Terpenoids

In honor of Al
Gore winning
the Nobel
Peace Prize in
2007 for
education about
global warming
 T1
Terpenoids
• Terpenoids (isoprenoids) are a very large, diverse
group of compounds all with a common origin.
• May contain 5-C to several hundred carbons
arranged in cyclic and acyclic compounds.
• Examples include essential oils, steroids, rubber,
many flavors and medicinal compounds.
• Terpenes refer specifically to hydrocarbon
compounds composed of the basic 5-C isoprene
unit or multiples of 5-C units.
• In contrast, terpenoids refer to all compounds built
of isoprene units regardless of additional or missing
carbons or functional groups.
 T2
• The “isoprene rule” states that all terpenes are multiples of 5-
C isoprene (isopentadiene or 2-methylbuta-1,3-diene).
H2C

C CH CH2 OR

CH3

• However, the “biogenic isoprene rule” states that all

terpenoids are synthesized from a common 5-C precursor,
but final structures can result from chemically reasonable
modifications of an integral number of the 5-C precursor
units.
• Isopentenyl Pyrophosphate (IPP), (3-methylbut-3-enyl-PP),
also known as “active isoprene” is the actual biosynthetic
precursor of the terpenoids. Formed from mevalonate.
H2C

C CH2 CH2OPP
H3C
 T3

• Terpenoids are grouped according to number of 5-C

units required for their synthesis.

Numer of
isoprene Number of
units Carbons Class Examples
1 C5 Hemiterpenoids Isoprene
2 C10 Monoterpenoids Essential oils
3 C15 Sesquiterpenoids Abscisic acid
4 C20 Diterpenoids Gibberellins
6 C30 Triterpenoids Sterols
8 C40 Tetraterpenoids Carotene
n Cnx5 Polyterpenoids Rubber
 T4

Synthesis of some terpenoids occurs in all

organisms; Synthesis by the acetate-
mevalonate pathway ubiquitous to all
organisms
Only the angiosperms can elaborate all types
however. For example, carotenoids are not
made by animals and sterols are not made by
insects (get from diet).
In general, the terpenoids are:
a) Lipid soluble.
b) Located in the cytoplasm and not the vacuole.
c) Extracted with methanol, petroleum ether, diethyl
ether, chloroform, i.e. polar to moderately polar
organic solvents.
 T5
Biosynthesis of the C5 Unit
1. Mevalonic acid (MVA, mevalonate) is the primary
precursor of IPP and thus all terpenoids.
CH3
HOCH2 CH2 C CH2 COOH
OH
1 of 3 acetate groups

2. Derived from condensation of three molecules of

acetyl-CoA.
3. First we will take a look at the MVA molecule
 T6

3. MVA has one chiral center at C3, but C2, C4 and

C5 are prochiral centers. R at C3, and only R
used. HR HO CH3
Hs
C2 C HR
Hs 3 4
C
COOH C 5 OH
1
HR
H Hs
C HR
OH
S C C
OH R
C
Hs
H
Prochiral: if one H changed for a new group, the molecule will have a new
chiral center. e.g., if an HR changed, the C becomes R. The Prochiral
centers allow for a great deal of chiral centers in isoprenoids.
 T7

4. Only the 3 R enantimomer is used in biosynthesis. (Is

the configuration shown really 3 R?)
5. Presence of the prochiral centers has allowed chemists
to establish that each step in the subsequent synthesis
of C-5 and C-10 isoprenoids is stereospecific.
6. By definition an achiral carbon that becomes chiral
when one of its ligands is changed is called a prochiral
carbon.
7. If in the case of C5 in MVA, HR is replaced by deuterium
or tritium, C5 will be chiral with an R configration.
8. Thus HR and HS are called pro-R or pro-S hydrogens
(ligands) of C5.
9. Proligands are most commonly (but not always) H
atoms.
 23HC C S CoA CH3COCH2COS-CoA
3
Acetyl-CoA
Transferase Acetylacetyl-CoA T8
Biosythesis of MVA O
Acetyl-CoA
+
CH3COS-CoA
(and subsequently HMG-CoA synthase

IPP) begins with CH3

2 NADPH
CH3

the condensation of HOOCC*H2CCH2CH2OH HOOCCH2CCH2COS-CoA

HMG-CoA
two molecules of reductase
OH
OH
acetyl-CoA via ATP
MVA 3-Hydroxy-3-methyl-glutaryl-CoA

action of a MVA kinase

CH3
transferase. 3rd CH3 ATP
HOOCCH2CHCH2CH2OPP
Acetate added via HOOCCH2CHCH2CH2OP MVA kinase
OH
a synthase. OH
MVA-5-phosphate
MVA-5-PP

ATP
Note: Different pathway MVA-PP
decarboxylase ADP
in Chloroplasts. The MEP CO2
(Methyl Erythritol Pi
Phosphate) Pathway. H3C H3C
From GA-3-P and C CHCH2OPP CCH2CH2OPP
Pyruvate to form IPP *CH3 IPP isomerase
*CH2
Dimethylallyl-PP (DMAPP) IPP
 T9

Notes on pathway:
a) Step 1 is a transfer of acetyl groups form one
acetyl-CoA to another.
b) Whereas step 2 is a condensation reaction
(via a lyase) with subsequent cleavage of
CoA. Same mechanism as oxaloacetate to
citrate step in the citric acid cycle.
 T10
Mechanism for Acetate addition:
O O AcetylCoA O O
Transferase
CH3CSCoA + CH3CSCoA CH3CCH2CSCoA + CoASH
Acetylacetyl CoA
O
Acidic proton due to
CH3CSCoA resonance structure
O O -O
CH2CSCoA - CH2CSCoA + H+ CH2=CSCoA
H
Nucleophilic
attack of
-O O O O
carbanion
on carbonyl CH3C CH2CSCoA CH3CCH2CSCoA + - SCoA
SCoA
SCoA is a good
leaving group
Mechanism for HMG-CoA production: T11

HMG-CoA
O O O O HO O
Synthase
CH3CCH2CSCoA + CH3CSCoA HOCCH2CCH2CSCoA + CoASH
CH3

O
3-Hydroxy-3-methyl Glutaryl (HMG) CoA
O
(C6 backbone for MVA formation)
CH3CCH2CSCoA
O -
O O O
CH2CSCoA - CH2CSCoA + H+ CH3CCH2CSCoA
H CH2CSCoA
Carbanion forms and Condensation
attacks ketone as O across (ketone)
with acetylCoA H+ carbonyl – lyase
transferase reaction

O HO O CoASH O HO O
HOCCH2CCH2CSCoA CoASCCH2CCH2CSCoA
Hydrolysis H2O
of CoASH CH3 CH3
 T12
c) Reduction of HMG-CoA to MVA is essentially
irreversible in vivo. A 4 e- reduction w/ 2 NADPH.
d) HMG-CoA reductase is probably the principle point
of regulation in isoprenoid biosynthesis.
e) The reductase is bound to the endoplasmic
reticulum and is apparently regulated in three ways:
i. Inactivated via phophorylation by a kinase (transferase)
and activated by a phophatase (hydrolase).
ii. By feedback control of mRNA for the enzyme.
iii. Enzyme turnover (synthesis and degradation) regulated by
the feedback control.
f) Competitive inhibition of HMG-reductase by
lovastatin is a common medical treatment for
controlling high levels of cholesterol in humans.
g) Lovastatin is a natural product obtained from fungi.
h) MVA is only used to produce terpenoids, i.e. it has no T13
other significant fate.
i) Steps 4&5, MVA is phosphorylated using 2 ATPs via
action of MVA kinase. Another point of regulation.
j) Step 6 constitutes a 2-part reaction using a third
molecule of ATP to phosphorylate the OH group.
k) Pi is a good leaving group.
l) CO2 is also lost to yield IPP, i.e. one of two types of
active isoprene.
m) Equilibrium of IPP:DMAPP is approximately 3:97.
n) Migration of the double bond in the isomers (3,2 shift)
occurs via electrophilic attack by H+ on methylene
carbon in IPP. The carbon cation produced forces a
shift in the double bond with loss of H+ from C-2.

H+ OPP + OPP OPP

H
Mechanism of IPP formation from MVA-PP T14

ADP
O CH3 ATP O CH3
C CH2 CCH2CH2OPP C CH2 CCH2CH2OPP
HO OH O OP
H

Reaction catalyzed by MVA Decarboxylase.

OH phosphorylated to make a good leaving
group to allow double bond formation

O CH3
Pi + OPP C + CH2 CCH2CH2OPP

IPP O H OP
 T15
10. IPP and DMAPP are the biosynthetic functional
equivalents of isoprene. They are two key
hemiterpenoids.
11. Their union leads to the subsequent production
of all higher molecular weight terpenoids.
12. DMAPP is an excellent alkylating agent, an
effective electrophile.
13. Electron “pressure” in the allylic group of
DMAPP facilitates the loss of PPi. The resulting
positive charge is dispersed over the allyl
radical, i.e. the carbon cation is resonance
stabilized.
14. Under influence of DMA transferase, C1 at tail of
DMAPP undergoes nucleophilic attack by -
electrons in head of IPP.
This tail to head condensation yields C10, T16
trans geranyl-PP (GPP).
Head
OPP Mechanism
OPP
+
-OPP Resonance
Tail Stabilization
+
DMAPP IPP OPP +

OPP
DMA (prenyl)
Net Reaction transferase

H
H+
H
OPP +
OPP

+PPi

C, trans geranyl PP (GPP)

(A monoterpenoid)
 T17
15. Note, shift in double bond of IPP to yield
DMAPP configuration at the tail of GPP.
16. Thus, the chain can be lengthened by
nucleophilic attack of another IPP on GPP to
yield C15 FPP.

GPP + IPP Farnesyl-PP (FPP)

Prenyl
transferase

1 8 13

2 5 7 10 12 15
3 4 6 9 11 14 OPP

A sesquiterpene 2-t, 6-t-FPP

 T18

17. Repetition of this tail to head condensation with

different enzymes lead to polymers, (C5H8)n,
e.g. rubber.

Rubber, mixture 1,4-polyisoprenes

 T20

18. Many plants produce latex from which rubber is

obtained, but commercial source is from Hevea
brasiliensis
19. Rubber shows a wide spectrum of molecular weights,
consisting of 1,500 to 60,000 isoprene (prenyl)
residues.
20. Tail to head condensation also holds for the mono
(C10), sesqui (C15) and diterpenes (C20).
21. In contrast, the mechanism of formation for the tri- and
tetra- terpenoids involves tail to tail condensations.
22. We can examine examples of the biosynthetic
relationships of compounds in different groups
terpenoids.
23. We will examine specific compounds in the main
groups of terpenoids
 T21

Biosynthetic
Relationships of
Terpenoids
Hemi-Terpenoids
 T22
Crosslinks DNA.
Hemiterpenoids Taken orally + sunlight
O
O
O promotes tanning.
Psoralen (a furanocoumarin) Treatment for Psoriasis.
Used in blood
sterilization
H3C
Found in all
C CH2 CH2 OH isopentenol
organisms.
H2C
In extracts, following
loss of PPi

H3C

C CH CH2 OH 3,3-dimethyllallyl alcohol

H3C

Found in plant oils, H3C

especially evergreens. C CH CH2 isoprene (2-methylbutadiene)
Detectable in forest air. H2C
 T23
Psoralen has one DMAPP

OPP +
HO
HO

O O O O