Targeting the Hexosamine Biosynthetic Pathway Prevents Plasmodium Developmental Cycle and Disease Pathology in Vertebrate Host

Abstract

Cerebral malaria (CM) is a clinical syndrome involving irreversible and lethal signs of brain injury associated to infection by parasites of the genus Plasmodium . The pathogenesis of CM derives from infection-induced proinflammatory cytokines associated with cytoadherence of parasitized red blood cells to brain microvasculature. Glycoconjugates are very abundant in the surface of Plasmodium spp., and are critical mediators of parasite virulence in host–pathogen interactions. Herein, we show that 6-Diazo-5-oxo-L-norleucine (DON) therapeutically used for blocking hexosamine biosynthetic pathway leads to recovery in experimental murine cerebral malaria. DON-induced protection was associated with decreased parasitism, which severely reduced Plasmodium transmission to mosquitoes. These findings point to a potential use of DON in combination therapies against malaria.

Sialylated N‐glycans mediate monocyte uptake of extracellular vesicles secreted from Plasmodium falciparum‐infected red blood cells

“…Pf can obtain GlcN and GlcNAc monosaccharides from external sources for its survival (Chi et al., 2020 ; Gomes et al., 2019 ), but uptake of full‐length N ‐glycans by Pf parasites is not yet reported. In addition, although Pf can express most subunits of the oligosaccharyl transferase complex (OST) needed to link N ‐glycans to proteins (Gomes et al., 2019 ), evidence for OST expression or synthesis of full length complex N ‐glycans or sialic acid has not been provided yet (Goerdeler et al., 2021 ; Macedo et al., 2010 ).…”

“…Pf can obtain GlcN and GlcNAc monosaccharides from external sources for its survival (Chi et al., 2020 ; Gomes et al., 2019 ), but uptake of full‐length N ‐glycans by Pf parasites is not yet reported. In addition, although Pf can express most subunits of the oligosaccharyl transferase complex (OST) needed to link N ‐glycans to proteins (Gomes et al., 2019 ), evidence for OST expression or synthesis of full length complex N ‐glycans or sialic acid has not been provided yet (Goerdeler et al., 2021 ; Macedo et al., 2010 ). Moreover, due to lack of suitable mannose and glucose Asn‐linked glycans (Alg) glycosyltransferases to elongate the precursor N ‐glycan during its synthesis in the Endoplasmic Reticulum, the parasites' N ‐glycans repertoire is limited to short structures composed of two GlcNAc moieties at most (Bushkin et al., 2010 ; Samuelson et al., 2005 ).…”

Unveiling the Sugary Secrets of Plasmodium Parasites

“…P. berghei-infected mice survived longer when treated with DON compared to untreated mice, thus indicating an essential role of the sugar nucleotide for Plasmodium viability. Notably, the protection was lost in mice co-injected with GlcN as GlcN is taken up by the parasite directly and converted to GlcNAc, thereby bypassing the DON-inhibited UDP-GlcNAc synthesis pathway (Gomes et al, 2019).…”

Distinct evolution of type I glutamine synthetase in Plasmodium and its species-specific requirement

“…Although the parasite lacks de novo purine synthesis and possesses hypoxanthine-guanine phosphoribosyltransferase (HGPRT) to salvage host purines, it has retained guanosine monophosphate synthetase (GMPS) for which, glutamine serves as an amide donor 11 , 12 . Glutamine is also utilized by glutamine-fructose-6-phosphate transaminase of hexosamine pathway to generate uridine diphosphate N-acetylglucosamine (UDP-GlcNAc) required for glycoprotein, proteoglycan and glycolipid biosynthesis 13 . In vitro metabolic labeling studies of Pf asexual and sexual stages carried out with 13 C-glutamine in the culture medium have suggested a flux of glutamine-derived carbon skeletons into TCA cycle that can possibly lead to the generation of reducing equivalents 14 .…”