Everybody needs sphingolipids, right! Mining for new drug targets in protozoan sphingolipid biosynthesis

Mina, John G.; Denny, Paul W.

doi:10.1017/s0031182017001081

Cited by 26 publications

(29 citation statements)

References 184 publications

(278 reference statements)

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“…In mammals, there is only one enzyme known as SM synthase (Merrill, 2011). Plants, fungi, and protozoa have other, called ceramide inositol phosphoryl ceramide (IPC) synthase (Holthuis and Menon, 2014;Mina and Denny, 2018). IPC has not been identified in E. histolytica and we did not find it in KEGG data base.…”

Section: Sphingolipids (Sl)mentioning

confidence: 77%

“…SL Synthesis and Metabolism SL are ubiquitous lipids in eukaryotic cell membranes, mainly in plasma membrane (Merrill and Sandhoff, 2002). They participate in membranes structure, domain formation, signal transduction, cell growth, differentiation, cell polarization, cellular trafficking, and apoptosis (Mina and Denny, 2018). SL are enriched in lipid rafts, since they are amphipathic molecules that interact with sterols and other sphingolipids to form aggregates within membranes through intra and intermolecular hydrogen bonds (Bruzik, 1988;Futerman and Hannun, 2004).…”

Section: Sphingolipids (Sl)mentioning

confidence: 99%

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Lipids in Entamoeba histolytica: Host-Dependence and Virulence Factors

Castellanos-Castro

Bolaños

Orozco

2020

Front. Cell. Infect. Microbiol.

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Lipids are essential players in parasites pathogenesis. In particular, the highly phagocytic trophozoites of Entamoeba histolytica, the causative agent of amoebiasis, exhibit a dynamic membrane fusion and fission, in which lipids strongly participate; particularly during the overstated motility of the parasite to reach and attack the epithelia and ingest target cells. Synthesis and metabolism of lipids in this protozoan present remarkable difference with those performed by other eukaryotes. Here, we reviewed the current knowledge on lipids in E. histolytica. Trophozoites synthesize phosphatidylcholine and phosphatidylethanolamine by the Kennedy pathway; and sphingolipids, phosphatidylserine, and phosphatidylinositol, by processes similar to those used by other eukaryotes. However, trophozoites lack enzymes for cholesterol and fatty acids synthesis, which are scavenged from the host or culture medium by specific mechanisms. Cholesterol, a fundamental molecule for the expression of virulence, is transported from the medium into the trophozoites by EhNPC1 and EhNPC2 proteins. Inside cells, lipids are distributed by different pathways, including by the participation of the endosomal sorting complex required for transport (ESCRT), involved in vesicle fusion and fission. Cholesterol interacts with the phospholipid lysobisphosphatidic acid (LBPA) and EhADH, an ALIX family protein, also involved in phagocytosis. In this review, we summarize the known information on phospholipids synthesis and cholesterol transport as well as their metabolic pathways in E. histolytica; highlighting the mechanisms used by trophozoites to dispose lipids involved in the virulence processes.

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Section: Sphingolipids (Sl)mentioning

confidence: 77%

Section: Sphingolipids (Sl)mentioning

confidence: 99%

Lipids in Entamoeba histolytica: Host-Dependence and Virulence Factors

Castellanos-Castro

Bolaños

Orozco

2020

Front. Cell. Infect. Microbiol.

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“…Knowing that stress stimuli can result in biosynthesis or remodeling of ceramides (34) and that ABC proteins are involved with the transport of sphingolipids (35,36), we evaluated whether ABCC transporters could mediate the transport of ceramides in T. cruzi. For this purpose, a preincubation with sphingosine, which is metabolized by ceramide synthase promoting the accumulation of ceramides (37), was performed prior to the CF efflux assay. In epimastigote forms of Y strain, preincubation with sphingosine increased CF MFI from 10.49 to 63.55 (Fig.…”

Section: Abcc-like Participates Of Ceramide Effluxmentioning

confidence: 99%

Thiol efflux mediated by an ABCC-like transporter participates forTrypanosoma cruziadaptation to environmental and chemotherapeutic stresses

Costa

et al. 2020

Preprint

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The protozoan Trypanosoma cruzi is the etiologic agent for Chagas disease, which affects 6-7 million people worldwide. The parasite presents high biological diversity, reflecting on the inefficiency of benznidazole in chronic or older patients. ABC superfamily proteins contain active transporters involved in the xenobiotic and endobiotic efflux and overexpressed in MDR cells. An ABCC-like transport was identified in the T. cruzi Y strain, being able to extrude thiol-conjugated compounds. As non-protein thiols represent prime line of defense towards reactive species, ABCC-like activity could participate in the regulation of mediators implicated in responses to cellular stress arising from a variety of stimuli, as environmental or chemotherapeutic. This study shows that T. cruzi ABCC-like protein transports GSH, GSSG and ceramides, all implicated in cellular stress. Hemin, representative from the hematophagous feeding of the vector, was transported as well, suggesting a role for ABCC as a metal-thiol transporter. In addition, all strains evaluated showed ABCC-like activity, while no ABCB1-like activity was detected. Also, results suggest that ABCC-like does not associate to natural resistance to benznidazole, considering that the sensitive strains CL Brener and Berenice showed higher ABCC-like activity than the resistant strains Y and Colombiana. Instead, ABCC-like efflux increased after continuous exposure of Y strain to benznidazole. Moreover, ABCC does not perform direct efflux of drug and its participation in the machinery of protection against stress depends on the efflux of metabolites in conjugation to or in cotransport with thiol.

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“…An S. cerevisiae substitution platform has also been used in HTS to identify inhibitors of the anti-leishmanial drug target inositol phosphorylceramide (IPC) synthase [39,40,41]. In this case, in the absence of a mammalian orthologue [42,43,44,45], counter screening was performed against the mutant complemented with the yeast orthologue AUR1 [41] to remove off-target, generically cytotoxic compounds.…”

Section: Substitutionmentioning

confidence: 99%

Yeast: bridging the gap between phenotypic and biochemical assays for high-throughput screening

Denny

2018

Expert Opinion on Drug Discovery

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Everybody needs sphingolipids, right! Mining for new drug targets in protozoan sphingolipid biosynthesis

Cited by 26 publications

References 184 publications

Lipids in Entamoeba histolytica: Host-Dependence and Virulence Factors

Lipids in Entamoeba histolytica: Host-Dependence and Virulence Factors

Thiol efflux mediated by an ABCC-like transporter participates forTrypanosoma cruziadaptation to environmental and chemotherapeutic stresses

Yeast: bridging the gap between phenotypic and biochemical assays for high-throughput screening

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