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Beschreibung

A cell-permeable benzimidazolyl-phenylamidosuccinate compound that acts as a potent, selective, and dose-dependent inhibitor against mitochondrial, but not cytosolic, sn-glycerol-3-phosphate dehydrogenase (IC50 against mGPDH = 6.3 microM). Shown to directly interact with a single, allosteric binding site on mGPDH and displays mixed type of inhibition kinetics (Kic = 9.5 microM and Kiu = 14.6 microM, glycerol phosphate/GP-competitive against free and GP-uncompetitive against GP-bound mGPDH). Reduces H2O2 production by IQ site (IC50 = 13.6 microM) and inhibits &Delta,&Psi,m driven by low concentrations of succinate (0.5 microM), but does not inhibit glutamate-, malate-, pyruvate-, or palmityoylcarnitine-driven &Delta,&Psi,m. Does not prevent pyruvate uptake into cells or mitochondria and has no direct effect on Glycolysis in synaptosomes., A cell-permeable thiadiazolyl-butyl-pyridazinyl compound that displays increased fluorescence with acidified pH (by 8-fold from pH 7.0 to 1.5, Ex 342 nm & Em 378 nm) and selectively inhibits mitochondrial sn-glycerol 3-phosphate (GP) dehydrogenase (mGPDH) activity (IC50 = 6.3 microM by DCPIP assay using rat skeletal muscle mitochondria preparation with 1 micro Ca2+), but not cytosolic GPDH (up to 80 microM using rabbit cGPDH), by targeting free mGPDH in a GP-competitive manner (KicKiu2-dependent complex I activity and little potency toward unbiquinol/QH2-dependent complex III activity, nor FMN-dependent complex I or II activity. Under conditions where Lactate dehydrogenase-mediated NAD+ generation is blocked by Oxamate in murine cortical synaptosome preparations, a small but significant dependence on mGPDH-mediated GP shuttle for NAD+ generation to support the high glycolytic demand for pyruvate generation from glucose (15 mM) is reported, as evidenced by a more pronounced mitochondrial respiration inhibition in the presence of FCCP and Oligomycin (4 microg/mL, Cat. No. 495455) with the combined treatment of 0.5 mM aminooxyacetate (AOA) and 100 microM iGP-1 than with AOA alone.