Biosynthesis of glycosylphosphatidylinositol (GPI) is required for anchoring proteins to the plasma membrane, and is essential for the integrity of the fungal cell wall. Here, we use a reporter gene-based screen in Saccharomyces cerevisiae for the discovery of antifungal inhibitors of GPI-anchoring of proteins, and identify the oligocyclopropyl-containing natural product jawsamycin (FR-900848) as a potent hit. The compound targets the catalytic subunit Spt14 (also referred to as Gpi3) of the fungal UDP-glycosyltransferase, the first step in GPI biosynthesis, with good selectivity over the human functional homolog PIG-A. Jawsamycin displays antifungal activity in vitro against several pathogenic fungi including Mucorales, and in vivo in a mouse model of invasive pulmonary mucormycosis due to Rhyzopus delemar infection. Our results provide a starting point for the development of Spt14 inhibitors for treatment of invasive fungal infections.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7341893 | PMC |
| http://dx.doi.org/10.1038/s41467-020-17221-5 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
ST8SIA6 Sialylates CD24 to Enhance Its Membrane Localization in BRCA.
Cells
December 2024
Key Laboratory of Marine Drugs (Ministry of Education), Shandong Provincial Key Laboratory of Glycoscience and Glycoengineering, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China.
CD24, a highly sialylated glycosyl-phosphatidyl-inositol (GPI) cell surface protein that interacts with sialic acid-binding immunoglobulin-like lectins (Siglecs), serves as an innate immune checkpoint and plays a crucial role in inflammatory diseases and tumor progression. Recently, cytoplasmic CD24 has been observed in samples from patients with cancer. However, whether sialylation governs the subcellular localization of CD24 in cancer remains unclear, and the impact of CD24 expression and localization on the clinical prognosis of cancer remains controversial.
View Article and Find Full Text PDFComprehensive analysis of the LTPG gene family in willow: Identification, expression profiling, and stress response.
Int J Biol Macromol
January 2025
Key Laboratory of Landscape Plant Genetics and Breeding, School of Life Sciences, Nantong University, Nantong, China; Key Lab of Landscape Plant Genetics and Breeding, Nantong 226000, China. Electronic address:
The non-specific lipid-transfer proteins (LTPs), particularly the glycosylphosphatidylinositol (GPI)-anchored LTPs (LTPGs), play pivotal roles in various plant physiological functions, particularly in the context of environmental stress adaptation. Despite their importance, LTPGs in willow (Salix matsudana), an ecologically and economically important species, remains poorly understood. This study systematically identified and characterized 30 SmLTPGs in the S.
View Article and Find Full Text PDFTwo Different Brain Injury Patterns Associated with Compound Heterozygosis of the PIGO Gene in a Term Newborn: A Case Report.
Biomedicines
December 2024
Diagnostic and Interventional Neuroradiology Unit, Bambino Gesù Children's Hospital, IRCCS, 00165 Rome, Italy.
The glycosylphosphatidylinositol (GPI) is a glycol-lipid that anchors several proteins to the cell surface. The GPI-anchor pathway is crucial for the correct function of proteins involved in cell function, and it is fundamental in early neurogenesis and neural development. The PIG gene family is a group of genes involved in this pathway with six genes identified so far, and defects in these genes are associated with a rare inborn metabolic disorder manifesting with a spectrum of clinical phenotypes in newborns and children.
View Article and Find Full Text PDFIn-Depth Phenotyping of -Related Disease and Its Role in 17q12 Genomic Disorder.
Biomolecules
December 2024
Institute for Maternal and Child Health, IRCCS "Burlo Garofolo", 34137 Trieste, Italy.
Glycosylphosphatidylinositol (GPI) biosynthesis defect 11 (GPIBD11), part of the heterogeneous group of congenital disorders of glycosylation, is caused by biallelic pathogenic variants in . This rare disorder has previously been described in only 12 patients. We report four novel patients: two sib fetuses with congenital anomalies affecting several organs, including the heart; a living girl with tetralogy of Fallot, global developmental delay, behavioral abnormalities, and atypic electroencephalography (EEG) without epilepsy; a girl with early-onset, treatment-resistant seizures, developmental regression, and recurrent infections, that ultimately passed away prematurely due to pneumonia.
View Article and Find Full Text PDFTopological confinement by a membrane anchor suppresses phase separation into protein aggregates: Implications for prion diseases.
Proc Natl Acad Sci U S A
January 2025
Department Biochemistry of Neurodegenerative Diseases, Institute of Biochemistry and Pathobiochemistry, Ruhr University Bochum, Bochum 44801, Germany.
Protein misfolding and aggregation are a hallmark of various neurodegenerative disorders. However, the underlying mechanisms driving protein misfolding in the cellular context are incompletely understood. Here, we show that the two-dimensional confinement imposed by a membrane anchor stabilizes the native protein conformation and suppresses liquid-liquid phase separation (LLPS) and protein aggregation.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!