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Published on: September 3, 2011
Phosphoglucose Isomerase Is Important for Aspergillus fumigatus Cell Wall Biogenesis
Yao Zhou1,2, Kaizhou Yan3, Qijian Qin1
1Guangxi Biological Sciences and Biotechnology Center, Guangxi Academy of Sciencesgrid.418329.5, Nanning, Guangxi, China.
Abstract:
Aspergillus fumigatus is a devastating opportunistic fungal pathogen causing hundreds of thousands of deaths every year. Phosphoglucose isomerase (PGI) is a glycolytic enzyme that converts glucose-6-phosphate to fructose-6-phosphate, a key precursor of fungal cell wall biosynthesis. Here, we demonstrate that the growth of A. fumigatus is repressed by the deletion of pgi, which can be rescued by glucose and fructose supplementation in a 1:10 ratio. Even under these optimized growth conditions, the Δpgi mutant exhibits severe cell wall defects, retarded development, and attenuated virulence in Caenorhabditis elegans and Galleria mellonella infection models. To facilitate exploitation of A. fumigatus PGI as an antifungal target, we determined its crystal structure, revealing potential avenues for developing inhibitors, which could potentially be used as adjunctive therapy in combination with other systemic antifungals. IMPORTANCE Aspergillus fumigatus is an opportunistic fungal pathogen causing deadly infections in immunocompromised patients. Enzymes essential for fungal survival and cell wall biosynthesis are considered potential drug targets against A. fumigatus. PGI catalyzes the second step of the glycolysis pathway, linking glycolysis and the pentose phosphate pathway. As such, PGI has been widely considered as a target for metabolic regulation and therefore a therapeutic target against hypoxia-related diseases. Our study here reveals that PGI is important for A. fumigatus survival and exhibit pleiotropic functions, including development, cell wall glucan biosynthesis, and virulence. We also solved the crystal structure of PGI, thus providing the genetic and structural groundwork for the exploitation of PGI as a potential antifungal target.
Insights
Deleting the phosphoglucose isomerase (PGI) gene in Aspergillus fumigatus severely impairs fungal growth, cell wall integrity, and virulence. The crystal structure of PGI provides a basis for developing new antifungal drugs targeting this essential enzyme.
Area of Science:
- Medical Mycology
- Molecular Biology
- Structural Biology
Background:
- Aspergillus fumigatus is a major opportunistic fungal pathogen responsible for life-threatening infections, particularly in immunocompromised individuals.
- Enzymes crucial for fungal survival and cell wall biosynthesis are prime targets for antifungal drug development.
- Phosphoglucose isomerase (PGI) is a key glycolytic enzyme linking glycolysis and the pentose phosphate pathway, implicated in metabolic regulation.
Purpose of the Study:
- To investigate the role of PGI in Aspergillus fumigatus survival, development, cell wall biosynthesis, and virulence.
- To determine the crystal structure of A. fumigatus PGI to inform the development of novel antifungal inhibitors.
- To explore PGI as a potential therapeutic target for treating invasive aspergillosis.
Main Methods:
- Gene deletion to create a PGI-deficient mutant (Δpgi) in A. fumigatus.
- Phenotypic characterization of the Δpgi mutant, including growth assays, cell wall analysis, and virulence studies in infection models (C. elegans and G. mellonella).
- X-ray crystallography to determine the three-dimensional structure of A. fumigatus PGI.
Main Results:
- Deletion of the PGI gene significantly repressed A. fumigatus growth, which could be partially rescued by specific glucose and fructose supplementation.
- The Δpgi mutant exhibited pronounced cell wall defects, impaired development, and reduced virulence in both C. elegans and G. mellonella models.
- The crystal structure of A. fumigatus PGI was successfully determined, providing structural insights for inhibitor design.
Conclusions:
- PGI is essential for A. fumigatus survival, exhibiting pleiotropic functions in development, cell wall integrity, and virulence.
- The structural data of PGI offers a foundation for developing targeted antifungal therapies, potentially as adjunctive treatments.
- Targeting PGI presents a promising strategy for combating deadly Aspergillus fumigatus infections.
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