Pentenediol-Type Compounds Specifically Bind to Voltage-Dependent Anion Channel 1 in Saccharomyces cerevisiae Mitochondria

Voltage-dependent anion channel 1 (VDAC1) situated in the outer mitochondrial membrane regulates the transfer of various metabolites and is a key player in mitochondria-mediated apoptosis. Although many small chemicals that modulate the functions of VDAC1 have been reported to date, most, if not all, of them cannot be regarded as specific reagents due to their interactions with other transporters or enzymes. By screening our chemical libraries using isolated Saccharomyces cerevisiae mitochondria, we found pentenediol (PTD)-type compounds (e.g., PTD-023) as new specific inhibitors of VDAC1. PTD-023 inhibited overall ADP-uptake/ATP-release reactions in isolated mitochondria at a single digit μM level. To identify the binding position of PTDs in VDAC1 by visualizing PTD-bound peptides, we conducted ligand-directed tosyl (LDT) chemistry using the synthetic LDT reagent t-PTD-023 derived from the parent PTD-023 in combination with mutagenesis experiments. t-PTD-023 made a covalent bond predominantly and subsidi...