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A novel xylosylphosphotransferase activity discovered in Cryptococcus neoformans.

ABSTRACT: Cryptococcus neoformans is a fungal pathogen that causes serious disease in immunocompromised individuals. The organism produces a distinctive polysaccharide capsule that is necessary for its virulence, a predominantly polysaccharide cell wall, and a variety of protein- and lipid-linked glycans. The glycan synthetic pathways of this pathogen are of great interest. Here we report the detection of a novel glycosylphosphotransferase activity in C. neoformans, identification of the corresponding gene, and characterization of the encoded protein. The observed activity is specific for UDP-xylose as a donor and for mannose acceptors and forms a xylose-alpha-1-phosphate-6-mannose linkage. This is the first report of a xylosylphosphotransferase activity in any system.

SUBMITTER: Reilly MC

PROVIDER: S-EPMC2794727 | biostudies-literature | 2009 Dec

REPOSITORIES: biostudies-literature

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A novel xylosylphosphotransferase activity discovered in Cryptococcus neoformans.

Reilly Morgann C MC Levery Steven B SB Castle Sherry A SA Klutts J Stacey JS Doering Tamara L TL

The Journal of biological chemistry 20091028 52

Cryptococcus neoformans is a fungal pathogen that causes serious disease in immunocompromised individuals. The organism produces a distinctive polysaccharide capsule that is necessary for its virulence, a predominantly polysaccharide cell wall, and a variety of protein- and lipid-linked glycans. The glycan synthetic pathways of this pathogen are of great interest. Here we report the detection of a novel glycosylphosphotransferase activity in C. neoformans, identification of the corresponding gen ...[more]

PMID: 19864415

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Project description:Cryptococcus neoformans is an opportunistic fungal pathogen that causes meningitis in >152,000 immunocompromised individuals annually, leading to 112,000 yearly deaths. The four classes of existing antifungal agents target plasma membrane sterols (ergosterol), nucleic acid synthesis, and cell wall synthesis. Existing drugs are not highly effective against Cryptococcus, and antifungal drug resistance is an increasing problem. A novel antimicrobial compound, a eumelanin-inspired indoylenepheyleneethynylene, EIPE-1, was synthesized and has antimicrobial activity against Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MSRA), but not towards Gram-negative organisms. Based on EIPE-1's antibacterial activity, we hypothesized that EIPE-1 could have antifungal activity. For these studies, we tested EIPE-1 against C. neoformans strain H99 and 6 additional cryptococcal clinical isolates. We examined antifungal activity, cytotoxicity, effects on fungal gene expression, and mechanism of action of EIPE-1. Results showed that EIPE-1 has fungicidal effects on seven cryptococcal strains with MICs ranging from 1.56 to 3.125 μg/mL depending on the strain, and it is non-toxic to mammalian cells. We conducted scanning and transmission electron microscopy on the exposed cells to examine structural changes to the organism following EIPE-1 treatment. Cells exposed displayed structural changes to their cell wall and membranes, with internal contents leaking out of the cells. To understand the effect of EIPE-1 on fungal gene expression, RNA sequencing was conducted. Results showed that EIPE-1 affects several processes involved stress response, ergosterol biosynthesis, capsule biosynthesis, and cell wall attachment and remodeling. Therefore, our studies demonstrate that EIPE-1 has antifungal activity against C. neoformans, which affects both cellular structure and gene expression of multiple fungal pathways involved in cell membrane stability and viability.

Dataset Information

A novel xylosylphosphotransferase activity discovered in Cryptococcus neoformans.

Publications

A novel xylosylphosphotransferase activity discovered in Cryptococcus neoformans.

Similar Datasets

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