Biochem/physiol Actions

Primary TargetmGPDH

Cell permeable: yes

General description

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 µM). Shown to directly interact with a single, allosteric binding site on mGPDH and displays mixed type of inhibition kinetics (K_ic = 9.5 µM and K_iu = 14.6 µM, glycerol phosphate/GP-competitive against free and GP-uncompetitive against GP-bound mGPDH). Reduces H₂O₂ production by IQ site (IC₅₀ = 13.6 µM) and inhibits ΔΨm driven by low concentrations of succinate (0.5 µM), but does not inhibit glutamate-, malate-, pyruvate-, or palmityoylcarnitine-driven ΔΨm. 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 µM by DCPIP assay using rat skeletal muscle mitochondria preparation with 1 µ Ca²⁺), but not cytosolic GPDH (up to 80 µM using rabbit cGPDH), by targeting free mGPDH in a GP-competitive manner (K_ic = 9.5 µM) as well as GP-bound mGPDH (K_iu = 14.6 µM) in a GP-uncompetitive manner via a 1:1 inhibitor:enzyme stoichiometric ratio. Shown to exhibit only weak effect against unbiquinol/QH₂-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 µg/mL; Cat. No. 495455) with the combined treatment of 0.5 mM aminooxyacetate (AOA) and 100 µM iGP-1 than with AOA alone.

Legal Information

CALBIOCHEM is a registered trademark of Merck KGaA, Darmstadt, Germany

Other Notes

Orr, A.L., et al. 2014. PLoS One9, e89938.

Packaging

25 mg in Glass bottle

Packaged under inert gas

Reconstitution

Following reconstitution, aliquot and freeze (-20°C). Stock solutions are stable for up to 6 months at -20°C.

Warning

Toxicity: Standard Handling (A)