Phosphoglucose Isomerase Is Important for Aspergillus fumigatus Cell Wall Biogenesis

Yao Zhou, Kaizhou Yan, Qijian Qin, Olawale Raimi, Chao Du, Bin Wang, Chukwuemeka Samson Ahamefule, Bartosz Kowalski, Cheng Jin, Daan van Aalten (Lead / Corresponding author), Wenxia Fang (Lead / Corresponding author)

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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 Dpgi 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.

Original languageEnglish
Article numbere0142622
Number of pages16
JournalMBio
Volume13
Issue number4
Early online date1 Aug 2022
DOIs
Publication statusPublished - 30 Aug 2022

Keywords

  • Aspergillus fumigatus
  • phosphoglucose isomerase
  • cell wall
  • carbon flux
  • drug target
  • structural biology
  • genetics
  • fungi

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