Plasmodium heme biosynthesis: To be or not to be essential?

Goldberg, Daniel E.; Sigala, Paul A.

doi:10.1371/journal.ppat.1006511

Cited by 35 publications

(30 citation statements)

References 26 publications

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“…Mutants that were reduced strongly (>100-fold) at the SG-B2 transition showed a remarkable enrichment (p < 0.01) for metabolic genes (15 of 31 genes in this category encoded enzymes versus only 4 expected; Table S2). Some of the pathways represented by lost mutants are consistent with the known importance of heme and fatty acid biosynthesis at the liver stage (Shears et al., 2015, Goldberg and Sigala, 2017); others implicate more unexpected roles for fatty acid elongation, amino sugar metabolism, and the electron transport chain (Table S2; Figure 3D). By comparison, we did not see liver-stage-specific essentiality for genes with functions in DNA repair, DNA replication, or proteolysis (Figure 3D).…”

Section: Resultssupporting

confidence: 55%

Genome-Scale Identification of Essential Metabolic Processes for Targeting the Plasmodium Liver Stage

Stanway

Bushell

Chiappino-Pepe

et al. 2019

Cell

115

177

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SummaryPlasmodium gene functions in mosquito and liver stages remain poorly characterized due to limitations in the throughput of phenotyping at these stages. To fill this gap, we followed more than 1,300 barcoded P. berghei mutants through the life cycle. We discover 461 genes required for efficient parasite transmission to mosquitoes through the liver stage and back into the bloodstream of mice. We analyze the screen in the context of genomic, transcriptomic, and metabolomic data by building a thermodynamic model of P. berghei liver-stage metabolism, which shows a major reprogramming of parasite metabolism to achieve rapid growth in the liver. We identify seven metabolic subsystems that become essential at the liver stages compared with asexual blood stages: type II fatty acid synthesis and elongation (FAE), tricarboxylic acid, amino sugar, heme, lipoate, and shikimate metabolism. Selected predictions from the model are individually validated in single mutants to provide future targets for drug development.

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Section: Resultssupporting

confidence: 55%

Genome-Scale Identification of Essential Metabolic Processes for Targeting the Plasmodium Liver Stage

Stanway

Bushell

Chiappino-Pepe

et al. 2019

Cell

115

177

View full text Add to dashboard Cite

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“…Whereas protein-driven hemozoin formation has been postulated before (101), lipid-driven mechanisms (102,103) and an autocatalytic process have also been proposed (104). Unsurprisingly, heme synthesis is not essential for Plasmodium during the intraerythrocytic development, but the pathway becomes fitness-conferring during liver stages and is essential for development in the mosquito (105)(106)(107)(108)(109). Specifically, the loss of FC impairs male gamete formation and ablates oocyst formation in mosquitoes, indicating that Plasmodium can utilize salvaged heme but relies on its synthesis when levels of exogeneous heme become limiting within the insect vector (105,106).…”

Section: Hemementioning

confidence: 99%

Vitamin and cofactor acquisition in apicomplexans: Synthesis versus salvage

Krishnan¹,

Kloehn²,

Lunghi³

et al. 2019

J. Biol. Chem.

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The Apicomplexa phylum comprises diverse parasitic organisms that have evolved from a free-living ancestor. These obligate intracellular parasites exhibit versatile metabolic capabilities reflecting their capacity to survive and grow in different hosts and varying niches. Determined by nutrient availability, they either use their biosynthesis machineries or largely depend on their host for metabolite acquisition. Because vitamins cannot be synthesized by the mammalian host, the enzymes required for their synthesis in apicomplexan parasites represent a large repertoire of potential therapeutic targets. Here, we review recent advances in metabolic reconstruction and functional studies coupled to metabolomics that unravel the interplay between biosynthesis and salvage of vitamins and cofactors in apicomplexans. A particular emphasis is placed on Toxoplasma gondii, during both its acute and latent stages of infection.

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“…Moreover, malaria parasites switch their requirement for de novo heme production at different infection stages. The de novo heme biosynthesis is dispensable in the blood-stage infection of Plasmodium falciparum [4,18], but is required for its liverstage infection [19,20], suggesting that intracellular pathogens could switch their heme requirements based on heme availability.…”

Section: Plos Pathogensmentioning

confidence: 99%

“…For example, two well-known representative species within the Apicomplexa Phylum, Toxoplasma gondii and Plasmodium spp., encode a complete heme biosynthesis pathway in their genomes [1] ( Fig 1A and S1 Table). The eight heme biosynthetic enzymes residing within this pathway are delivered to three subcellular locations [1][2][3][4], including the mitochondrion, cytoplasm, and apicoplast. The apicoplast is a remnant chloroplast and specifically exists in apicomplexan parasites.…”

Section: Introductionmentioning

confidence: 99%

Toxoplasma gondii requires its plant-like heme biosynthesis pathway for infection

et al. 2020

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Heme, an iron-containing organic ring, is essential for virtually all living organisms by serving as a prosthetic group in proteins that function in diverse cellular activities ranging from diatomic gas transport and sensing, to mitochondrial respiration, to detoxification. Cellular heme levels in microbial pathogens can be a composite of endogenous de novo synthesis or exogenous uptake of heme or heme synthesis intermediates. Intracellular pathogenic microbes switch routes for heme supply when heme availability fluctuates in their replicative environment throughout infection. Here, we show that Toxoplasma gondii, an obligate intracellular human pathogen, encodes a functional heme biosynthesis pathway. A chloroplastderived organelle, termed apicoplast, is involved in heme production. Genetic and chemical manipulation revealed that de novo heme production is essential for T. gondii intracellular growth and pathogenesis. Surprisingly, the herbicide oxadiazon significantly impaired Toxoplasma growth, consistent with phylogenetic analyses that show T. gondii protoporphyrinogen oxidase is more closely related to plants than mammals. This inhibition can be enhanced by 15-to 25-fold with two oxadiazon derivatives, lending therapeutic proof that Toxoplasma heme biosynthesis is a druggable target. As T. gondii has been used to model other apicomplexan parasites, our study underscores the utility of targeting heme biosynthesis in other pathogenic apicomplexans, such as Plasmodium spp., Cystoisospora, Eimeria, Neospora, and Sarcocystis.

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Plasmodium heme biosynthesis: To be or not to be essential?

Cited by 35 publications

References 26 publications

Genome-Scale Identification of Essential Metabolic Processes for Targeting the Plasmodium Liver Stage

Genome-Scale Identification of Essential Metabolic Processes for Targeting the Plasmodium Liver Stage

Vitamin and cofactor acquisition in apicomplexans: Synthesis versus salvage

Toxoplasma gondii requires its plant-like heme biosynthesis pathway for infection

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