The molecular basis for sugar import in malaria parasites

Qureshi, Abdul Aziz; Suades, Albert; Matsuoka, Ryota; Brock, Joseph S.; McComas, Sarah; Nji, Emmanuel; Orellana, Laura; Claesson, Magnus; Delemotte, Lucie; Drew, David

doi:10.1038/s41586-020-1963-z

Cited by 75 publications

(201 citation statements)

References 49 publications

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“…Indeed, there exist other examples in which the alteration of a de novo sugar nucleotide metabolic route does not cause a significant reduction of the pathway’s product ( 37 ), and our own data show that P. falciparum gna1 mutant growth is rescued in vitro by GlcNAc medium supplementation. Thus, P. falciparum parasites seem to be able to take up and activate GlcNAc when the amino sugar pathway is disrupted ( 38 ), in agreement with the wide range of sugars that can be imported through its hexose transporter 1 ( 39 ). Nevertheless, P. falciparum potential GlcNAc uptake is deemed to be negligible in vivo , as this is not an abundant free sugar in the parasite host ( 40 ), opening the door to explore the selective inhibition of Pf GNA1 as a new approach to treat malaria.…”

Section: Discussionmentioning

confidence: 70%

Plasmodium falciparum Apicomplexan-Specific Glucosamine-6-Phosphate N -Acetyltransferase Is Key for Amino Sugar Metabolism and Asexual Blood Stage Development

Chi

Cova

Rivas

et al. 2020

mBio

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UDP-N-acetylglucosamine (UDP-GlcNAc), the main product of the hexosamine biosynthetic pathway, is an important metabolite in protozoan parasites since its sugar moiety is incorporated into glycosylphosphatidylinositol (GPI) glycolipids and N- and O-linked glycans. Apicomplexan parasites have a hexosamine pathway comparable to other eukaryotic organisms, with the exception of the glucosamine-phosphate N-acetyltransferase (GNA1) enzymatic step that has an independent evolutionary origin and significant differences from nonapicomplexan GNA1s. By using conditional genetic engineering, we demonstrate the requirement of GNA1 for the generation of a pool of UDP-GlcNAc and for the development of intraerythrocytic asexual Plasmodium falciparum parasites. Furthermore, we present the 1.95 Å resolution structure of the GNA1 ortholog from Cryptosporidium parvum, an apicomplexan parasite which is a leading cause of diarrhea in developing countries, as a surrogate for P. falciparum GNA1. The in-depth analysis of the crystal shows the presence of specific residues relevant for GNA1 enzymatic activity that are further investigated by the creation of site-specific mutants. The experiments reveal distinct features in apicomplexan GNA1 enzymes that could be exploitable for the generation of selective inhibitors against these parasites, by targeting the hexosamine pathway. This work underscores the potential of apicomplexan GNA1 as a drug target against malaria. IMPORTANCE Apicomplexan parasites cause a major burden on global health and economy. The absence of treatments, the emergence of resistances against available therapies, and the parasite’s ability to manipulate host cells and evade immune systems highlight the urgent need to characterize new drug targets to treat infections caused by these parasites. We demonstrate that glucosamine-6-phosphate N-acetyltransferase (GNA1), required for the biosynthesis of UDP-N-acetylglucosamine (UDP-GlcNAc), is essential for P. falciparum asexual blood stage development and that the disruption of the gene encoding this enzyme quickly causes the death of the parasite within a life cycle. The high-resolution crystal structure of the GNA1 ortholog from the apicomplexan parasite C. parvum, used here as a surrogate, highlights significant differences from human GNA1. These divergences can be exploited for the design of specific inhibitors against the malaria parasite.

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Section: Discussionmentioning

confidence: 70%

Plasmodium falciparum Apicomplexan-Specific Glucosamine-6-Phosphate N -Acetyltransferase Is Key for Amino Sugar Metabolism and Asexual Blood Stage Development

Chi

Cova

Rivas

et al. 2020

mBio

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“…Some studies show that not only the residues directly involved in sugar binding are important for transport, but also those ones mapped far from sugar. Qureshi et al [73] showed that polar interactions of residues about 15 Å from sugar are determinant for the transport of glucose and fructose in PfHT1 from Plasmodium falciparum. The authors concluded that the substrate promiscuity is not devoid to sugar-binding site, but substrate-gating dynamics.…”

Section: Discussionmentioning

confidence: 99%

Novel xylose transporter Cs4130 expands the sugar uptake repertoire in recombinant Saccharomyces cerevisiae strains at high xylose concentrations

Bueno

Borelli

Corrêa

et al. 2020

Biotechnol Biofuels

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Background: The need to restructure the world's energy matrix based on fossil fuels and mitigate greenhouse gas emissions stimulated the development of new biobased technologies for renewable energy. One promising and cleaner alternative is the use of second-generation (2G) fuels, produced from lignocellulosic biomass sugars. A major challenge on 2G technologies establishment is the inefficient assimilation of the five-carbon sugar xylose by engineered Saccharomyces cerevisiae strains, increasing fermentation time. The uptake of xylose across the plasma membrane is a critical limiting step and the budding yeast S. cerevisiae is not designed with a broad transport system and regulatory mechanisms to assimilate xylose in a wide range of concentrations present in 2G processes. Results: Assessing diverse microbiomes such as the digestive tract of plague insects and several decayed lignocellulosic biomasses, we isolated several yeast species capable of using xylose. Comparative fermentations selected the yeast Candida sojae as a potential source of high-affinity transporters. Comparative genomic analysis elects four potential xylose transporters whose properties were evaluated in the transporter null EBY.VW4000 strain carrying the xylose-utilizing pathway integrated into the genome. While the traditional xylose transporter Gxf1 allows an improved growth at lower concentrations (10 g/L), strains containing Cs3894 and Cs4130 show opposite responses with superior xylose uptake at higher concentrations (up to 50 g/L). Docking and normal mode analysis of Cs4130 and Gxf1 variants pointed out important residues related to xylose transport, identifying key differences regarding substrate translocation comparing both transporters. Conclusions: Considering that xylose concentrations in second-generation hydrolysates can reach high values in several designed processes, Cs4130 is a promising novel candidate for xylose uptake. Here, we demonstrate a novel eukaryotic molecular transporter protein that improves growth at high xylose concentrations and can be used as a promising target towards engineering efficient pentose utilization in yeast.

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“…Comparing the structures of PfHT1 (18,19) and hGLUT1 (20), we identified an additional pocket adjacent to the substrate-binding site. This discovery led to a hypothesis that another pharmacophore tethered to the carbohydrate core might render selective inhibitors for PfHT1.…”

Section: Introductionmentioning

confidence: 97%

Orthosteric-allosteric dual inhibitors of PfHT1 as selective anti-malarial agents

Huang

Yuan

Zhao

et al. 2020

Preprint

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Artemisinin-resistant malaria parasites have emerged and been spreading, posing a significant public health challenge. Anti-malarial drugs with novel mechanisms of action are therefore urgently needed. In this report, we exploit a “selective starvation” strategy by selectively inhibiting Plasmodium falciparum hexose transporter 1 (PfHT1), the sole hexose transporter in Plasmodium falciparum, over human glucose transporter 1 (hGLUT1), providing an alternative approach to fight against multidrug-resistant malaria parasites. Comparison of the crystal structures of human GLUT3 and PfHT1 bound to C3361, a PfHT1-specific moderate inhibitor, revealed an inhibitor binding-induced pocket that presented a promising druggable site. We thereby designed small-molecules to simultaneously block the orthosteric and allosteric pockets of PfHT1. Through extensive structure-activity relationship (SAR) studies, the TH-PF series was identified to selectively inhibit PfHT1 over GLUT1 and potent against multiple strains of the blood-stage P. falciparum. Our findings shed light on the next-generation chemotherapeutics with a paradigm-shifting structure-based design strategy to simultaneously targeting the orthosteric and allosteric sites of a transporter.Significance statementBlocking sugar uptake in P. falciparum by selectively inhibiting the hexose transporter PfHT1 kills the blood-stage parasites without affecting the host cells, indicating PfHT1 as a promising therapeutic target. Here, we report the development of novel small-molecule inhibitors that are selectively potent to the malaria parasites over human cell lines by simultaneously targeting the orthosteric and the allosteric binding sites of PfHT1. Our findings established the basis for the rational design of next-generation anti-malarial drugs.

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The molecular basis for sugar import in malaria parasites

Cited by 75 publications

References 49 publications

Plasmodium falciparum Apicomplexan-Specific Glucosamine-6-Phosphate N -Acetyltransferase Is Key for Amino Sugar Metabolism and Asexual Blood Stage Development

Plasmodium falciparum Apicomplexan-Specific Glucosamine-6-Phosphate N -Acetyltransferase Is Key for Amino Sugar Metabolism and Asexual Blood Stage Development

Novel xylose transporter Cs4130 expands the sugar uptake repertoire in recombinant Saccharomyces cerevisiae strains at high xylose concentrations

Orthosteric-allosteric dual inhibitors of PfHT1 as selective anti-malarial agents

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