Biomedical Engineering Reference
In-Depth Information
21.5.3 D
RUGS
T
ARGETING
D
EOXYXYLULOSEPHOSPHATE
-R
EDUCTOISOMERASE
In plants, the biosynthesis of isopentenyl diphosphate (
21.16
), the precursor of all terpenoids, follows
two independent pathways: (1) the mevalonate pathway and (2) the 1-deoxy-d-xylulose-5-phosphate
pathway (the nonmevalonate—or the Röhmer pathway). In plants, the mevalonate pathway occurs
in the cytosolic compartment, but the deoxyxylulose pathway takes place in the plastids, which are
analogous to apicoplasts. A search in the genome of
Plasmodium
parasites revealed the presence of
genes encoding the enzymes of the deoxyxylulose pathway including the genes encoding 1-deoxy-
d-xylulose 5-phosphate reductoisomerase (DOXP-reductoisomerase). This enzyme catalyses a
crucial step in the deoxyxylulose pathway (Scheme 21.2): the reductive rearrangement of 1-deoxy-
d-xylulose 5-phosphate (
21.13
) into 2-C-methyl-d-erythritol 4-phosphate (
21.15
).
Fosmidomycin (
21.17
) (Scheme 21.2), an antibiotic and herbicidal agent isolated from cul-
tures of
Streptomyces lavendulae
, efi ciently inhibits the plants' carotenoid and phytol synthesis.
Fosmidomycin is a structural analog to 2-methylerythrose 4-phosphate (
21.14
), a never isolated
compound but likely to be an intermediate in the conversion of (
21.13
) into (
21.15
). Combination
therapy using fosmidomycin and clindamycin has revealed high antimalarial activity and only mild
gastrointestinal side effects. The drug, however, is still in development.
H
H
O
O
O
O
O
O
O
O
O
O
O
OH
OH
OH
OH
+
P
P
P
P
OH
OH
OH
OH
OH
OH
OH
O
OH
OH
OH
21.14
21.13
H
+
DOXP-reductoisomerase
O
PP
O
O
OO
OH
OH
OH
OH
P
OH
O
OH
OH
OH
21.15
21.16
OH
O
OH
P
N
OH
O
21.17
SCHEME 21.2
Reductive rearrangement of 1-deoxy-d-xylulose 5-phosphate (
21.13
) to 2-C-methyl-d-
erythritol 4-phosphate (
21.15
) in the deoxyxylulose pathway via the never isolated 2-methylerythrose
4-phosphate (
21.14
). Isopentenyl diphoshate (
21.16
) is the precursor for terpenoids. Coni guration of the
DOXP-reductoisomerase inhibitor, fosmidomycin (
21.17
).
21.5.4 D
RUGS
T
ARGETING
M
ITOCHONDRIAL
F
UNCTIONS
In contrast to the hosts, the mitochondrial electron transport of
Plasmodium
parasites is not coupled
to the synthesis of ATP. An important function of the mitochondria is to maintain an electron
transport needed for nucleotide synthesis. Parasites are dependent on
de novo
synthesis of the nucle-
otides. The mitochondrial cytochrome
bc
1
complex is a part of the electron transport. The enzyme
consists of a cytochrome and a Rieske protein bound to an iron sulfur subunit. In the ubiquinol
binding pocket, two electrons are transferred from ubiquinol via the subunit to cytochrome c heme
iron (Scheme 21.3).
