Abstract
The flagellated protozoan Giardia duodenalis is a worldwide parasite causing giardiasis, an acute and chronic diarrheal disease. Metabolism in G. duodenalis has a limited complexity thus making metabolic enzymes ideal targets for drug development. However, only few metabolic pathways (i.e., carbohydrates) have been described so far. Recently, the parasite homolog of the mitochondrial-like glycerol-3-phosphate dehydrogenase (gG3PD) has been identified among the interactors of the g14-3-3 protein. G3PD is involved in glycolysis, electron transport, glycerophospholipids metabolism, and hyperosmotic stress response, and is emerging as promising target in tumor treatment. In this work, we demonstrate that gG3PD is a functional flavoenzyme able to convert glycerol-3-phosphate into dihydroxyacetone phosphate and that its activity and the intracellular glycerol level increase during encystation. Taking advantage of co-immunoprecipitation assays and deletion mutants, we provide evidence that gG3PD and g14-3-3 interact at the trophozoite stage, the intracellular localization of gG3PD is stage dependent and it partially co-localizes with mitosomes during cyst development. Finally, we demonstrate that the gG3PD activity is affected by the antitumoral compound 6-(7-nitro-2,1,3-benzoxadiazol-4-ylthio)hexanol, that results more effective in vitro at killing G. duodenalis trophozoites than the reference drug metronidazole. Overall, our results highlight the involvement of gG3PD in processes crucial for the parasite survival thus proposing this enzyme as target for novel antigiardial interventions.
Highlights
The flagellated protozoan Giardia duodenalis is a parasite of the upper part of small intestine of mammals, including humans
In this work we have characterized, for the first time, the FADdependent glycerol-3-phosphate dehydrogenase of G. duodenalis both at molecular and functional level, and we have shown that the antitumoral 7-nitro benzoxadiazole (NBD) derivative NBDHEX displays a remarkable antigiardial activity, targets the gG3PD and, when in vivo administered to G. duodenalis, induces gG3PD activity reduction
The presence in the grampositive anaerobic actinobacteria Eggerthella sp. of an orthologue of the first 950 amino acids suggests that a first gene fusion event between a GlpA-like gG3PD and a pyridine nucleotidedisulphide oxidoreductase occurred in this prokaryotic lineage
Summary
The flagellated protozoan Giardia duodenalis (syn. lamblia, intestinalis) is a parasite of the upper part of small intestine of mammals, including humans. Infection with G. duodenalis causes giardiasis, one of the most common foodborne and waterborne gastroenteric diseases (Halliez and Buret, 2013; Ryan and Cacciò, 2013). No human vaccine for giardiasis is available and treatment relies only on a limited panel of effective approved drugs. Treatment failure has been reported in 10–20% of cases and strains resistant to different compounds have been either clinically isolated or induced in vitro (Lalle, 2010; Watkins and Eckmann, 2014). In this scenario, alternative, safe, and effective therapies are required
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