university of kwazulu-natal faculty of science and agriculture school ...

In the mevalonic acid pathway, the biosynthesis starts with the Claisen condensation
reaction where two molecules of acetyl-CoA react to produce acetoacetyl-CoA which
reacts further with an additional molecule of acetyl-CoA in a stereospecific aldol reaction
producing HMG-CoA (β-hydroxy-β-methylglutaryl-CoA) (figure 6). The carbonyl
group in HMG-CoA is then reduced with NADPH to the primary alcohol producing
mevaldic acid hemithioacetal, then mevaldic acid and further reduction to mevalonic acid
(MVA). The addition of two ATP molecules leads to the sequential phosphorylation of
MVA to mevalonic acid diphosphate and a further molecule of ATP results in the release
of CO2 producing isopentenyl disphosphate (IPP) which is subsequently isomerised to
DMAPP in a reversible reaction. The forward reaction is favoured due to the
electrophilic nature of DMAPP.
H
O
1
HO2C 2
SCoA
O
6
H
O
3
SCoA
OH
4
mevalonic acid
(MVA)
2 x ATP
OH
OH
NADPH
O OPP
5
Claisen
reaction
mevalonic acid diphosphate
O
H
O
OH P O ADP
OH
HO 2C
-CO 2
O
SCoA
acetoacetyl-CoA
O
-H +
CoA
OH
mevaldic acid
H
4
5
3
H R
2
O
Linkage
Hydrolysis of
acetyl-CoA
H S
isopentenyl PP
(IPP)
1
-H +
OPP
HO 2C
HO 2C
isomerase
HMG-CoA
reductase
OH
O
HMG-CoA
OH
NADPH
OH
H
mevaldic acid
hemithioacetal
dimethylallyl PP
(DMAPP)
Figure 6: IPP derived from mevalonic acid (MVA), (reproduced from Dewick, 2002)
SCoA
SCoA
OPP
EnzSH
8