124
J. Pospíšil et al.
originated from laboratory research [64, 65] were inspired by traditional medicines
[66]. Unfortunately, many of these compound leads are only at the beginning of their
journey from the laboratory to patients [64–66]. As will be suggested in the next
sections of this chapter, it is believed that structural design based on the skeletons of
phenylpropanoid dimers can bring an answer to the search for new antileishmanial
drugs.
3 Secondary Metabolites of the Shikimate Pathway
Behind the colorful and diverse world of phenylpropanoid (PP) metabolites is the
shikimate pathway (SP) of plant biosynthesis, the producer of aromatic compounds.
The shikimate pathway can be seen as a seven-step enzymatic process that interconnects the primary metabolism products, phosphoenolpyruvate ((13) from glycolysis) and d-erythrose-4-phosphate ((12) from the pentose phosphate pathway) [67]
with phenylpropanoid metabolites (Fig. 3). In short, the aldol condensation of
12 and 13 that is catalyzed with 3-deoxy-d-arabino-heptulosanate 7-phosphate
synthase (DAHPS) produces 3-deoxy-d-arabino-heptulosanate 7-phosphate (14)
(the metabolic regulation of this process in plants seem to be preferentially controlled
at genetic level) [67]. Generation of a phosphate-intermediate is followed by
enzymatic transformation with the participation of five enzymes [68, 69]. In the
second step of transformation, enolization/intramolecular aldolization catalyzed
with monomeric 3-dehydroquinate synthase and requiring NAD
+ , yields the tertiary
alcohol-containing 3-dehydroquinic acid (15) [68]. Compound 15 is then dehydrated
to 3-dehydroshikimate (16). The reaction is catalyzed by 3-dehydroquinate dehydratase that exists in two forms, type I and II. These differ in their secondary structure
(50% vs. 75% of α-helix) and in the mechanism whereby H 2 O is eliminated (synvs. anti-elimination) [70]. Type I (characterized in Escherichia coli), uses Schiff
base (lysine) formation in the active site to eliminate the H 2 O molecule. This site
is not present in type II 3-dehydroquinate dehydratase (characterized in Aspergillus
nidulans) and is known to eliminate the water molecule via an anti-elimination
mechanism [71, 72]. Next, the reduction of 16 to shikimate (17) is carried out. The
reduction is catalyzed by the bi-functional enzyme complex DHQ/shikimate dehydrogenase and NADP-oxidoreductase, which uses NADP (in plants) as a cofactor
[69, 73, 74]. Shikimate (17) is phosphorylated by shikimate kinase and generates
the shikimate-3-phosphate (18). Irreversible phosphorylation of 17 is driven by ATP
substrate formation and is linked with the chloroplast environment [75, 76]. At this
stage, phosphoenolpyruvate (12) becomes involved and reversible condensation with
18 results in the formation of 5-enolpyruvylshikimate-3-phosphate (19) and HPO 4
2– .
The reaction is mediated by EPSP-synthase (the only target for the glyphosate herbicide that is supposed to make this minimally toxic for human and environment) [77].
Finally, a “deoxygenation” step generates the key intermediate of AAA metabolism
in plants (chorismate (20)). The chorismate (20) generation is characterized by an
anti-1,4-elimination of the phosphate group from 19 [78]. Chorismate synthase is
J. Pospíšil et al.
originated from laboratory research [64, 65] were inspired by traditional medicines
[66]. Unfortunately, many of these compound leads are only at the beginning of their
journey from the laboratory to patients [64–66]. As will be suggested in the next
sections of this chapter, it is believed that structural design based on the skeletons of
phenylpropanoid dimers can bring an answer to the search for new antileishmanial
drugs.
3 Secondary Metabolites of the Shikimate Pathway
Behind the colorful and diverse world of phenylpropanoid (PP) metabolites is the
shikimate pathway (SP) of plant biosynthesis, the producer of aromatic compounds.
The shikimate pathway can be seen as a seven-step enzymatic process that interconnects the primary metabolism products, phosphoenolpyruvate ((13) from glycolysis) and d-erythrose-4-phosphate ((12) from the pentose phosphate pathway) [67]
with phenylpropanoid metabolites (Fig. 3). In short, the aldol condensation of
12 and 13 that is catalyzed with 3-deoxy-d-arabino-heptulosanate 7-phosphate
synthase (DAHPS) produces 3-deoxy-d-arabino-heptulosanate 7-phosphate (14)
(the metabolic regulation of this process in plants seem to be preferentially controlled
at genetic level) [67]. Generation of a phosphate-intermediate is followed by
enzymatic transformation with the participation of five enzymes [68, 69]. In the
second step of transformation, enolization/intramolecular aldolization catalyzed
with monomeric 3-dehydroquinate synthase and requiring NAD
+ , yields the tertiary
alcohol-containing 3-dehydroquinic acid (15) [68]. Compound 15 is then dehydrated
to 3-dehydroshikimate (16). The reaction is catalyzed by 3-dehydroquinate dehydratase that exists in two forms, type I and II. These differ in their secondary structure
(50% vs. 75% of α-helix) and in the mechanism whereby H 2 O is eliminated (synvs. anti-elimination) [70]. Type I (characterized in Escherichia coli), uses Schiff
base (lysine) formation in the active site to eliminate the H 2 O molecule. This site
is not present in type II 3-dehydroquinate dehydratase (characterized in Aspergillus
nidulans) and is known to eliminate the water molecule via an anti-elimination
mechanism [71, 72]. Next, the reduction of 16 to shikimate (17) is carried out. The
reduction is catalyzed by the bi-functional enzyme complex DHQ/shikimate dehydrogenase and NADP-oxidoreductase, which uses NADP (in plants) as a cofactor
[69, 73, 74]. Shikimate (17) is phosphorylated by shikimate kinase and generates
the shikimate-3-phosphate (18). Irreversible phosphorylation of 17 is driven by ATP
substrate formation and is linked with the chloroplast environment [75, 76]. At this
stage, phosphoenolpyruvate (12) becomes involved and reversible condensation with
18 results in the formation of 5-enolpyruvylshikimate-3-phosphate (19) and HPO 4
2– .
The reaction is mediated by EPSP-synthase (the only target for the glyphosate herbicide that is supposed to make this minimally toxic for human and environment) [77].
Finally, a “deoxygenation” step generates the key intermediate of AAA metabolism
in plants (chorismate (20)). The chorismate (20) generation is characterized by an
anti-1,4-elimination of the phosphate group from 19 [78]. Chorismate synthase is