Fungal infections are the leading cause of mortality by eukaryotic pathogens, with an estimated 150 million severe life-threatening cases and 1.7 million deaths reported annually. The rapid emergence of multidrug-resistant fungal isolates highlights the urgent need for new drugs with new mechanisms of action. In fungi, pantothenate phosphorylation, catalyzed by PanK enzyme, is the first step in the utilization of pantothenic acid and coenzyme A biosynthesis. In all fungi sequenced so far, this enzyme is encoded by a single PanK gene. Here, we report the crystal structure of a fungal PanK alone as well as with high-affinity inhibitors from a single chemotype identified through a high-throughput chemical screen. Structural, biochemical, and functional analyses revealed mechanisms governing substrate and ligand binding, dimerization, and catalysis and helped identify new compounds that inhibit the growth of several Candida species. The data validate PanK as a promising target for antifungal drug development.
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| Gene | Phenotype | Experiment Type | Mutant Information | Strain Background | Chemical | Details |
|---|---|---|---|---|---|---|
| CAB1 | heat sensitivity: increased | classical genetics | conditional Allele: cab1-G351A G351A; decreased Vmax and and ∼2.5-fold increase in Km | Other | Temperature: elevated temperature, 37 °C Details: severe decrease in growth | |
| CAB1 | heat sensitivity: increased | classical genetics | conditional Allele: cab1-S158A S158A; catalytic pocket mutated; weak kinase activity | Other | Temperature: elevated temperature, 37 °C Details: severe decrease in growth | |
| CAB1 | heat sensitivity: increased | classical genetics | conditional Allele: cab1-Y220A Y220A; catalytic pocket mutated; weak kinase activity | Other | Temperature: elevated temperature, 37 °C Details: severe decrease in growth | |
| CAB1 | heat sensitivity: increased | classical genetics | conditional Allele: cab1-Y197A Y197A; ATP binding domain mutated; decreased Vmax and 43-fold increase in Km | Other | Temperature: elevated temperature, 37 °C Details: significant growth defect | |
| CAB1 | heat sensitivity: increased | classical genetics | conditional Allele: cab1-R173A R173A; dimer interface residues mutated; weak kinase activity | Other | Temperature: elevated temperature, 37 °C Details: significant growth defect | |
| CAB1 | heat sensitivity: increased | classical genetics | conditional Allele: cab1-N290A N290A; dimer interface residues mutated; weak kinase activity | Other | Temperature: elevated temperature, 37 °C Details: significant growth defect | |
| CAB1 | heat sensitivity: increased | classical genetics | reduction of function Allele: cab1-G351S G351S; enzyme catalysis reduced by ~90% | Other | Temperature: elevated temperature, 37 °C Details: severe decrease in growth | |
| CAB1 | respiratory growth: decreased | classical genetics | conditional Allele: cab1-G351A G351A; decreased Vmax and and ∼2.5-fold increase in Km | Other | Media: non-fermentable carbon source Temperature: permissive temperature Details: severe or significant growth defects on lactate, glycerol and ethanol-containing media | |
| CAB1 | respiratory growth: decreased | classical genetics | conditional Allele: cab1-S158A S158A; catalytic pocket mutated; weak kinase activity | Other | Media: non-fermentable carbon source Temperature: permissive temperature Details: severe or significant growth defects on lactate, glycerol and ethanol-containing media | |
| CAB1 | respiratory growth: decreased | classical genetics | conditional Allele: cab1-Y197A Y197A; ATP binding domain mutated; decreased Vmax and 43-fold increase in Km | Other | Media: non-fermentable carbon source Temperature: permissive temperature Details: severe or significant growth defects on lactate, glycerol and ethanol-containing media |