Mevalonate Pathway

Introduction
• The terpenoids form a large and structurally diverse family of natural products derived from C5
isoprene units joined in a head to-tail fashion.
natural
rubber head
D
C tail .
C

C C C C
C C
C C
isoprene isoprene
unit
• Typical structures contain carbon skeletons represented by (C5)n, and are classified as hemiterpenes
(C5), monoterpenes (C10), sesquiterpenes (C15), diterpenes (C20), sesterterpenes (C25), triterpenes
(C30) and tetraterpenes (C40).
• The biochemical isoprene units may be derived by two pathways, by way of intermediates
mevalonic acid (MVA) or 1-deoxy-Dxylulose 5-phosphate (deoxyxylulose phosphate; DXP). This
pathway is also referred to as the mevalonate-independent pathway or the methylerythritol
phosphate pathway.
The 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
D
C tail .
C

C C C C
C C
C C
isoprene isoprene
unit
He called these compounds “terpenes”.
 JOINING ISOPRENE UNITS

.
C Head-to-Tail

The terms head-to-tail and C C

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

an extra
Tail-to-Tail bond

Head-to-Tail
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 PathwayO acetoacetyl-CoA
acetyltransferase O
H2C C SCoA
C
H H2 C SCoA
B:
acetyl CoA Claisen
condensation O O

SCoA

acetoacetyl CoA
O O
Enzyme-Cys-SH
H3C C SCoA H3C C S-Cys-Enzyme

acetyl CoA
HMG-CoA aldol HMG-CoA
O
synthase O condensation H3C OH O reductase H3C OH
H2C C SCoA HO2C HO2C
C SCoA 2 NADPH OH
H H2 C SCoA
B: 3-Hydroxy-3-methylglutaric acid Mevalonic acid
acetyl CoA
B H (HMG-CoA)
O O

SCoA
acetoacetyl CoA
 Conversion of mevalonic acid to IPP and DMAPP

ATP AMP ATP ADP

H3C OH O H3C OH O H3C OPO 2-
O O
3 O O - PO43-
HO2C H H
OH O O P O P O- O O P O P O-
O- O- O- O-
Mevalonic acid

H+
O CH3 O O O O
O O rearrangment
H O P O P O- O P O P O-
O O P O P O- H H O- O- H O- O-
B: O- O- B:

isopentenyl-PP dimethylallyl-PP
(IPP) (DMAPP)
• The mevalonate pathway does not use malonyl derivatives and it thus diverges from
the acetate pathway at the very first stepThree molecules of acetyl-coenzyme A are
used to form mevalonic acid.
• Two molecules combine initially in a Claisen condensation to give acetoacetyl-CoA, and
a third is incorporated via a stereospecific aldol addition giving the branched-chain
ester β-hydroxy-β- methylglutaryl-CoA (HMG-CoA).
• This third acetyl-CoA molecule appears to be bound to the enzyme via a thiol group,
and this linkage is subsequently hydrolysed to form the free acid group of HMG-CoA.
• In the second step, it should be noted that, on purely chemical grounds, acetoacetyl-
CoA is the more acidic substrate, and might be expected to act as the nucleophile
rather than the third acetyl-CoA molecule.
• The enzyme thus achieves what is a less favourable reaction. The conversion of
HMGCoA into (3R)-MVA involves a two-step reduction of the thioester group to a
primary alcohol, and provides an essentially irreversible and rate limiting
transformation.
• Drug-mediated inhibition of this enzyme (HMG-CoA reductase) can be used to regulate
the biosynthesis of mevalonate and ultimately of the steroid cholesterol.
• The six-carbon compound MVA is transformed into the five-carbon phosphorylated isoprene units in a series of
reactions, beginning with phosphorylation of the primary alcohol group. Two different ATP-dependent enzymes are
involved, resulting in mevalonic acid diphosphate, and decarboxylation/dehydration then follow to give IPP.
• Whilst a third molecule of ATP is required for this last transformation, there is no evidence for phosphorylation of
the tertiary hydroxyl, though this would convert the hydroxyl into a better leaving group.
• Perhaps ATP assists the loss of the hydroxyl. IPP is isomerized to the other isoprene unit, DMAPP, by an isomerase
enzyme which stereospecifically removes the pro-R proton (HR) from C-2, and incorporates a proton from water on
to C-4.
• Whilst the isomerization is reversible, the equilibrium lies heavily on the side of DMAPP. This conversion generates
a reactive electrophile and therefore a good alkylating agent. DMAPP possesses a good leaving group, the
diphosphate, and can yield via an SN1 process an allylic carbocation which is stabilized by charge delocalization

• In contrast, IPP with its terminal double bond is more likely to act as a nucleophile, especially towards the
electrophilic DMAPP.
• These differing reactivities are the basis of terpenoid biosynthesis, and carbocations feature strongly in mechanistic
rationalizations of the pathways.