Functional profiles of orphan membrane transporters in the life cycle of the malaria parasite

Kenthirapalan, Sanketha; Waters, Andrew P.; Matuschewski, Kai; Kooij, Taco W. A.

doi:10.1038/ncomms10519

Cited by 75 publications

(154 citation statements)

References 39 publications

(47 reference statements)

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“…Parasites lacking an alternative zinc-iron permease (ZIPCO) are severely affected in liver-stage development in vitro and show a delay in prepatency of two days 35. A similar delay in prepatency was observed following needle injection of ctr2- sporozoites despite developing normally in culture 23. Interestingly, these parasites were most severely affected during natural transmission by infectious mosquito bites or following subcutaneous injection of the sporozoites.…”

Section: Resultsmentioning

confidence: 94%

“…Our initial localization studies were hampered by very low expression levels of the protein and hence difficult to interpret, but appeared to indicate an intraparasitic staining including a specific, small structure that may well be the apicoplast 23. In blood-stage parasites, the single critical role of the apicoplast was shown to be the production of isopentenyl pyrophosphate (IPP) 53 and it is tempting to speculate that DMT2 is the dedicated IPP transport protein.…”

Section: Resultsmentioning

confidence: 98%

“…In addition to the well-studied CRT 51, these include a hexose transporter HT 52, which is well conserved including in humans (Figure 1), and the putative drug metabolite transporter DMT2 23. The latter presents a particularly interesting case considering the orthology discovery.…”

Section: Resultsmentioning

confidence: 99%

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Phylogenetic profiles of all membrane transport proteins of the malaria parasite highlight new drug targets

Weiner

Kooij

2016

Microb Cell

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In order to combat the on-going malaria epidemic, discovery of new drug targets remains vital. Proteins that are essential to survival and specific to malaria parasites are key candidates. To survive within host cells, the parasites need to acquire nutrients and dispose of waste products across multiple membranes. Additionally, like all eukaryotes, they must redistribute ions and organic molecules between their various internal membrane bound compartments. Membrane transport proteins mediate all of these processes and are considered important mediators of drug resistance as well as drug targets in their own right. Recently, using advanced experimental genetic approaches and streamlined life cycle profiling, we generated a large collection of Plasmodium berghei gene deletion mutants and assigned essential gene functions, highlighting potential targets for prophylactic, therapeutic, and transmission-blocking anti-malarial drugs. Here, we present a comprehensive orthology assignment of all Plasmodium falciparum putative membrane transport proteins and provide a detailed overview of the associated essential gene functions obtained through experimental genetics studies in human and murine model parasites. Furthermore, we discuss the phylogeny of selected potential drug targets identified in our functional screen. We extensively discuss the results in the context of the functional assignments obtained using gene targeting available to date.

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Section: Resultsmentioning

confidence: 94%

Section: Resultsmentioning

confidence: 98%

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Phylogenetic profiles of all membrane transport proteins of the malaria parasite highlight new drug targets

Weiner

Kooij

2016

Microb Cell

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“…Initial clues for the importance of this gene fusion have come from Plasmodium, which expresses two stage-specific guanylate cyclases (Carucci et al, 2000), where GCα is likely essential for asexual blood stages (Kenthirapalan et al, 2016) and GCβ regulates ookinete motility and invasion in the mosquito midgut (Hirai et al, 2006; Moon et al, 2009). An important distinction between Plasmodium GCα and GCβ lies in the P-type ATPase domain, which has degenerated in GCβ, suggesting that the two GCs may have modes of regulation and/or perform separate functions.…”

Section: Discussionmentioning

confidence: 99%

Essential cGMP Signaling in Toxoplasma Is Initiated by a Hybrid P-Type ATPase-Guanylate Cyclase

Brown

Sibley

2018

Cell Host & Microbe

101

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Summary (150) Apicomplexan parasites rely on cyclic nucleotide-dependent kinases for host cell infection, yet the mechanisms that control their activation remain unknown. Here we show that an apically-localized guanylate cyclase (GC) controls microneme secretion and lytic growth in the model apicomplexan Toxoplasma gondii. Cell permeable cGMP reversed the block in microneme secretion seen in a knockdown of TgGC, linking its function to production of cGMP. TgGC possesses an N-terminal P-type-ATPase domain fused to a C-terminal heterodimeric guanylate cyclase domain, an architecture found only in Apicomplexa and related protists. Complementation with a panel of mutants revealed a critical requirement for the P-type ATPase domain for maximum GC function. We further demonstrate that knockdown of TgGC in vivo protects mice from lethal infection by blocking parasite expansion and dissemination. Collectively this work demonstrates that cGMP-mediated signaling in Toxoplasma relies on a multi-domain architecture, which may serve a conserved role in related parasites.

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“…These studies have for the most part focused on essentiality and growth rate phenotypes in the asexual blood stage of the parasite and have ranged from those which specifically targeted subsets of transporter genes to the large‐scale knockout screen of 2578 P. berghei genes (Bushell et al ., ). The transporters targeted by the small‐scale screens have included the genes encoding 35 ‘orphan transporters’ (Kenthirapalan et al ., ), ATP‐binding cassette (ABC) type pumps (Rijpma et al ., ), and transporters predicted to localise to the membranes of the apicoplast (Sayers et al ., ).…”

Section: The Plasmodium Transportomementioning

confidence: 99%

The transportome of the malaria parasite

Martin

2019

Biological Reviews

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Membrane transport proteins, also known as transporters, control the movement of ions, nutrients, metabolites, and waste products across the membranes of a cell and are central to its biology. Proteins of this type also serve as drug targets and are key players in the phenomenon of drug resistance. The malaria parasite has a relatively reduced transportome, with only approximately 2.5% of its genes encoding transporters. Even so, assigning functions and physiological roles to these proteins, and ascertaining their contributions to drug action and drug resistance, has been very challenging. This review presents a detailed critique and synthesis of the disruption phenotypes, protein subcellular localisations, protein functions (observed or predicted), and links to antimalarial drug resistance for each of the parasite's transporter genes. The breadth and depth of the gene disruption data are particularly impressive, with at least one phenotype determined in the parasite's asexual blood stage for each transporter gene, and multiple phenotypes available for 76% of the genes. Analysis of the curated data set revealed there to be relatively little redundancy in the Plasmodium transportome; almost two‐thirds of the parasite's transporter genes are essential or required for normal growth in the asexual blood stage of the parasite, and this proportion increased to 78% when the disruption phenotypes available for the other parasite life stages were included in the analysis. These observations, together with the finding that 22% of the transportome is implicated in the parasite's resistance to existing antimalarials and/or drugs within the development pipeline, indicate that transporters are likely to serve, or are already serving, as drug targets. Integration of the different biological and bioinformatic data sets also enabled the selection of candidates for transport processes known to be essential for parasite survival, but for which the underlying proteins have thus far remained undiscovered. These include potential transporters of pantothenate, isoleucine, or isopentenyl diphosphate, as well as putative anion‐selective channels that may serve as the pore component of the parasite's ‘new permeation pathways’. Other novel insights into the parasite's biology included the identification of transporters for the potential development of antimalarial treatments, transmission‐blocking drugs, prophylactics, and genetically attenuated vaccines. The syntheses presented herein set a foundation for elucidating the functions and physiological roles of key members of the Plasmodium transportome and, ultimately, to explore and realise their potential as therapeutic targets.

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Functional profiles of orphan membrane transporters in the life cycle of the malaria parasite

Cited by 75 publications

References 39 publications

Phylogenetic profiles of all membrane transport proteins of the malaria parasite highlight new drug targets

Phylogenetic profiles of all membrane transport proteins of the malaria parasite highlight new drug targets

Essential cGMP Signaling in Toxoplasma Is Initiated by a Hybrid P-Type ATPase-Guanylate Cyclase

The transportome of the malaria parasite

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