Genetic validation of Aspergillus fumigatus phosphoglucomutase as a viable therapeutic target in invasive aspergillosis

Yan, Kaizhou; Stanley, Mathew; Kowalski, Bartosz; Raimi, O.G.; Ferenbach, Andrew T.; Wei, Pingzhen; Fang, Wenxia; Aalten, Daan M. F. van

doi:10.1016/j.jbc.2022.102003

Cited by 3 publications

(1 citation statement)

References 189 publications

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“…Nucleotide sugars, such as UDP-glucose, UDP-GlcNAc, and GDP-Man, are the precursors for cell wall biosynthesis [19][20][21]. Previously, AGM1, UAP1, GNA1, PMM, PGM, and PGI have been reported as potential drug targets against Aspergillus fumigatus [19][20][21][22][23][24].…”

Section: Introductionmentioning

confidence: 99%

Loss of Phosphomannose Isomerase Impairs Growth, Perturbs Cell Wall Integrity, and Reduces Virulence of Fusarium oxysporum f. sp. cubense on Banana Plants

Usman

et al. 2023

JoF

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Fusarium oxysporum f. sp. cubense tropical race 4 (Foc TR4) causes Fusarium wilt of banana, necessitating urgent measures to control this disease. However, the molecular mechanisms underlying Foc TR4 virulence remain elusive. Phosphomannose isomerase is a key enzyme involved in the biosynthesis of GDP mannose, an important precursor of fungal cell walls. In this study, two phosphomannose isomerases were identified in the Foc TR4 genome, of which only Focpmi1 was highly expressed throughout all developmental stages. Generated null mutants in Foc TR4 showed that only the ΔFocpmi1 mutant required exogenous mannose for growth, indicating that Focpmi1 is the key enzyme involved in GDP mannose biosynthesis. The Focpmi1 deficient strain was unable to grow without exogenous mannose and exhibited impaired growth under stress conditions. The mutant had reduced chitin content in its cell wall, rendering it vulnerable to cell wall stresses. Transcriptomic analysis revealed up- and down-regulation of several genes involved in host cell wall degradation and physiological processes due to the loss of Focpmi1. Furthermore, Focpmi1 was also found to be crucial for Foc TR4 infection and virulence, making it a potential antifungal target to address the threats posed by Foc TR4.

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Section: Introductionmentioning

confidence: 99%

Loss of Phosphomannose Isomerase Impairs Growth, Perturbs Cell Wall Integrity, and Reduces Virulence of Fusarium oxysporum f. sp. cubense on Banana Plants

Usman

et al. 2023

JoF

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Metabolic modulation: Pneumocystis phosphoglucomutase is a target influencing host recognition

Kottom,

Carmona,

Lepenies

et al. 2024

The Cell Surface

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Characterization of the Pneumocystis jirovecii and Pneumocystis murina phosphoglucomutases (Pgm2s): a potential target for Pneumocystis therapy

Kottom,

Carmona,

Limper

2024

Antimicrob Agents Chemother

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Pneumocystis cyst life forms contain abundant β-glucan carbohydrates, synthesized using β-1,3 and β-1,6 glucan synthase enzymes and the donor uridine diphosphate (UDP)-glucose. In yeast, phosphoglucomutase (PGM) plays a crucial role in carbohydrate metabolism by interconverting glucose 1-phosphate and glucose 6-phosphate, a vital step in UDP pools for β-glucan cell wall formation. This pathway has not yet been defined in Pneumocystis . Herein, we surveyed the Pneumocystis jirovecii and Pneumocystis murina genomes, which predicted a homolog of the Saccharomyces cerevisiae major PGM enzyme. Furthermore, we show that PjPgm2p and PmPgm2p function similarly to the yeast counterpart. When both Pneumocystis pgm2 homologs are heterologously expressed in S. cerevisiae pgm2Δ cells, both genes can restore growth and sedimentation rates to wild-type levels. Additionally, we demonstrate that yeast pgm2Δ cell lysates expressing the two Pneumocystis pgm2 transcripts individually can restore PGM activities significantly altered in the yeast pgm2Δ strain. The addition of lithium, a competitive inhibitor of yeast PGM activity, significantly reduces PGM activity. Next, we tested the effects of lithium on P. murina viability ex vivo and found the compound displays significant anti- Pneumocystis activity. Finally, we demonstrate that a para-aryl derivative (ISFP10) with known inhibitory activity against the Aspergillus fumigatus PGM protein and exhibiting 50-fold selectivity over the human PGM enzyme homolog can also significantly reduce Pmpgm2 activity in vitro . Collectively, our data genetically and functionally validate phosphoglucomutases in both P. jirovecii and P. murina and suggest the potential of this protein as a selective therapeutic target for individuals with Pneumocystis pneumonia.

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Genetic validation of Aspergillus fumigatus phosphoglucomutase as a viable therapeutic target in invasive aspergillosis

Cited by 3 publications

References 189 publications

Loss of Phosphomannose Isomerase Impairs Growth, Perturbs Cell Wall Integrity, and Reduces Virulence of Fusarium oxysporum f. sp. cubense on Banana Plants

Loss of Phosphomannose Isomerase Impairs Growth, Perturbs Cell Wall Integrity, and Reduces Virulence of Fusarium oxysporum f. sp. cubense on Banana Plants

Metabolic modulation: Pneumocystis phosphoglucomutase is a target influencing host recognition

Characterization of the Pneumocystis jirovecii and Pneumocystis murina phosphoglucomutases (Pgm2s): a potential target for Pneumocystis therapy

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