Sterylglucoside Catabolism in Cryptococcus neoformans with Endoglycoceramidase-related Protein 2 (EGCrP2), the First Steryl-β-glucosidase Identified in Fungi

Watanabe, Takashi; Ito, Tomoharu; Goda, Hatsumi M.; Ishibashi, Yoshihiro; Miyamoto, Tomofumi; Ikeda, Kazutaka; Taguchi, Ryo; Okino, Nozomu; Ito, Makoto

doi:10.1074/jbc.m114.616300

Cited by 31 publications

(34 citation statements)

References 47 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The most common sugar moiety is the pyranose form of D-glucose in β configuration[22,23]. The most abundant SGs chemical structure in fungi is ergosterol-3β-glucoside, which has been characterized by mass spectrometry and two dimensional nuclear magnetic resonance analyses (NMR) by various research groups ( Figure 1 )[27,28]. …”

Section: Lipids As Fungal Virulence Factorsmentioning

confidence: 99%

“…In contrast, very limited literature is available on the steryl hydrolase, the enzyme that degrades SGs into sterol and glucose. Sterylglycosyltransferases and sterylglucosidases have been identified in fungi, yeast and plants[27,37-42]. The first sterolglycosyltransferase enzymes were described in fungi in 1999 by Warnecke and colleagues [37].…”

Section: Lipids As Fungal Virulence Factorsmentioning

confidence: 99%

“…Recently, the first sterylglucosidase in fungi, endoglycoceramidase-related protein 2 ( EGCrP2 ), was identified and characterized[27]. This protein exhibited glucosylceramidase activity on short chain C 6 -NBD-GlcCer[43].…”

Section: Lipids As Fungal Virulence Factorsmentioning

confidence: 99%

“…This protein exhibited glucosylceramidase activity on short chain C 6 -NBD-GlcCer[43]. The disruption of EGCrP2 gene in C. neoformans resulted in the accumulation of ergosteryl-β–glucoside, but not GlcCer ( Figure 1B )[27]. The homologue of EGCrP2 in S. cerevisiae , Egh1 (ORF name, Yir007w), was also recently described.…”

Section: Lipids As Fungal Virulence Factorsmentioning

confidence: 99%

See 3 more Smart Citations

Plasma membrane lipids and their role in fungal virulence

Rella

Farnoud

Poeta

2016

Progress in Lipid Research

110

View full text Add to dashboard Cite

There has been considerable evidence in recent years suggesting that plasma membrane lipids are important regulators of fungal pathogenicity. Various glycolipids have been shown to impart virulent properties in several fungal species, while others have been shown to play a role in host defense. In addition to their role as virulence factors, lipids also contribute to other virulence mechanisms such as drug resistance, biofilm formation, and release of extracellular vesicles. In addition, lipids also affect the mechanical properties of the plasma membrane through the formation of packed microdomains composed mainly of sphingolipids and sterols. Changes in the composition of lipid microdomains has been shown to disrupt the localization of virulence factors and affect fungal pathogenicity. This review gathers evidence on the various roles of plasma membrane lipids in fungal virulence and how lipids might contribute to the different processes that occur during infection and treatment. Insight into the role of lipids in fungal virulence can lead to an improved understanding of the process of fungal pathogenesis and the development of new lipid-mediated therapeutic strategies.

show abstract

Section: Lipids As Fungal Virulence Factorsmentioning

confidence: 99%

Section: Lipids As Fungal Virulence Factorsmentioning

confidence: 99%

Section: Lipids As Fungal Virulence Factorsmentioning

confidence: 99%

Section: Lipids As Fungal Virulence Factorsmentioning

confidence: 99%

See 2 more Smart Citations

Plasma membrane lipids and their role in fungal virulence

Rella

Farnoud

Poeta

2016

Progress in Lipid Research

110

View full text Add to dashboard Cite

show abstract

“…Other glycosylceramidases classified in family GH5 are bacterial (Rhodococcus sp.) endogalactosylceramidase, first named EGCIII (50,51); Cryptococcus neoformans glucocerebrosidase EGCrP1 (52); steryl--glucosidase EGCrP2 (53); and Saccharomyces cerevisiae steryl--glucosidase EGH1 (54). The endoglycoceramidases and EGPr1 degrade only glycolipids with a ceramide moiety.…”

Section: Figmentioning

confidence: 99%

Distinguishing the differences in β-glycosylceramidase folds, dynamics, and actions informs therapeutic uses

Bdira

Artola

Overkleeft

et al. 2018

Journal of Lipid Research

View full text Add to dashboard Cite

Glycoconjugates play essential roles in diverse biological processes and abnormalities and have been linked to multiple pathologies. The staggering structural diversity of glycoconjugates stems from the almost infinite possible combinations by which multiple monosaccharide building blocks may be linked with each other (1). For instance, 1,056 unique trisaccharides can be formed just from 3 different monosaccharides. Polysaccharides are very stable compounds: their spontaneous hydrolysis takes place at a rate of 10 15 s 1 , corresponding to a half-life of 4.7 million years (2). To allow for the efficient metabolism of glycoconjugates, enzymes have evolved as specialized catalysts. In most organisms, an estimated 1% to 3% of the genes encode carbohydrate-active enzymes (3). Among these are glycoside hydrolases (GHs) that can enhance the rate of hydrolysis of specific carbohydrate glycosidic bonds in glycoconjugates more than 10 17 times (2). These GH enzymes show marked specificity regarding number, position, and configuration of the hydroxyl groups in their substrate sugar. They are widely applied in biotechnology, for example, in biofuel production, paper pulp bleaching, and the food industry (4, 5). Likewise, specific GH inhibitors are extensively used as agrochemicals and therapeutic agents (6-8). Abnormalities in GHs underlie metabolic disorders in humans, for instance, inherited lysosomal storage disorders and lactose intolerance (9, 10). GH enzymes differ in substrate specificity, mode of enzymatic attack Abstract Glycosyl hydrolases (GHs) are carbohydrate-active enzymes that hydrolyze a specific -glycosidic bond in glycoconjugate substrates; -glucosidases degrade glucosylceramide, a ubiquitous glycosphingolipid. GHs are grouped into structurally similar families that themselves can be grouped into clans. GH1, GH5, and GH30 glycosidases belong to clan A hydrolases with a catalytic (/) 8 TIM barrel domain, whereas GH116 belongs to clan O with a catalytic (/) 6 domain. In humans, GH abnormalities underlie metabolic diseases. The lysosomal enzyme glucocerebrosidase (family GH30), deficient in Gaucher disease and implicated in Parkinson disease etiology, and the cytosol-facing membrane-bound glucosylceramidase (family GH116) remove the terminal glucose from the ceramide lipid moiety. Here, we compare enzyme differences in fold, action, dynamics, and catalytic domain stabilization by binding site occupancy. We also explore other glycosidases with reported glycosylceramidase activity, including human cytosolic -glucosidase, intestinal lactase-phlorizin hydrolase, and lysosomal galactosylceramidase. Last, we describe the successful translation of research to practice: recombinant glycosidases and glucosylceramide metabolism modulators are approved drug products (enzyme replacement therapies). Activity-based probes now facilitate the diagnosis of enzyme deficiency and screening for compounds that interact with the catalytic pocket of glycosidases. Future research may deepen the understanding of the function...

show abstract

Fungal Glycolipid Hydrolase Inhibitors and Their Effect on Cryptococcus neoformans

Santana

Tysoe

et al. 2017

ChemBioChem

View full text Add to dashboard Cite

Pathogenic fungi kill an estimated 1.3 million people each year. This number is predicted to rise as drug resistance spreads, thus antifungal drugs with novel modes of action are urgently required. Fungal endoglycoceramidase-related proteins 1 and 2 (EGCrP-1 and -2), which hydrolyse glucosylceramide and ergosteryl β-glucoside, respectively, are important for fungal cell growth and have been identified as potential targets for drug development. A library of iminosugar derivatives was screened against EGCrP-1 and -2, and a number of competitive inhibitors with nanomolar affinities were identified. In addition, a mechanism-based inhibitor was shown to form a covalent derivative with EGCrP-2. Nine of the inhibitors were evaluated against Cryptococcus neoformans. Several showed growth inhibitory activity, but only against a C. neoformans strain lacking the outer fungal polysaccharide capsule; this implies that penetration into the cell is a significant handicap for these inhibitors. Pro-drug versions of these inhibitors could address this issue.

show abstract

Sterylglucoside Catabolism in Cryptococcus neoformans with Endoglycoceramidase-related Protein 2 (EGCrP2), the First Steryl-β-glucosidase Identified in Fungi

Cited by 31 publications

References 47 publications

Plasma membrane lipids and their role in fungal virulence

Plasma membrane lipids and their role in fungal virulence

Distinguishing the differences in β-glycosylceramidase folds, dynamics, and actions informs therapeutic uses

Fungal Glycolipid Hydrolase Inhibitors and Their Effect on Cryptococcus neoformans

Contact Info

Product

Resources

About