Reconstitution of an apicoplast‐localised electron transfer pathway involved in the isoprenoid biosynthesis of <i>Plasmodium falciparum</i>

Röhrich, René C; Englert, Nadine; Troschke, Katrin; Reichenberg, Armin; Hintz, Martin; Seeber, Frank; Balconi, E.; Aliverti, Alessandro; Zanetti, G.; Köhler, Uwe; Pfeiffer, Mat­thias; Beck, Ewald; Jomaa, Hassan; Wiesner, Jochen

doi:10.1016/j.febslet.2005.10.037

Cited by 96 publications

(91 citation statements)

References 25 publications

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“…In the dark, ferredoxin together with NADP + -ferredoxin-reductase and NADPH serves as electron donor. A very similar apicoplastlocated electron transfer system was found to interact with IspH in P. falciparum [56]. Little data are available about the isoprenoid metabolism in P. falciparum downstream of IPP and DMAPP.…”

Section: Isoprenoid Synthesismentioning

confidence: 97%

The Plastid-Like Organelle of Apicomplexan Parasites as Drug Target

Wiesner

Reichenberg²,

Heinrich³

et al. 2008

CPD

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Apicomplexan parasites infectious to humans include Plasmodium spp., Babesia spp., Toxoplasma gondii, Cryptosporidium spp., Isospora belli and Cyclospora cayetanensis. With exception of Cryptosporidium spp., these parasites possess a non-photosynthetic plastid-like organelle called apicoplast. The apicoplast possesses a small circular genome and harbours prokaryotic-type biochemical pathways. As the most important metabolic functions, the mevalonate independent 1-deoxy-D-xylulose 5-phosphate pathway of isoprenoid synthesis and the type II fatty acid synthesis system are operative inside the apicoplast. Classical antibacterial drugs such as ciprofloxacin, tetracycline, doxycycline, clindamycin and spiramycin inhibit the apicoplast-located gyrase and translation machinery, respectively, and are currently used in the clinic for the treatment of infections with apicomplexan parasites. As an inhibitor of isoprenoid synthesis, fosmidomycin was proven to be effective against acute P. falciparum malaria in clinical phase II studies. Triclosan, an inhibitor of fatty acid synthesis, was active in a malaria mouse model. In vitro antimalarial activity was shown for inhibitors of peptide deformylase and the import of apicoplast-targeted proteins. Work on various other inhibitors of apicoplast-located biochemical processes is ongoing.

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Section: Isoprenoid Synthesismentioning

confidence: 97%

The Plastid-Like Organelle of Apicomplexan Parasites as Drug Target

Wiesner

Reichenberg²,

Heinrich³

et al. 2008

CPD

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“…[437] A methyl viologen based colorimetric assay was developed for the iron-sulfurcluster-containing enzyme LytB (IspH), which catalyzes the last step of the synthesis. [438] Lead discovery is in progress for this enzyme.…”

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confidence: 99%

Malaria Chemotherapeutics Part I: History of Antimalarial Drug Development, Currently Used Therapeutics, and Drugs in Clinical Development

2007

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Since ancient times, humankind has had to struggle against the persistent onslaught of pathogenic microorganisms. Nowadays, malaria is still the most important infectious disease worldwide. Considerable success in gaining control over malaria was achieved in the 1950s and 60s through landscaping measures, vector control with the insecticide DDT, and the widespread administration of chloroquine, the most important antimalarial agent ever. In the late 1960s, the final victory over malaria was believed to be within reach. However, the parasites could not be eradicated because they developed resistance against the most widely used and affordable drugs of that time. Today, cases of malaria infections are on the rise and have reached record numbers. This review gives a short description of the malaria disease, briefly addresses the history of antimalarial drug development, and focuses on drugs currently available for malaria therapy. The present knowledge regarding their mode of action and the mechanisms of resistance are explained, as are the attempts made by numerous research groups to overcome the resistance problem within classes of existing drugs and in some novel classes. Finally, this review covers all classes of antimalarials for which at least one drug candidate is in clinical development. Antimalarial agents that are solely in early development stages will be addressed in a separate review.

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“…At its center of mass, the protein features an iron-sulfur cluster which is coordinated by the cysteine residues 12, 96, and 197 (one from each of the three folding domains, amino acid residue numbers refer to E. coli). Although it is mostly assumed that IspH protein requires a [4Fe-4S] cluster for catalytic activity (7,8), all published structures so far showed [3Fe-4S] clusters (5,6). Notably, the E. coli protein crystallized in a closed conformation with the iron-sulfur cluster located inside a solvent-inaccessible central cavity that also contained a pyrophosphate or malonate ion, depending on crystallization conditions (5).…”

mentioning

confidence: 99%

Probing the reaction mechanism of IspH protein by x-ray structure analysis

Gräwert

Span

Eisenreich

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

102

228

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Isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP) represent the two central intermediates in the biosynthesis of isoprenoids. The recently discovered deoxyxylulose 5-phosphate pathway generates a mixture of IPP and DMAPP in its final step by reductive dehydroxylation of 1-hydroxy-2-methyl-2-butenyl 4-diphosphate. This conversion is catalyzed by IspH protein comprising a central iron-sulfur cluster as electron transfer cofactor in the active site. The five crystal structures of IspH in complex with substrate, converted substrate, products and PP i reported in this article provide unique insights into the mechanism of this enzyme. While IspH protein crystallizes with substrate bound to a [4Fe-4S] cluster, crystals of IspH in complex with IPP, DMAPP or inorganic pyrophosphate feature [3Fe-4S] clusters. The IspH:substrate complex reveals a hairpin conformation of the ligand with the C(1) hydroxyl group coordinated to the unique site in a [4Fe-4S] cluster of aconitase type. The resulting alkoxide complex is coupled to a hydrogen-bonding network, which serves as proton reservoir via a Thr167 proton relay. Prolonged x-ray irradiation leads to cleavage of the C(1)-O bond (initiated by reducing photo electrons). The data suggest a reaction mechanism involving a combination of Lewis-acid activation and proton coupled electron transfer. The resulting allyl radical intermediate can acquire a second electron via the iron-sulfur cluster. The reaction may be terminated by the transfer of a proton from the β-phosphate of the substrate to C(1) (affording DMAPP) or C(3) (affording IPP).iron-sulfur protein | LytB protein | nonmevalonate pathway | terpene biosynthesis | isoprenoid biosynthesis

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Reconstitution of an apicoplast‐localised electron transfer pathway involved in the isoprenoid biosynthesis of Plasmodium falciparum

Cited by 96 publications

References 25 publications

The Plastid-Like Organelle of Apicomplexan Parasites as Drug Target

The Plastid-Like Organelle of Apicomplexan Parasites as Drug Target

Malaria Chemotherapeutics Part I: History of Antimalarial Drug Development, Currently Used Therapeutics, and Drugs in Clinical Development

Probing the reaction mechanism of IspH protein by x-ray structure analysis

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