High-resolution crystal structure and chemical screening reveal pantothenate kinase as a new target for antifungal development

Gihaz, Shalev; Gareiss, Peter C.; Choi, Jae‐Yeon; Renard, Isaline; Pal, Anasuya; Surovsteva, Yulia; Chiu, Joy E.; Plummer, Mark S.; Hungerford, William; Montgomery, Micaela L.; Hosford, Alanah; Adams, Emily M.; Lightfoot, Jorge; Fox, David; Ojo, Kayode K.; Staker, Bart L.; Fuller, Kevin K.; Mamoun, Choukri Ben

doi:10.1016/j.str.2022.09.001

Cited by 6 publications

(13 citation statements)

References 30 publications

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“…The pantazine analog, PZ-2891, an orthosteric activator of human PANK3 17 , showed the highest potentiation among all compounds tested. Unlike other known Cab1 inhibitors 12,16 , PZ-2891 did not inhibit pantothenate utilization of both WT and cab1 mutant enzymes (Fig. S5).…”

Section: Small Molecule Modulation Of the Pca Pathway Leads To Increa...mentioning

confidence: 80%

“…A minimum of 8 technical replicates were performed for each experiment at 30°C. The seeded plate was centrifuged at 500 PanK activity of recombinant Cab1 in the presence of PZ-2891 and AcCoA--Histagged Cab1 recombinant enzyme was produced and purified as was previously described 16 . A Kinase-Glo (Promega) assay kit for kinase activity was used to determine the activity of the purified PanK under different conditions 16 .…”

Section: Seahorse Analysis--mentioning

confidence: 99%

“…The cab1 ts thermosensitive strain (JS91. [14][15][16][17][18][19][20][21][22][23][24] was generated following EMS mutagenesis to select mutants altered in saturated fatty acid biosynthesis 13,18 . The cab1 ts mutant harbors, among multiple other genetic mutations (40 identified following whole genome sequence (unpublished data), a mutated Cab1 enzyme with 4 individual substitutions, one of which, G351S, is directly linked to the thermosensitive phenotype 13 .…”

Section: Introductionmentioning

confidence: 99%

“…In contrast, in Saccharomyces cerevisiae as well as most causative agents of invasive fungal infections, a single copy of the PanK enzyme performs the first step in the PCA pathway 12,13 . Fungal PANK genes have all been shown to be essential for cell viability as complete or conditional knockouts of these genes lead to cell death [12][13][14][15][16] . As a result, efforts to identify inhibitors of fungal PanK enzymes has been considered an attractive strategy for the development of new antifungal drugs.…”

Section: Introductionmentioning

confidence: 99%

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Vitamin B5 Metabolism is Essential for Vacuolar and Mitochondrial Integrity and Xenobiotic Detoxification in Fungi

Choi,

Gihaz,

Munshi

et al. 2023

Preprint

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SUMMARYFungal infections, a leading cause of mortality among eukaryotic pathogens, pose a growing global health threat due to the rise of drug-resistant strains. New therapeutic strategies are urgently needed to combat this challenge. The PCA pathway for biosynthesis of Co-enzyme A (CoA) and Acetyl-CoA (AcCoA) from vitamin B5 (pantothenic acid) has been validated as an excellent target for the development of new antimicrobials against fungi and protozoa. The pathway regulates key cellular processes including metabolism of fatty acids, amino acids, sterols, and heme. In this study, we provide genetic evidence that disruption of the PCA pathway results in a significant alteration in the susceptibility of fungi to a wide range of xenobiotics, including clinically approved antifungal drugs through alteration of vacuolar integrity and drug detoxification. The drug potentiation-mediated by genetic regulation of genes in the PCA pathway could be recapitulated using the pantazine analog PZ-2891 as well as the celecoxib derivative, AR-12 through inhibition of fungal AcCoA synthase activity. Collectively, the data validate the PCA pathway as a suitable target for enhancing the efficacy and safety of current antifungal therapies.

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Section: Small Molecule Modulation Of the Pca Pathway Leads To Increa...mentioning

confidence: 80%

Section: Seahorse Analysis--mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Vitamin B5 Metabolism is Essential for Vacuolar and Mitochondrial Integrity and Xenobiotic Detoxification in Fungi

Choi,

Gihaz,

Munshi

et al. 2023

Preprint

Self Cite

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“…In addition, VitB5 contributes to the regulation of Th17 immunity in IBD [7]. In addition to Pan effect on host cells, infectious agents also require Pan to sustain their metabolic activity, and inhibitors of microbial PANK enzymes, called pantothenamides, are consid-ered potential anti-infectious drugs in parasite, bacterial, or fungal infections [88][89][90][91][92][93][94]. Finally, one could speculate that the link between Pan and inflammation might also involve ACh signaling.…”

Section: Coa Homeostasis In Inflammatory Diseasesmentioning

confidence: 99%

The vitamin B5/coenzyme A axis: A target for immunomodulation?

et al. 2023

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Coenzyme A (CoA) serves as a vital cofactor in numerous enzymatic reactions involved in energy production, lipid metabolism, and synthesis of essential molecules. Dysregulation of CoA‐dependent metabolic pathways can contribute to chronic diseases, such as inflammatory diseases, obesity, diabetes, cancer, and cardiovascular disorders. Additionally, CoA influences immune cell activation by modulating the metabolism of these cells, thereby affecting their proliferation, differentiation, and effector functions. Targeting CoA metabolism presents a promising avenue for therapeutic intervention, as it can potentially restore metabolic balance, mitigate chronic inflammation, and enhance immune cell function. This might ultimately improve the management and outcomes for these diseases. This review will more specifically focus on the contribution of pathways regulating the availability of the CoA precursor Vitamin B5/pantothenate in vivo and modulating the development of Th17‐mediated inflammation, CD8‐dependent anti‐tumor immunity but also tissue repair processes in chronic inflammatory or degenerative diseases.

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Hitting them where it hurts: Pantothenate kinase targeting in pathogenic fungi

Pierce

Park²

2022

Structure

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High-resolution crystal structure and chemical screening reveal pantothenate kinase as a new target for antifungal development

Cited by 6 publications

References 30 publications

Vitamin B5 Metabolism is Essential for Vacuolar and Mitochondrial Integrity and Xenobiotic Detoxification in Fungi

Vitamin B5 Metabolism is Essential for Vacuolar and Mitochondrial Integrity and Xenobiotic Detoxification in Fungi

The vitamin B5/coenzyme A axis: A target for immunomodulation?

Hitting them where it hurts: Pantothenate kinase targeting in pathogenic fungi

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