2<i>C</i>-Methyl-<scp>d</scp>-erythritol 4-Phosphate Enhances and Sustains Cyclodiphosphate Synthase IspF Activity

Bitok, J. Kipchirchir; Meyers, Caren L. Freel

doi:10.1021/cb300243w

Cited by 38 publications

(47 citation statements)

References 60 publications

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“…For example, interaction of IspD with other MEP enzymes may be important for the flux of intermediates through the pathway and final product formation. In addition, feedback regulation by MEP pathway intermediates and isoprenoid products has been shown for IspF, another pathway enzyme (36). Investigating how the L244I and E688Q mutations result in resistance to inhibition by MMV-08138 will also be revealing.…”

Section: Discussionmentioning

confidence: 97%

A Chemical Rescue Screen Identifies a Plasmodium falciparum Apicoplast Inhibitor Targeting MEP Isoprenoid Precursor Biosynthesis

Herrera

Ebert

et al. 2015

Antimicrob Agents Chemother

109

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The apicoplast is an essential plastid organelle found in Plasmodium parasites which contains several clinically validated antimalarial-drug targets. A chemical rescue screen identified MMV-08138 from the "Malaria Box" library of growth-inhibitory antimalarial compounds as having specific activity against the apicoplast. MMV-08138 inhibition of blood-stage Plasmodium falciparum growth is stereospecific and potent, with the most active diastereomer demonstrating a 50% effective concentration (EC 50 ) of 110 nM. Whole-genome sequencing of 3 drug-resistant parasite populations from two independent selections revealed E688Q and L244I mutations in P. falciparum IspD, an enzyme in the MEP (methyl-D-erythritol-4-phosphate) isoprenoid precursor biosynthesis pathway in the apicoplast. The active diastereomer of MMV-08138 directly inhibited PfIspD activity in vitro with a 50% inhibitory concentration (IC 50 ) of 7.0 nM. MMV-08138 is the first PfIspD inhibitor to be identified and, together with heterologously expressed PfIspD, provides the foundation for further development of this promising antimalarial drug candidate lead. Furthermore, this report validates the use of the apicoplast chemical rescue screen coupled with target elucidation as a discovery tool to identify specific apicoplast-targeting compounds with new mechanisms of action. Despite encouraging progress over the past decade, malaria caused by Plasmodium parasites continues to pose an enormous disease burden (1). New antimalarials with novel mechanisms of action are needed to circumvent existing or emerging drug resistance (2). The apicoplast is a plastid organelle unique to Plasmodium spp. (and other pathogenic Apicomplexa parasites) and is a key target for development of new antimalarials. Due to its prokaryotic origin and evolution as a secondary plastid, it contains pathways that have no counterpart in the human host (3, 4). The apicoplast in Plasmodium is essential for both intraerythrocytic and intrahepatic development in the human host (5, 6).Despite efforts to develop inhibitors of apicoplast function, to date, there have been no primary agents for treatment of acute malaria whose mechanism of action targets this unusual plastid organelle. Antibiotics that inhibit prokaryotic transcription and translation, such as doxycycline and clindamycin, block expression of the apicoplast genome and are active against Plasmodium parasites (5). Unfortunately, these drugs show a "delayed death" phenotype, in which growth inhibition occurs only after 2 replication cycles (96 h). The slow kinetics limit the use of doxycycline and clindamycin to chemoprophylaxis or as partner drugs in combination therapies with faster-acting compounds. Fosmidomycin, which inhibits the enzyme DoxR/IspC for MEP (methyl-D-erythritol-4-phosphate) isoprenoid precursor biosynthesis in the apicoplast, has immediate onset but shows high recrudescence rates clinically when used as monotherapy (7,8). The efficacy of fosmidomycin-based combination therapy is currently being evaluated, with mixe...

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Section: Discussionmentioning

confidence: 97%

A Chemical Rescue Screen Identifies a Plasmodium falciparum Apicoplast Inhibitor Targeting MEP Isoprenoid Precursor Biosynthesis

Herrera

Ebert

et al. 2015

Antimicrob Agents Chemother

109

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“…All of this evidence suggests a regulatory role for DXS in the MEP pathway. Recently, a feed-forward activation of IspF enzyme (2-C-methyl-D-erythritol-2,4-cyclodiphosphate synthase) by MEP and a feedback inhibition of IspF-MEP complex by a downstream isoprenoid farnesyl diphosphate have been reported in E. coli (67). This explains a new regulatory mechanism that modulates the synthesis of one of the key intermediates of the MEP pathway.…”

Section: Discussionmentioning

confidence: 97%

Feedback Inhibition of Deoxy-d-xylulose-5-phosphate Synthase Regulates the Methylerythritol 4-Phosphate Pathway

Banerjee

et al. 2013

Journal of Biological Chemistry

156

186

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Background:The methylerythritol phosphate (MEP) pathway is required for the biosynthesis of plastid-derived isoprenoids from plants. Results: Deoxyxylulose-5-phosphate synthase (DXS) was cloned from Populus trichocarpa, and metabolic regulation was tested. Conclusion: Both isopentenyl diphosphate and dimethylallyl diphosphate inhibit DXS by competing with thiamine pyrophosphate. Significance: Prediction of isoprene emission from trees and bioengineering of MEP pathway will be aided by these results.

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“…A recent study identified a feedforward mechanism of MEP pathway regulation in E. coli. The MEP pathway enzyme 2-C-methyl-D-erythritol 2,4-cyclodiphosphate synthase (EC 4.6.1.12, PlasmoDB ID PF3D7_0209300) is activated by the upstream intermediate MEP (146). Additionally, IPP and DMAPP have been shown to cause feedback inhibition of the rate-limiting enzyme DXS in Populus trichocarpa (147).…”

Section: Regulation Of Isoprenoid Synthesismentioning

confidence: 99%

Isoprenoid Biosynthesis in Plasmodium falciparum

2014

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bMalaria kills nearly 1 million people each year, and the protozoan parasite Plasmodium falciparum has become increasingly resistant to current therapies. Isoprenoid synthesis via the methylerythritol phosphate (MEP) pathway represents an attractive target for the development of new antimalarials. The phosphonic acid antibiotic fosmidomycin is a specific inhibitor of isoprenoid synthesis and has been a helpful tool to outline the essential functions of isoprenoid biosynthesis in P. falciparum. Isoprenoids are a large, diverse class of hydrocarbons that function in a variety of essential cellular processes in eukaryotes. In P. falciparum, isoprenoids are used for tRNA isopentenylation and protein prenylation, as well as the synthesis of vitamin E, carotenoids, ubiquinone, and dolichols. Recently, isoprenoid synthesis in P. falciparum has been shown to be regulated by a sugar phosphatase. We outline what is known about isoprenoid function and the regulation of isoprenoid synthesis in P. falciparum, in order to identify valuable directions for future research.

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2C-Methyl-d-erythritol 4-Phosphate Enhances and Sustains Cyclodiphosphate Synthase IspF Activity

Cited by 38 publications

References 60 publications

A Chemical Rescue Screen Identifies a Plasmodium falciparum Apicoplast Inhibitor Targeting MEP Isoprenoid Precursor Biosynthesis

A Chemical Rescue Screen Identifies a Plasmodium falciparum Apicoplast Inhibitor Targeting MEP Isoprenoid Precursor Biosynthesis

Feedback Inhibition of Deoxy-d-xylulose-5-phosphate Synthase Regulates the Methylerythritol 4-Phosphate Pathway

Isoprenoid Biosynthesis in Plasmodium falciparum

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