
Phosphorylation of 5 produces mevalonic
acid-5-phosphate (6) by using one molecule of
ATP. Further phosphorylation of 6 produces
mevalonic acid-5-pyrophosphate (7), which is
converted to 8 [isopentenyl pyrophosphate
(IPP)] by the removal of CO2 and H2O.
The biogenetic isoprene unit is in the form of
3-methyl-3-butenyl pyrophosphate, which in
the presence of an appropriate enzyme
isomerizes to DMAPP (3-methyl-buta-2-enyl
(β,β-dimethylallyl) pyrophosphate)
Formation of Geranyl pyrophosphate
The next step of terpenoids biosynthesis is the formation of geranyl pyrophosphate (10, 11, GPP) (10 carbon
molecule), which arises by the combination of (8) and (9). 3-Methyl-3-butenyl pyrophosphate (IPP) acts as a
nucleophile and 3-methyl-2-butenyl pyrophosphate (DMAPP) as an electrophile to form a head-to-tail union.
The GPP is the precursor for all the monoterpenes
Biosynthesis of Monoterpenes
Formation of Farnesyl pyrophosphate
Geranyl pyrophosphate reacts with 3-methyl-but-3-enyl pyrophosphate to extend the chain
by a five-carbon unit. This affords the trans and cis isomers of farnesyl pyrophosphate, (FPP)
a 15-carbon compound (18, 19). FPP is the main precursor for sesquiterpenes
Biosynthesis of Sesquiterpenoids
Formation of Geranyl-geranyl pyrophosphate
FPP (18) reacts with IPP to give GGPP [geranyl-geranyl pyrophosphate (20)]. “ It is the
precursor for diterpenoids
Biosynthesis of Diterpenoids
Biosynthesis of Diterpenoids
Synthesis of Squalene
Two molecules of FPP combine in
head to head manner to produce
presqualene (21), which changes to
squalene (22) after rearrangement. It
also acting as synthetic tool for all
terpenoids.
Structure of terpenoids formed is dependent to cyclization route of squalene

Cyclization of Squalene
The remarkable process of cyclization of squalene (22) starts with the formation
of an incipient carbocation at the tertiary carbon of the terminal double bond of
the squalene.
The cyclization of squalene can be promoted in two ways
1. oxidative or
2. non-oxidative agents
In oxidative route either the squalene is converted into 2, 3-epoxy squalene (23)
followed by its transformation into cyclic derivatives via protonation and
Markownikoff opening of the epoxide ring (route a). Non-oxidative cyclization of
squalene is initiated by attack on a proton (route b).
Nonoxidative paths Oxidative Path
Primary Triterpenes
The triterpenes which are directly derived from the cyclization of

squalene or of its 2,3-epoxide are called primary triterpenes. Such
triterpenes can be divided into the following sub-groups according to
their origin.
1. Oxidative cyclization arising from only one terminal part of

squalene.
2. Non-oxidative cyclization, also arising from only one terminal

part of squalene.
3. Cyclization (oxidative and non-oxidative) which independently

involves both the terminal double bonds of squalene.
19
Oxidative Cyclization of Squalene
Different types of tetra and pentacyclic triterpenoids are formed according to the conformation
that squalene epoxide (23) adopts, presumably at an enzyme surface prior to cyclization. Each
stereospecifically leads to a particular cyclization product according to the biogenetic isoprene
rule.
Formation of Dammarene
Chair-chair-chair-boat sequence of squalene epoxide is adopted on enzyme surface to
convert it into dammarenediol (25, 26) after cyclization. Isomerization of non-classical
cation 23 into 24 is responsible for production of dammarene 25 or 26 [48].

Dammarene
Lanosterol
Dammarenyl cation (24) undergoes enzymatic stabilization and intramolecular
rearrangement assisted by enzymes converted 23 to cycloartenol and lanosterol (Scheme
11& 12). Both of these are of great importance regarding to biosynthesis of tetracyclic
triterpenes (steroids).
Cycloartenol
Biosynthesis of α-amyrin and β-amyrin
Formation of 24 from oxidative cyclization of 22 further undergoes ring expansion
with production of baccharenyl cation (30). This cation undergo many rearrangements
and finally produce α-amyrin or β-amyrin. α-amyrin relates to ursane series while β-
amyrin belongs to oleanane skeleton.

Oleane series
Ursene series
Various stereospecific 1, 2-migrations occur in β-Amyrin cation and rearranges into many
skeleton like taraxerol (34), glutinol (35) and friedaline (36)
Lupane and Hopane Series
These two small but biogenetically important groups are considered together for convenience,
since both have five membered ring E. The lupane skeleton (37) originates by the same
biosynthetic processes as the ursane and oleanane skeletons. It is derived by elimination from
the intermediate lupenyl cation in the biogenesis of b-amyrin.
The hopane skeleton (39) can result from direct cyclization of a folded squalene molecule
without rearrangement. It arises by the attack of water and HO+ (protonated oxene) on the all
chair conformation of (38).
Pentacyclic skeleton
Cyclization of 2,3-epoxy squalene leading to the formation of a pentacyclic skeleton

Chair-chair-chair-chair-boat
(40) conformation leads to
moretenol (41), whereas
chair-boat-chair-chair-boat
(42) affords arborinol (43)
(Scheme-17).
Non-oxidative Cyclization of Squalene
This type of cyclization is less common as compared to the oxidative cyclization. This occurs
directly from the all trans-squalene instead of its 2,3-epoxide. There are only a few triterpenes
which are formed directly from squalene by proton-induced simple cyclizations e.g. diploptene
(44) and tetrahymanol (45).
Cyclization at both ends of Squalene
The biosynthesis of terpenes such as onocerin (46) can be explained by involving two
independent electrophilic attacks at both ends of the squalene molecule (Scheme-19). The
two attacks are both oxidative in the case of formation of onocerin (46).
Biosynthesis of Steroids
Formation of Cholesterol from Lanosterol

Biosynthesis of Terpenes

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Biosynthesis of Terpenes

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Biosynthesis of

The biogenetic route for

SCoA Component of Acetyl Coenzyme A

Following three steps are involved in terpenes biosynthesis.

1. Formation of isoprene unit from acetate.

2. Condensation of isoprene unit to produce acyclic terpenoids

3. Conversion of acyclic terpenes to cyclic one and introduction of functional

Structure of terpenoids formed is dependent to cyclization route of squalene

The cyclization of squalene can be promoted in two ways

The triterpenes which are directly derived from the cyclization of

1. Oxidative cyclization arising from only one terminal part of

2. Non-oxidative cyclization, also arising from only one terminal

3. Cyclization (oxidative and non-oxidative) which independently

Chair-chair-chair-boat sequence of squalene epoxide is adopted on enzyme surface to

convert it into dammarenediol (25, 26) after cyclization. Isomerization of non-classical

cation 23 into 24 is responsible for production of dammarene 25 or 26 [48].

Formation of 24 from oxidative cyclization of 22 further undergoes ring expansion

amyrin belongs to oleanane skeleton.

Cyclization of 2,3-epoxy squalene leading to the formation of a pentacyclic skeleton

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