Exploring Drug Targets in Isoprenoid Biosynthetic Pathway for<i>Plasmodium falciparum</i>

Qidwai, Tabish; Jamal, Farrukh; Khan, M. Firoze; Sharma, Bechan

doi:10.1155/2014/657189

Cited by 15 publications

(8 citation statements)

References 55 publications

(66 reference statements)

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“…More recently, an entire subclass of isoprenoids called monoterpenes, typically found in plants, were discovered and are believed to function as volatile chemoattractants for mosquitoes [50]. While the MEP pathway has received attention as an attractive source of potential drug targets [51,52], the identity and essentiality of the full complement of isoprenoids generated by the parasite remains to be fully elucidated. Isoprenoids are the most abundant class of small molecules [53,54] and further discovery of these compounds is likely to provide additional insights into parasite biochemistry and may allow for the identification of additional druggable pathways.…”

Section: Discussionmentioning

confidence: 99%

A mevalonate bypass system facilitates elucidation of plastid biology in malaria parasites

et al. 2020

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Malaria parasites rely on a plastid organelle for survival during the blood stages of infection. However, the entire organelle is dispensable as long as the isoprenoid precursor, isopentenyl pyrophosphate (IPP), is supplemented in the culture medium. We engineered parasites to produce isoprenoid precursors from a mevalonate-dependent pathway, creating a parasite line that replicates normally after the loss of the apicoplast organelle. We show that carbon-labeled mevalonate is specifically incorporated into isoprenoid products, opening new avenues for researching this essential class of metabolites in malaria parasites. We also show that essential apicoplast proteins, such as the enzyme target of the drug fosmidomycin, can be deleted in this mevalonate bypass parasite line, providing a new method to determine the roles of other important apicoplast-resident proteins. Several antibacterial drugs kill malaria parasites by targeting basic processes, such as transcription, in the organelle. We used metabolomic and transcriptomic methods to characterize parasite metabolism after azithromycin treatment triggered loss of the apicoplast and found that parasite metabolism and the production of apicoplast proteins is largely unaltered. These results provide insight into the effects of apicoplast-disrupting drugs, several of which have been used to treat malaria infections in humans. Overall, the mevalonate bypass system provides a way to probe essential aspects of apicoplast biology and study the effects of drugs that target apicoplast processes.

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Section: Discussionmentioning

confidence: 99%

A mevalonate bypass system facilitates elucidation of plastid biology in malaria parasites

et al. 2020

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“…Other roles of isoprenoids include regulation of cell growth and energy production, intracellular signaling, and membrane structural support (15,21,22). Recent reviews discuss apicoplast metabolism and, specifically, isoprenoid synthesis, as drug targets in P. falciparum (23,24). Here, we address the key questions in the field: what isoprenoids does the malaria parasite make, and why?…”

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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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“…The Fd-FNR redox system is an important supplier of electrons in the apicoplast for isoprenoid precursor synthesis [20]. Defects in ferredoxin might affect isoprenoid synthesis leading to a decrease of precursors for molecules such as PI3P, important for vesicular formation.…”

Section: Discussionmentioning

confidence: 99%

Apicoplast ribosomal protein S10-V127M enhances artemisinin resistance of a Kelch13 transgenic Plasmodium falciparum

Kampoun

Srichairatanakool²,

Prommana³

et al. 2022

Malar J

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Background The resistance of Plasmodium falciparum to artemisinin-based (ART) drugs, the front-line drug family used in artemisinin-based combination therapy (ACT) for treatment of malaria, is of great concern. Mutations in the kelch13 (k13) gene (for example, those resulting in the Cys580Tyr [C580Y] variant) were identified as genetic markers for ART-resistant parasites, which suggests they are associated with resistance mechanisms. However, not all resistant parasites contain a k13 mutation, and clearly greater understanding of resistance mechanisms is required. A genome-wide association study (GWAS) found single nucleotide polymorphisms associated with ART-resistance in fd (ferredoxin), arps10 (apicoplast ribosomal protein S10), mdr2 (multidrug resistance protein 2), and crt (chloroquine resistance transporter), in addition to k13 gene mutations, suggesting that these alleles contribute to the resistance phenotype. The importance of the FD and ARPS10 variants in ART resistance was then studied since both proteins likely function in the apicoplast, which is a location distinct from that of K13. Methods The reported mutations were introduced, together with a mutation to produce the k13-C580Y variant into the ART-sensitive 3D7 parasite line and the effect on ART-susceptibility using the 0−3 h ring survival assay (RSA0−3 h) was investigated. Results and conclusion Introducing both fd-D193Y and arps10-V127M into a k13-C580Y-containing parasite, but not a wild-type k13 parasite, increased survival of the parasite in the RSA0−3 h. The results suggest epistasis of arps10 and k13, with arps10-V127M a modifier of ART susceptibility in different k13 allele backgrounds.

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Exploring Drug Targets in Isoprenoid Biosynthetic Pathway forPlasmodium falciparum

Cited by 15 publications

References 55 publications

A mevalonate bypass system facilitates elucidation of plastid biology in malaria parasites

A mevalonate bypass system facilitates elucidation of plastid biology in malaria parasites

Isoprenoid Biosynthesis in Plasmodium falciparum

Apicoplast ribosomal protein S10-V127M enhances artemisinin resistance of a Kelch13 transgenic Plasmodium falciparum

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