Modulation of the mitochondrial cytochrome bc1 complex activity by chromanols and related compounds.
Tocopherols (alpha-, beta-, gamma-, and delta-Toc) and tocopheryl quinones (alpha-, beta-, gamma-, and delta-TQ) were recently suggested to modulate mitochondrial electron transfer in mammals. Intriguingly, Tocs and stigmatellin, a potent inhibitor of the mitochondrial cytochrome (cyt) bc(1) complex, possess a common structural feature: the chroman core. Therefore, we studied the interference of Tocs as well as synthetic model compounds (low molecular weight TQ analogues and tetramethyl chromanones) at the mitochondrial cyt bc(1) complex. Enzymatic experiments revealed that besides the inhibitor stigmatellin, among natural vitamin E-related derivatives, gamma-TQ/delta-TQ and, among synthetic compounds, TMC2O (6-hydroxy-4,4,7,8-tetramethyl-chroman-2-one) were most effective in decreasing the cyt bc(1) activities. Stopped-flow photometric and low-temperature electron paramagnetic resonance spectroscopic experiments showed for TMC2O an inhibition of electron transfer to cyt c(1) and a modulation of the environment of the Rieske iron-sulfur protein (ISP). Docking experiments suggest a binding interaction of the 6-OH group and 1-O atom/2-C( horizontal lineO) group of TMC2O with Glu-271 (cyt b) and His-161 (ISP) in the cyt bc(1) complex, respectively. This binding pose is similar but not identical to the potent inhibitor stigmatellin. The data suggest that chroman-2-ones are possible templates for modulatory molecules for the cyt bc(1) target.
Müllebner
Andrea
A
Molecular Pharmacology and Toxicology Unit, Department of Biomedical Sciences, University of Veterinary Medicine Vienna, Veterinarplatz 1, A-1210 Vienna, Austria.
Patel
Anjan
A
Stamberg
Werner
W
Staniek
Katrin
K
Rosenau
Thomas
T
Netscher
Thomas
T
Gille
Lars
L
D000818:Animals; D000975:Antioxidants / Q000737:chemistry* / Q000633:toxicity; D001665:Binding Sites; D002417:Cattle; D003198:Computer Simulation; D004578:Electron Spin Resonance Spectroscopy; D004579:Electron Transport / Q000187:drug effects; D014450:Electron Transport Complex III / Q000037:antagonists & inhibitors / Q000378:metabolism*; D024505:Tocopherols / Q000737:chemistry* / Q000633:toxicity; D014810:Vitamin E / Q000031:analogs & derivatives / Q000737:chemistry / Q000633:toxicity
D000975:Antioxidants; D014810:Vitamin E; C002421:tocopherylquinone; D014450:Electron Transport Complex III; D024505:Tocopherols