The Shikimate Pathway and Its Branches in Apicomplexan Parasites

Roberts, Craig W.; Roberts, Fiona; Lyons, Russell E.; Kirisits, Michael J.; Mui, Ernest; Finnerty, John R.; Johnson, Jennifer J.; Ferguson, David J. P.; Coggins, John R.; Krell, Tino; Coombs, Graham H.; Milhous, Wilbur K.; Kyle, Dennis E.; Tzipori, Saul; Barnwell, John W.; Dame, John B.; Carlton, Jane M.; McLeod, Rima

doi:10.1086/338004

Cited by 136 publications

(90 citation statements)

References 95 publications

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“…Based on these results, Roberts C. W. et al 48) suggested that glyphosate or other inhibitors of the shikimate pathway might be good antimalarials. Considering the high IC 50 of glyphosate, this compound has not been further studied or developed for treatment for malaria.…”

Section: Discussionmentioning

confidence: 99%

A Survey of Synthetic and Natural Phytotoxic Compounds and Phytoalexins as Potential Antimalarial Compounds

Bajsa

Singh

Nanayakkara

et al. 2007

Biological & Pharmaceutical Bulletin

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The apicomplexan parasites pathogens such as Plasmodium spp. possess an apicoplast, a plastid organelle similar to those of plants. The apicoplast has some essential plant-like metabolic pathways and processes, making these parasites susceptible to inhibitors of these functions. The main objective of this paper is to determine if phytotoxins with plastid target sites are more likely to be good antiplasmodial compounds than are those with other modes of action. The antiplasmodial activities of some compounds with established phytotoxic action were determined in vitro on a chloroquine (CQ) sensitive (D6, Sierra Leone) strain of Plasmodium falciparum. In this study, we provide in vitro activities of almost 50 such compounds, as well as a few phytoalexins against P. falciparum. Endothall, anisomycin, and cerulenin had sufficient antiplasmodial action to be considered as new lead antimalarial structures. Some derivatives of fusicoccin possessed markedly improved antiplasmodial action than the parent compound. Our results suggest that phytotoxins with plastid targets may not necessarily be better antiplasmodials than those that act at other molecular sites. The herbicides, phytotoxins and the phytoalexins reported here with significant antiplasmodial activity may be useful probes for identification of new antimalarial drug targets and may also be used as new lead structures for new antiplasmodial drug discovery.

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Section: Discussionmentioning

confidence: 99%

A Survey of Synthetic and Natural Phytotoxic Compounds and Phytoalexins as Potential Antimalarial Compounds

Bajsa

Singh

Nanayakkara

et al. 2007

Biological & Pharmaceutical Bulletin

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“…The importance of the shikimate pathway is exemplified by the common herbicide glyphosate, which inhibits the enzyme 5-enolpyruvylshikimate-3-phosphate synthase. Recent studies have also shown that glyphosate blocks the shikimate pathway in apicomplexan parasites and is effective in controlling their growth (3). The shikimate pathway consists of seven enzymatic steps initiated by the condensation of phosphoenolpyruvate and erythrose-4-phosphate by 3-deoxy-Darabino-heptolosonate 7-phosphate synthase.…”

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confidence: 99%

Crystal Structure of a Novel Shikimate Dehydrogenase from Haemophilus influenzae

Singh

Korolev

Королева

et al. 2005

Journal of Biological Chemistry

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To date two classes of shikimate dehydrogenases have been identified and characterized, YdiB and AroE. YdiB is a bifunctional enzyme that catalyzes the reversible reductions of dehydroquinate to quinate and dehydroshikimate to shikimate in the presence of either NADH or NADPH. In contrast, AroE catalyzes the reversible reduction of dehydroshikimate to shikimate in the presence of NADPH. Here we report the crystal structure and biochemical characterization of HI0607, a novel class of shikimate dehydrogenase annotated as shikimate dehydrogenase-like. The kinetic properties of HI0607 are remarkably different from those of AroE and YdiB. In comparison with YdiB, HI0607 catalyzes the oxidation of shikimate but not quinate. The turnover rate for the oxidation of shikimate is ϳ1000-fold lower compared with that of AroE. Phylogenetic analysis reveals three independent clusters representing three classes of shikimate dehydrogenases, namely AroE, YdiB, and this newly characterized shikimate dehydrogenase-like protein. In addition, mutagenesis studies of two invariant residues, Asp-103 and Lys-67, indicate that they are important catalytic groups that may function as a catalytic pair in the shikimate dehydrogenase reaction. This is the first study that describes the crystal structure as well as mutagenesis and mechanistic analysis of this new class of shikimate dehydrogenase.The shikimate pathway occupies a central position for aromatic biosynthesis in microbes and plants but is not present in humans and other higher animals. The absence of the shikimate pathway in animals makes it an ideal target for herbicide and anti-microbial drug design. Recently the shikimate pathway was identified in apicomplexan parasites, including Toxoplasma gondii and Plasmodium falciparum, which has renewed interest in better understanding the enzymes in the pathway (1, 2). The importance of the shikimate pathway is exemplified by the common herbicide glyphosate, which inhibits the enzyme 5-enolpyruvylshikimate-3-phosphate synthase. Recent studies have also shown that glyphosate blocks the shikimate pathway in apicomplexan parasites and is effective in controlling their growth (3). The shikimate pathway consists of seven enzymatic steps initiated by the condensation of phosphoenolpyruvate and erythrose-4-phosphate by 3-deoxy-Darabino-heptolosonate 7-phosphate synthase. The last enzymatic step produces the branch point intermediate, chorismate, which serves in turn as the precursor for a number of pathways including those involved in aromatic amino acid, phytoalexin, flavanoid, and lignin biosynthesis.The fourth enzyme in the pathway, shikimate dehydrogenase (shikimate:NADP ϩ oxidoreductase; EC 1.1.1.25), is involved in the NADPH-dependent reduction of dehydroshikimate to shikimate. This enzymatic reaction proceeds in both the forward and reverse direction with similar rates and similar Michaelis constants for substrates in either direction. Kinetic studies with substrate analogues and isotope exchange demonstrated that the shikimate dehydrogena...

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“…The only other enzyme known to catalyze a similar reaction is 5-enolpyruvyl shikimate-3-phosphate synthase (EC 2.5.1.19), also known as EPSPS or AroA. 5-Enolpyruvyl shikimate-3-phosphate synthase is the sixth enzyme in the shikimate pathway toward the synthesis of aromatic amino acids in microorganisms and plants (7,8). Both enzymes exist in an open, substrate-free state and a closed, liganded state, indicating that their reactions follow an induced-fit mechanism (9 -13).…”

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confidence: 99%

A Novel Inhibitor That Suspends the Induced Fit Mechanism of UDP-N-acetylglucosamine Enolpyruvyl Transferase (MurA)

Eschenburg

Priestman

Abdul-Latif³

et al. 2005

Journal of Biological Chemistry

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The Shikimate Pathway and Its Branches in Apicomplexan Parasites

Cited by 136 publications

References 95 publications

A Survey of Synthetic and Natural Phytotoxic Compounds and Phytoalexins as Potential Antimalarial Compounds

A Survey of Synthetic and Natural Phytotoxic Compounds and Phytoalexins as Potential Antimalarial Compounds

Crystal Structure of a Novel Shikimate Dehydrogenase from Haemophilus influenzae

A Novel Inhibitor That Suspends the Induced Fit Mechanism of UDP-N-acetylglucosamine Enolpyruvyl Transferase (MurA)

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